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Purpose: The objectives of this study were to determine the incidence of the MYB-NFIB fusion in salivary adenoid cystic carcinoma (ACC), to establish the clinicopathologic significance of the fusion, and to analyze the expression of MYB in ACCs in the context of the MYB-NFIB fusion.Experimental Design: We did an extensive analysis involving 123 cancers of the salivary gland, including primary and metastatic ACCs, and non-ACC salivary carcinomas. MYB-NFIB fusions were identified by reverse transcriptase-PCR (RT-PCR) and sequencing of the RT-PCR products, and confirmed by fluorescence in situ hybridization. MYB RNA expression was determined by quantitative RT-PCR and protein expression was analyzed by immunohistochemistry.Results: The MYB-NFIB fusion was detected in 28% primary and 35% metastatic ACCs, but not in any of the non-ACC salivary carcinomas analyzed. Different exons in both the MYB and NFIB genes were involved in the fusions, resulting in expression of multiple chimeric variants. Notably, MYB was overexpressed in the vast majority of the ACCs, although MYB expression was significantly higher in tumors carrying the MYB-NFIB fusion. The presence of the MYB-NFIB fusion was significantly associated (P = 0.03) with patients older than 50 years of age. No correlation with other clinicopathologic markers, factors, and survival was found.Conclusions: We conclude that the MYB-NFIB fusion characterizes a subset of ACCs and contributes to MYB overexpression. Additional mechanisms may be involved in MYB overexpression in ACCs lacking the MYB-NFIB fusion. These findings suggest that MYB may be a specific novel target for tumor intervention in patients with ACC. Clin Cancer Res; 16(19); 4722–31. ©2010 AACR.

Purpose: Aggressive cutaneous squamous cell carcinoma (cSCC) is often a disfiguring and lethal disease. Very little is currently known about the mutations that drive aggressive cSCC.Experimental Design: Whole-exome sequencing was performed on 39 cases of aggressive cSCC to identify driver genes and novel therapeutic targets. Significantly, mutated genes were identified with MutSig or complementary methods developed to specifically identify candidate tumor suppressors based upon their inactivating mutation bias.Results: Despite the very high-mutational background caused by UV exposure, 23 candidate drivers were identified, including the well-known cancer-associated genes TP53, CDKN2A, NOTCH1, AJUBA, HRAS, CASP8, FAT1, and KMT2C (MLL3). Three novel candidate tumor suppressors with putative links to cancer or differentiation, NOTCH2, PARD3, and RASA1, were also identified as possible drivers in cSCC. KMT2C mutations were associated with poor outcome and increased bone invasion.Conclusions: The mutational spectrum of cSCC is similar to that of head and neck squamous cell carcinoma and dominated by tumor-suppressor genes. These results improve the foundation for understanding this disease and should aid in identifying and treating aggressive cSCC. Clin Cancer Res; 20(24); 6582–92. ©2014 AACR.

Supplementary Figure S1. Global chromosomal rearrangements in ACCs. Supplementary Figure S2. Shared mutated genes in ACC with MYB-/MYBL1-NFIB fusions and Non-fusion. Supplementary Figure. S3. Characterization of MYBL1-NFIB fusion transcripts. Supplementary Figure S4. (A-E) Nucleotide and Amino acid of MYBL1-NFIB fusion genes. Supplementary Figure S5. Characterization of MYBL1-YTHDF3 fusion transcripts. Supplementary Figure S6. Characterization of MYBL1 truncations. Supplementary Figure S7. Analysis of NFIB fusions at the 5'end of the gene. Supplementary Figure S8. Kaplan-Meier survival curves of ACCs patients.

Supplemental Tables S1-S4 and S6-S13. Supplemental Table S1: Summary of Patient Characteristics. Supplemental Table S2: Patient Characteristics and Key Mutations. Supplemental Table S3: Tumor purity and ploidy calculations. Supplemental Table S4: Sequencing Coverages. Supplemental Table S6: Allele fraction analysis. Supplemental Table S7: MutSig analysis. Supplemental Table S8: IntOGen mutational significance analysis. Supplemental Table S9: Chi-square mutational significance analysis. Supplemental Table S10: Multinomial mutational significance analysis. Supplemental Table S11: Kappa analysis for gene-gene associations. Supplemental Table S12: ABSOLUTE copy number analysis segmentation data. Supplemental Table S13: Clinical and mutation associations.

Supplementary Figure S1. Distribution of RET981 cell line. Supplementary Figure S2. Detection of AR splice variants in SDCs. Supplementary Figure S3. Cleaved PARP increased by AR siRNAs.

Purpose: Salivary duct carcinoma overexpresses epidermal growth factor receptor (EGFR) and HER-2, although the underlying mechanisms remain undefined. Because of the potential utilization of these markers as treatment targets, we evaluated protein and gene status by several techniques to determine complementary value.Experimental Design: A tissue microarray of 66 salivary duct carcinomas was used for immunohistochemical analysis of HER-2 and EGFR expression (semiquantitatively evaluated into a three-tiered system), and fluorescence in situ hybridization for gene copy number, and chromosomes 7 and 17 ploidy status. Sequencing of exons 18, 19, and 21 of the EGFR gene for mutations was carried out.Result: For EGFR, 46 (69.7%) of the 66 tumors showed some form of EGFR expression (17 at 3+, 17 at 2+, 12 at 1+) but none gene amplification. Five (9.4%) of 53 tumors showed mutations in exon 18 (n = 3) and exon 19 (n = 2). Polysomy of chromosome 7 (average >2.5 copies/cell) was detected in 15 (25.0%) of 60 tumors (6 at 3+, 5 at 2+, 2 at 1+, 2 at 0+ expression) and correlated with poor 3-year survival (P = 0.015). For HER-2, 17 (25.8%) of 66 tumors expressed HER-2 (10 at 3+, 3 at 2+, 4 at 1+). Eight tumors showed HER-2 gene amplification (6 at 3+, 1 at 1+, 1 at 0+ protein expression). Chromosome 17 polysomy was found in 8 (15.7%) of 51 tumors; two had HER-2 expression (3+, 1+).Conclusion: Our study shows that salivary duct carcinomas (a) harbor EGFR gene mutations in a subset of tumors that may guide therapy, (b) pursue an aggressive clinical course in cases with chromosome 7 polysomy and high EGFR expression, and (c) with HER-2 gene amplification and protein high expression, may be selected for targeted therapy. Clin Cancer Res; 16(8); 2266–74. ©2010 AACR.

Purpose: To investigate the molecular events associated with the activation of androgen receptor (AR) as a potential therapeutic target in patients with salivary duct carcinoma (SDC).Experimental Design: Comprehensive molecular and expression analysis of the AR gene in 35 tumor specimens (20 males and 15 females) and cell lines derived from SDC using Western blotting and RT-PCR, FISH analysis, and DNA sequencing was conducted. In vitro and in vivo animal studies were also performed.Results: AR expression was detected in 70% of the tumors and was mainly nuclear and homogenous in both male and female SDCs, although variable cytoplasmic and/or nuclear localization was also found. We report the identification of ligand-independent AR splice variants, mutations, and extra AR gene copy in primary untreated SDC tumors. In contrast to prostate cancer, no AR gene amplification was observed. In vitro knockdown of AR in a female derived SDC cell line revealed marked growth inhibition in culture and in vivo androgen-independent tumor growth.Conclusions: Our study provides new detailed information on the molecular and structural alterations associated with AR gene activation in SDC and sheds more light on the putative functional role of AR in SDC cells. On the basis of these data, we propose that patients with SDC (male and female) can be stratified for hormone-based therapy in future clinical trials. Clin Cancer Res; 20(24); 6570–81. ©2014 AACR.

Supplementary Figure from Pilot Phase II Trial of Neoadjuvant Immunotherapy in Locoregionally Advanced, Resectable Cutaneous Squamous Cell Carcinoma of the Head and Neck

Supplementary Data from Genetic and Expression Analysis of HER-2 and EGFR Genes in Salivary Duct Carcinoma: Empirical and Therapeutic Significance

Purpose:In locoregionally advanced, resectable cutaneous squamous cell carcinoma of the head and neck (CSCC-HN), surgery followed by radiotherapy is standard but can be cosmetically and functionally devastating, and many patients will have recurrence.Patients and Methods:Newly diagnosed or recurrent stage III–IVA CSCC-HN patients amenable to curative-intent surgery received two cycles of neoadjuvant PD-1 inhibition. The primary endpoint was ORR per RECIST 1.1. Secondary endpoints included pathologic response [pathologic complete response (pCR) or major pathologic response (MPR; ≤10% viable tumor)], safety, DSS, DFS, and OS. Exploratory endpoints included immune biomarkers of response.Results:Of 20 patients enrolled, 7 had recurrent disease. While only 6 patients [30%; 95% confidence interval (CI), 11.9–54.3] had partial responses by RECIST, 15 patients (75%; 95% CI, 50.9–91.3) had a pCR (n = 11) or MPR (n = 4). No SAEs ocurred during or after the neoadjuvant treatment. At a median follow-up of 22.6 months (95% CI, 21.7–26.1), one patient progressed and died, one died without disease, and two developed recurrence. The 12-month DSS, DFS, and OS rates were 95% (95% CI, 85.9–100), 89.5% (95% CI, 76.7–100), and 95% (95% CI, 85.9–100), respectively. Gene expression studies revealed an inflamed tumor microenvironment in patients with pCR or MPR, and CyTOF analyses demonstrated a memory CD8+ T-cell cluster enriched in patients with pCR.Conclusions:Neoadjuvant immunotherapy in locoregionally advanced, resectable CSCC-HN is safe and induces a high pathologic response rate. Pathologic responses were associated with an inflamed tumor microenvironment.

Supplementary Table S1. PCR primer sequences in this study. Supplementary Table S2. AR IHC and FISH result Supplementary Table S3. AR mutation detail result in this study.

Purpose: To determine the disease control rate and toxicity of treating patients with aggressive cutaneous squamous cell carcinoma (CSCC) with neoadjuvant gefitinib.Experimental Design: A prospective phase II clinical trial evaluating neoadjuvant gefitinib given prior to standard treatment with surgery and/or radiotherapy. Patients with stable disease after one cycle received escalated doses. Patients who responded were given gefitinib during radiation therapy, as well as maintenance therapy after definitive treatment. We analyzed the correlation between epidermal growth factor receptor (EGFR) expression, mutation status, and gene copy number on available tissue samples and clinical response.Results: Twenty-three patients were accrued and 22 patients were evaluable for response prior to definitive local treatment; complete responses were attained by 18.2% of patients and partial responses by 27.3%. Grades 2 to 3 toxicities were observed in 59.1% of patients experiencing class-specific effects during induction therapy. After induction, 11.8% underwent surgery alone, 17.6% had definitive radiation, 11.8% were treated with radiation and concurrent gefitinib, and 47% had surgery with postoperative radiation and concurrent gefitinib. Median follow-up for the censored observations was 32 months. Two-year overall, disease-specific, and progression-free survival rates were 72.1%, 72.1%, and 63.6%, respectively. No EGFR-activating mutations were identified in tumor samples available from 10 patients. No associations between EGFR correlative studies and patient outcomes were identified.Conclusions: Gefitinib, in the neoadjuvant setting, was active and well tolerated in patients with aggressive CSCC and did not interfere with definitive treatment. In view of the 18% complete response rate we observed, EGFR tyrosine kinase inhibitors should be further explored in the treatment of aggressive CSCC. Clin Cancer Res; 18(5); 1435–46. ©2012 AACR.

Supplemental Figures S1-S2 and Methods. Figure S1: Mutation types and number by previous radiation treatment. Figure S2: Copy number alterations.

Supplementary Table from Pilot Phase II Trial of Neoadjuvant Immunotherapy in Locoregionally Advanced, Resectable Cutaneous Squamous Cell Carcinoma of the Head and Neck

Supplemental Table S5: mutation annotation file.

Objective: To investigate the molecular genetic heterogeneity associated with the t(6:9) in adenoid cystic carcinoma (ACC) and correlate the findings with patient clinical outcome.Experimental Design: Multimolecular and genetic techniques complemented with massive pair-ended sequencing and single-nucleotide polymorphism array analyses were used on tumor specimens from 30 new and 52 previously analyzed fusion transcript–negative ACCs by reverse transcriptase PCR (RT-PCR). MYB mRNA expression level was determined by quantitative RT-PCR. The results of 102 tumors (30 new and 72 previously reported cases) were correlated with the clinicopathologic factors and patients' survival.Results: The FISH analysis showed 34 of 82 (41.5%) fusion-positive tumors and molecular techniques identified fusion transcripts in 21 of the 82 (25.6%) tumors. Detailed FISH analysis of 11 out the 15 tumors with gene fusion without transcript formation showed translocation of NFIB sequences to proximal or distal sites of the MYB gene. Massive pair-end sequencing of a subset of tumors confirmed the proximal translocation to an NFIB sequence and led to the identification of a new fusion gene (NFIB–AIG1) in one of the tumors. Overall, MYB–NFIB gene fusion rate by FISH was in 52.9% whereas fusion transcript forming incidence was 38.2%. Significant statistical association between the 5′ MYB transcript expression and patient survival was found.Conclusions: We conclude that: (i) t(6;9) results in complex genetic and molecular alterations in ACC, (ii) MYB–NFIB gene fusion may not always be associated with chimeric transcript formation, (iii) noncanonical MYB–NFIB gene fusions occur in a subset of tumors, (iv) high MYB expression correlates with worse patient survival. Clin Cancer Res; 17(22); 7003–14. ©2011 AACR.

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Purpose: Radiotherapy plays an integral role in the treatment of head and neck squamous cell carcinoma (HNSCC). Although proteins involved in DNA repair may predict HNSCC response to radiotherapy, none has been validated in this context. We examined whether differential expression of double-strand DNA break (DSB) repair proteins in HNSCC, the chief mediators of DNA repair following irradiation, predict for treatment outcomes.Experimental Design: Archival HNSCC tumor specimens (n = 89) were assembled onto a tissue microarray and stained with antibodies raised against 38 biomarkers. The biomarker set was enriched for proteins involved in DSB repair, in addition to established mechanistic markers of radioresistance. Staining was correlated with treatment response and survival alongside established clinical and pathologic covariates. Results were validated in an independent intramural cohort (n = 34).Results: Ku80, a key mediator of DSB repair, correlated most closely with clinical outcomes. Ku80 was overexpressed in half of all tumors, and its expression was independent of all other covariates examined. Ku80 overexpression was an independent predictor for both locoregional failure and mortality following radiotherapy (P < 0.01). The predictive power of Ku80 overexpression was confined largely to HPV-negative HNSCC, where it conferred a nine-fold greater risk of death at two years.Conclusions: Ku80 overexpression is a common feature of HNSCC, and is a candidate DNA repair-related biomarker for radiation treatment failure and death, particularly in patients with high-risk HPV-negative disease. It is a promising, mechanistically rational biomarker to select individual HPV-negative HNSCC patients for strategies to intensify treatment. Clin Cancer Res; 17(7); 2035–43. ©2011 AACR.

Supplementary Table S1. Sample description of Adenoid cystic carcinoma in this study. Supplementary Table S2. Somatic mutations identified in 21 Adenoid cystic carcinomas by WGS. Supplementary Table S3. Identification of fusion genes by whole genome sequencing in ACCs. Supplementary Table S4. PCR Primer information. Supplementary Table S5. MYB or MYBL1 fusion information in expression array set. Supplementary Table S6. Gene set enrichment analysis (GSEA) of MYB/MYBL1-NFIB fusions in ACC. Supplementary Table S7. Clinicopathologic and MYB/MYBL1 alterations in salivary adenoid cystic carcinoma.

Supplementary Figures S1-S3; Supplementary Tables S1-S4.

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Purpose: Adenoid cystic carcinoma (ACC) is an indolent salivary gland malignancy, characterized by t(6;9) translocations and MYB–NFIB gene fusions in approximately 50% of the tumors. The genetic alterations underlying t(6;9)-negative and t(6;9)-positive/MYB–NFIB fusion–negative ACC remain unknown. To uncover the genetic alterations in ACC lacking the canonical translocation and fusion transcript and identify new abnormalities in translocation positive tumors.Experimental Design: We performed whole-genome sequencing in 21 salivary ACCs and conducted targeted molecular analyses in a validation set (81 patients). Microarray gene-expression data were also analyzed to explore the biologic differences between fusion positive and negative tumors.Results: We identified a novel MYBL1–NFIB gene fusion as a result of t(8;9) translocation and multiple rearrangements in the MYBL1 gene in 35% of the t(6;9)-negative ACCs. All MYBL1 alterations involved deletion of the C-terminal negative regulatory domain and were associated with high MYBL1 expression. Reciprocal MYB and MYBL1 expression was consistently found in ACCs. In addition, 5′-NFIB fusions that did not involve MYB/MYBL1 genes were identified in a subset of t(6;9)-positive/fusion-negative tumors. We also delineated distinct gene-expression profiles in ACCs associated with the length of the MYB or MYBL1 fusions, suggesting a biologic importance of the C-terminal part of these fusions.Conclusions: Our study defines new molecular subclasses of ACC characterized by MYBL1 rearrangements and 5′-NFIB gene fusions. Clin Cancer Res; 22(3); 725–33. ©2015 AACR.

OBJECTIVES: To analyze charges, complications, survival, and functional outcomes for definitive surgery of mandibular osteoradionecrosis (ORN). MATERIALS AND METHODS: Retrospective analysis of 76 patients who underwent segmental mandibulectomy with reconstruction from 2000 to 2009. RESULTS: Complications occurred in 49 (65%) patients and were associated with preoperative drainage (odds ratio [OR] 4.40, 95% confidence interval [CI] 1.01–19.27). The adjusted median charge was $343 000, and higher charges were associated with double flap reconstruction (OR 8.15, 95% CI 2.19–30.29) and smoking (OR 5.91, 95% CI 1.69–20.72). Improved swallow was associated with age

The NCCN Guidelines for Head and Neck Cancers address tumors arising in the oral cavity (including mucosal lip), pharynx, larynx, and paranasal sinuses. Occult primary cancer, salivary gland cancer, and mucosal melanoma (MM) are also addressed. The specific site of disease, stage, and pathologic findings guide treatment (eg, the appropriate surgical procedure, radiation targets, dose and fractionation of radiation, indications for systemic therapy). The NCCN Head and Neck Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel’s most recent recommendations regarding management of HPV-positive oropharynx cancer and ongoing research in this area.

PURPOSE: The combination of cisplatin and radiation or cetuximab and radiation improves overall survival of patients with locoregionally advanced head and neck carcinoma. NRG Oncology conducted a phase 3 trial to test the hypothesis that adding cetuximab to radiation and cisplatin would improve progression-free survival (PFS). METHODS AND MATERIALS: Eligible patients with American Joint Committee on Cancer sixth edition stage T2 N2a-3 M0 or T3–4 N0–3 M0 were accrued from November 2005 to March 2009 and randomized to receive radiation and cisplatin without (arm A) or with (arm B) cetuximab. Outcomes were correlated with patient and tumor features. Late reactions were scored using Common Terminology Criteria for Adverse Events (version 3). RESULTS: Of 891 analyzed patients, 452 with a median follow-up of 10.1 years were alive at analysis. The addition of cetuximab did not improve PFS (hazard ratio [HR], 1.06; 95% confidence interval [CI], 0.89–1.26; P = .74), with 10-year estimates of 43.6% (95% CI, 38.8–48.4) for arm A and 40.2% (95% CI, 35.4–45.0) for arm B. Cetuximab did not reduce locoregional failure (HR, 1.21; 95% CI, 0.95–1.53; P = .94) or distant metastasis (HR, 0.79; 95% CI, 0.54–1.14; P = .10) or improve overall survival (HR, 0.97; 95% CI, 0.80–1.16; P = .36). Cetuximab did not appear to improve PFS in either p16-positive oropharynx (HR, 1.30; 95% CI, 0.87–1.93) or p16-negative oropharynx or nonoropharyngeal primary (HR, 0.94; 95% CI, 0.73–1.21). Grade 3 to 4 late toxicity rates were 57.4% in arm A and 61.3% in arm B (P = .26). CONCLUSIONS: With a median follow-up of more than 10 years, this updated report confirms the addition of cetuximab to radiation therapy and cisplatin did not improve any measured outcome in the entire cohort or when stratifying by p16 status.

Patients with head and neck cancer experience a broad array of negative quality-of-life issues, but particularly common are dental complications following radiation therapy, and compromised nutrition with significant weight loss. At the NCCN 2021 Virtual Annual Conference, a panel of experts used a case-based approach to discuss some of these common adverse effects of head and neck cancer and its treatment, as well as optimal supportive care strategies to manage them.

Background Neoadjuvant chemotherapy (NAC) is used in head and neck squamous cell carcinoma (HNSCC) for downstaging advanced disease and decreasing distant metastasis (DM). To the authors' knowledge, no study has specifically examined the impact of a delayed time to surgery (TTS) after NAC on oncologic outcomes. They thus aimed to identify a cutoff for TTS after NAC and its effect on survival indices. Methods This was a retrospective review of all patients with HNSCC receiving NAC followed by surgery with curative intent between March 2016 and March 2019 at the MD Anderson Cancer Center. Receiver operating characteristic analysis was used to identify a cutoff for TTS, and this cutoff was used to analyze the overall survival (OS), locoregional recurrence rate, DM-free rate, and disease-free survival (DFS). A multivariate Cox regression analysis was performed. Results One hundred one patients were analyzed with a median follow-up of 24.7 months. The 3-year OS and locoregional recurrence rates did not differ with a TTS ≥ 34 days. However, the 3-year DM-free rate was significantly worse (56% vs 90%; P = .001) in the group with a TTS ≥ 34 days, and the 3-year DFS was significantly lower (26% vs 64%; P = .006). In a multivariate analysis, a TTS ≥ 34 days (hazard ratio [HR], 4.92; 95% confidence interval [CI], 1.84-13.13) and extracapsular extension (HR, 3.01; 95% CI, 1.13-8.00) were significant independent predictors of a poorer DM-free rate. Weight loss > 10% (HR, 5.53; 95% CI, 1.02-30.24) was the only independent predictor for a TTS ≥ 34 days. Conclusions Emphasis should be placed on early definitive locoregional treatment after NAC, particularly in patients who do not respond to NAC. There is a need to validate these findings and establish new benchmarks for the interval between NAC and surgery.

Background The last revision of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual included a specific system for cutaneous squamous cell carcinoma (CSCC) of the head and neck. Here, we assessed the prognostic performance of six candidate modified T-classification models in head and neck CSCC patients. Methods Analysis of 916 patients with head and neck CSCC given treatment with curative intent at The University of Texas MD Anderson Cancer Center between 1995 and 2019 was performed. The main outcome was disease-specific survival (DSS), and the impact of depth of invasion (DOI) was analyzed using multivariable regression models. Candidate models were developed using the optimal DOI cut points for each AJCC T classification based on goodness of fit of the model and the simplicity of the model. Staging systems were compared using Harrell's concordance index. Results Median age was 70 years (range, 19–97years) and median follow-up time of 22 months (range, 1–250months). The median DOI was 6.0 mm (range, 0.1–70.0 mm). The five-year DSS rate was 80.7% (95%CI, 77.4–83.7%). We found significant association between DOI (hazard ratio, 1.21 [95%CI: 1.01–1.43]) and DSS on multivariable analysis. Based on a low Akaike information criterion score, improvement in the concordance index, and Kaplan–Meier curves, model 6 surpassed the AJCC staging system. Conclusions Incorporation of DOI in the current AJCC staging system improves discrimination of T classifications in head and neck CSCC patients. Lay summary The current staging system for head and neck cutaneous squamous cell carcinoma demonstrates wide prognostic variability and provides suboptimal risk stratification. Incorporation of depth of invasion in the T-classification system improves risk prediction and patient counseling. Precis We propose improved head and neck cutaneous squamous cell carcinoma T staging that will include depth of invasion and should be considered in future versions of the American Joint Committee on Cancer after external validation.

Background The prognostic performance of the recently updated American Joint Committee on Cancer lymph node classification of cutaneous head and neck squamous cell carcinoma (HNSCC) has not been validated. The objective of this study was to assess the prognostic role of extranodal extension (ENE) in cutaneous HNSCC. Methods This was a retrospective analysis of 1258 patients with cutaneous HNSCC who underwent surgery with or without adjuvant therapy between 1995 and 2019 at The University of Texas MD Anderson Cancer Center. The primary outcome was disease-specific survival (DSS). Local, regional, and distant metastases-free survival were secondary outcomes. Recursive partitioning analysis (RPA) and a Cox proportional hazards regression model were used to assess the fitness of staging models. Results No significant differences in 5-year DSS were observed between patients with pathologic lymph node-negative (pN0) disease (67.4%) and those with pN-positive/ENE-negative disease (68.2%; hazard ratio, 1.02; 95% CI, 0.61-1.79) or between patients with pN-positive/ENE-negative disease and those with pN-positive/ENE-positive disease (52.7%; hazard ratio, 0.57; 95% CI, 0.31-1.01). The RPA-derived model achieved better stratification between high-risk patients (category III, ENE-positive with >2 positive lymph nodes) and low-risk patients (category I, pN0; category II, ENE-positive/pN1 and ENE-negative with >2 positive lymph nodes). The performance of the RPA-derived model was better than that of the pathologic TNM classification (Akaike information criterion score, 1167 compared with 1176; Bayesian information criterion score, 1175 compared with 1195). Conclusions The number of metastatic lymph nodes and the presence of ENE are independent prognostic factors for DSS in cutaneous HNSCC, and incorporation of these factors in staging systems improves the performance of the American Joint Committee on Cancer lymph node classification.

Historically USPIO has been used to help with nodal staging but not in primary tumors. The ability to concentrate USPIO may help to differentiate BMT from other types of parotid tumors.

Enhanced recovery after surgery (ERAS) pathways are well established in certain surgical specialties because findings have shown significant improvements in outcomes. Convincing literature in head and neck cancer (HNC) surgery is lacking. This study aimed to assess the effect of an ERAS pathway on National Surgical Quality Improvement Program (NSQIP)-based occurrences and pain-related outcomes in HNC surgery. The study matched 200 patients undergoing head and neck oncologic surgery on an ERAS pathway between 1 March 2016 and 31 March 2019 with control subjects (1:1 ratio) during the same period. Demographic and perioperative data collected from the NSQIP database were extracted. Pain scores and medication usage were electronically extracted from our electronic medical record system and compared. Risk factors for high opioid usage also were assessed. Both groups were statistically similar in baseline characteristics. The ERAS group had fewer planned intensive care unit (ICU) admissions (4% vs. 14%; p

Background Postoperative complications are an independent predictor of poor survival across several tumors. However, there is limited literature on the association between postoperative morbidity and long-term survival following total laryngectomy (TL) for cancer. Methods We conducted a retrospective review of all TL patients at a single institution from 2008 to 2013. Demographic and clinical data were collected and analyzed, including postsurgical outcomes, which were classified using the Clavien-Dindo system. Multivariable Cox regression analyses were performed to identify factors associated with overall survival (OS) and disease-free survival (DFS). Results A total of 362 patients were identified. The mean age was 64 years, and the majority of patients were male (81%). The median follow-up interval was 21 months. Fifty-seven percent of patients had received preoperative radiation, and 40% had received preoperative chemotherapy. Fifty-seven percent of patients underwent salvage TL, and 60% underwent advanced reconstruction (45% free flap and 15% pedicled flap). A total of 136 patients (37.6%) developed postoperative complications, 92 (25.4%) of which were major. Multivariable modeling demonstrated that postoperative complications independently predicted shorter OS (hazard ratio [HR], 1.50; 95% CI, 1.16-1.96; P = .002) and DFS (HR, 1.36; 95% CI, 1.05-1.76; P = .021). Other independent negative predictors of OS and DFS included positive lymph node status, preoperative chemotherapy, comorbidity grade, and delayed adjuvant therapy. Severity of complication and reason for TL (salvage vs primary) were not shown to be predictive of OS or DFS. Conclusion Postoperative complications are associated with worse long-term OS and DFS relative to uncomplicated cases. Patient optimization and timely management of postoperative complications may play a critical role in long-term survival.

Author(s): MD Anderson Head and Neck Surgery Treatment Guidelines Consortium; Consortium members; Maniakas, Anastasios; Jozaghi, Yelda; Zafereo, Mark E; Sturgis, Erich M; Su, Shirley Y; Gillenwater, Ann M; Gidley, Paul W; Lewis, Carol M; Diaz, Eduardo; Goepfert, Ryan P; Kupferman, Michael E; Gross, Neil D; Hessel, Amy C; Pytynia, Kristen B; Nader, Marc-Elie; Wang, Jennifer R; Lango, Miriam N; Kiong, Kimberley L; Guo, Theresa; Zhao, Xiao; Yao, Christopher MKL; Appelbaum, Eric; Alpard, Jennifer; Garcia, Jose A; Terry, Shawn; Flynn, Jill E; Bauer, Sarah; Fournier, Danielle; Burgess, Courtlyn G; Wideman, Cayla; Johnston, Matthew; You, Chenxi; De Luna, Rolando; Joseph, Liza; Diersing, Julia; Prescott, Kaitlin; Heiberger, Katherine; Mugartegui, Lilian; Rodriguez, Jessica; Zendehdel, Sara; Sellers, Justin; Friddell, Rebekah A; Thomas, Ajay; Khanjae, Sonam J; Schwarzlose, Katherine B; Chambers, Mark S; Hofstede, Theresa M; Cardoso, Richard C; Wesson, Ruth Aponte; Won, Alex; Otun, Adegbenga O; Gombos, Dan S; Al-Zubidi, Nagham; Hutcheson, Katherine A; Gunn, G Brandon; Rosenthal, David I; Gillison, Maura L; Ferrarotto, Renata; Weber, Randal S; Hanna, Ehab Y; Myers, Jeffrey N; Lai, Stephen Y | Abstract: BackgroundCOVID-19 pandemic has strained human and material resources around the world. Practices in surgical oncology had to change in response to these resource limitations, triaging based on acuity, expected oncologic outcomes, availability of supportive resources, and safety of health care personnel.MethodsThe MD Anderson Head and Neck Surgery Treatment Guidelines Consortium devised the following to provide guidance on triaging head and neck cancer (HNC) surgeries based on multidisciplinary consensus. HNC subsites considered included aerodigestive tract mucosa, sinonasal, salivary, endocrine, cutaneous, and ocular.RecommendationsEach subsite is presented separately with disease-specific recommendations. Options for alternative treatment modalities are provided if surgical treatment needs to be deferred.ConclusionThese guidelines are intended to help clinicians caring for patients with HNC appropriately allocate resources during a health care crisis, such as the COVID-19 pandemic. We continue to advocate for individual consideration of cases in a multidisciplinary fashion based on individual patient circumstances and resource availability.

The COVID‐19 pandemic has had a dramatic impact on care delivery among health care institutions and providers in the United States. As a categorical cancer center, MD Anderson has prioritized care for our patients based on acuity of their disease. We continue to implement measures to protect patients and employees from acquiring the infection within our facilities, and to provide acute management of cancer patients with concomitant COVID‐19 infections who are considered at high risk of death. The Division of Patient Experience, formerly established in October 2016, has played an integral role in the institution's pandemic response from its inception. The team actively supported programs and processes in anticipation of the pandemic's effect on our patients and employees. We will describe how the team continues to serve in the ever‐dynamic environment as we approach the expected surge in COVID‐19 cases among our patient population, our employees, and in our community.

Map regional lymph node metastases for lateralized oral cavity squamous cell carcinoma (OCSCC) and evaluate factors associated with regional metastases and recurrence.Retrospective cohort study of 715 patients with lateralized OCSCC surgically treated in 1997-2011. Analysis was performed using log-rank, Kaplan-Meier, and multivariable logistic and Cox regression.Regional metastases were identified in ipsilateral levels IIA (24%), IB (18%), III (13%), V (9%), IV (7%), IA (2%) and IIB (1%) and the contralateral neck (3%). Lymphovascular invasion (LVI) (Hazard Ratio [HR] 2.2, 95% Confidence Interval [CI] 1.2-3.9) and T category (T3 vs. T1: HR 4.1, 95% CI 1.9-9.3; T4 vs. T1: HR 2.3, 95% CI 1.2-4.3) were associated with regional metastases. Most (71%) isolated regional metastatic recurrences were in undissected levels of the neck, including 58% in levels IV and V. Tumors of the hard palate (HR 4.3, 95% CI 1.2-16.1), upper alveolus (HR 3.2, 95% CI 1.0-4.7) or with LVI (HR 2.0, 95% CI 1.0-3.9) were associated with isolated regional recurrence. For upper alveolar/hard palate tumors, depth of invasion (DOI) ≥4 mm (P = .003) and LVI (P = .04) were associated with regional metastases.For lateralized OCSCC, elective neck dissection of level IIB or the contralateral neck may rarely be needed, but additional surgical or radiation treatment of levels IV and V may be considered based on patient risk factors, including T category 3-4 or LVI. For upper alveolar/hard palate tumors, DOI ≥4 mm is an appropriate threshold for elective neck dissection.

We sought to determine overall survival (OS), prognostic factors, cost, and functional outcomes after surgery for locally recurrent oral cavity squamous cell carcinoma (OCSCC).We retrospectively reviewed 399 cases of locally recurrent OCSCC from 1997 to 2011, of which 259 patients were treated with salvage surgery. Survival and prognostic factors were evaluated using univariable and multivariable Cox regression, the Kaplan-Meier method, and the log-rank test.The 5-year OS for patients undergoing surgical salvage, nonsurgical therapy, or supportive care was 44.2%, 1.5%, and 0%, respectively. For patients who underwent surgical salvage, 133 (51%) patients experienced a second recurrence at a median of 17 months. Factors associated with OS included disease-free interval ≤ 6 months (P =.0001), recurrent stage III-IV disease (P lt;.0001), and prior radiation (P =.0001). Patients with both advanced stage and prior radiation had a 23% 5-year OS, compared with 70% for those with neither risk (P lt;.001). Functionally, 85% of patients had gt; 80% speech intelligibility and 81% were able to eat by mouth following salvage surgery. Of the patients who required tracheostomy, 78% were decannulated. The adjusted median hospital and professional charges for patients were $129,696 (range $9,238-$956,818).Patients with recurrent OCSCC who underwent salvage surgery have favorable functional outcomes with half of alive at 5 years but poorer OS for advanced disease, disease-free interval ≤ 6 months, and prior radiation. Additionally, treatment is associated with high cost, and about half of patients ultimately develop another recurrence.

Purpose: In locoregionally advanced, resectable cutaneous squamous cell carcinoma of the head and neck (CSCC-HN), surgery followed by radiotherapy is standard but can be cosmetically and functionally devastating, and many patients will have recurrence. Patients and Methods: Newly diagnosed or recurrent stage III–IVA CSCC-HN patients amenable to curative-intent surgery received two cycles of neoadjuvant PD-1 inhibition. The primary endpoint was ORR per RECIST 1.1. Secondary endpoints included pathologic response [pathologic complete response (pCR) or major pathologic response (MPR; ≤10% viable tumor)], safety, DSS, DFS, and OS. Exploratory endpoints included immune biomarkers of response. Results: Of 20 patients enrolled, 7 had recurrent disease. While only 6 patients [30%; 95% confidence interval (CI), 11.9–54.3] had partial responses by RECIST, 15 patients (75%; 95% CI, 50.9–91.3) had a pCR (n = 11) or MPR (n = 4). No SAEs ocurred during or after the neoadjuvant treatment. At a median follow-up of 22.6 months (95% CI, 21.7–26.1), one patient progressed and died, one died without disease, and two developed recurrence. The 12-month DSS, DFS, and OS rates were 95% (95% CI, 85.9–100), 89.5% (95% CI, 76.7–100), and 95% (95% CI, 85.9–100), respectively. Gene expression studies revealed an inflamed tumor microenvironment in patients with pCR or MPR, and CyTOF analyses demonstrated a memory CD8+ T-cell cluster enriched in patients with pCR. Conclusions: Neoadjuvant immunotherapy in locoregionally advanced, resectable CSCC-HN is safe and induces a high pathologic response rate. Pathologic responses were associated with an inflamed tumor microenvironment.

Background Surveillance in head and neck cancer (HNC) is essential to detect recurrent or new lesions and to optimize function. This study describes drivers of surveillance adherence in patients with HNC and its effect on prognosis. Methods Adherence with surveillance of HNC patients was determined using the National Comprehensive Cancer Network HNC guidelines. Logistic regression and Cox proportional hazards models were used to determine predictors of adherence and overall survival (OS). Results Results showed that 110 of 221 patients (50.2%) were adherent with surveillance. Distance from the treatment center was the only significant association. Adherence was not associated with OS following multivariate adjustment (adjusted hazard ratio [aHR] = 0.68, 95% confidence interval [CI] = 0.43-1.09). However, 5-10 years after treatment completion, adherence was an independent predictor of survival (aHR = 0.24, 95% CI = 0.09-0.61). Conclusion Adherence with surveillance is important in improving survival in patients with HNC, especially in the long term.

Spiradenoma and cylindroma are related sweat gland tumors. To delineate their histogenesis, gene profiles, and their potential drivers, we performed a whole-transcriptome sequencing analysis of fourteen samples of spiradenoma/cylindroma in comparison to normal samples. A total of 12 spiradenomas, 5 cylindromas, 3 hybrid spiradenomas/cylindromas and 2 adnexal carcinomas were included in this study. 1335 characteristic genes and transcripts expressed over all 14 spiradenoma/cylindroma tumors were identified, and two groups of expression profiles were observed. Highest upregulated top 7 gene signatures characterized benign tumors with developmental and differentiation related genes, and carcinomas with top 7 genes mainly related to signaling, reorganization and metabolism of membranes. Immunohistochemistry of protein expressions validated 4 upregulated genes (ODAM, HOXB13, MYB and SOX10) considered important and as potential biomarkers for spiradenomas and cylindromas. We further compared the transcriptome of eccrine adnexal tumors with the transcriptome of adenoid cystic carcinoma (ACC) to identify the overlapping genes that may indicate histogenesis. There were 36 specific genes overlapping between adnexal carcinomas and the epithelial-dominant subtype of ACC, and 27 specific genes overlapping benign adnexal tumors with the myoepithelial-dominant subtype of ACC, At this point there is no known specific biomarker to aid in the diagnosis of eccrine spiradenoma and cylindroma in small samples or biopsies within the context of morphological overlap with ACC. In conclusion, spiradenomas and cylindromas are characterized by overexpressed developmental genes, where LHX2 and activated WNT signaling possibly drive associated carcinomas.

Background The optimal treatment for regional lymphatic recurrences from head and neck cancer has not been fully established. In order to explore the therapeutic benefit of surgical resection and adjuvant brachytherapy, the authors reviewed their experience utilizing interstitial brachytherapy (IBT) at the M. D. Anderson Cancer Center. Methods A retrospective chart review of the 51 patients who received salvage surgical resection of lymphatic recurrences and adjuvant IBT between 1993 and 2012 at the M. D. Anderson Cancer Center was undertaken. All patients underwent neck dissection with complete resection and intraoperative placement of afterloading brachytherapy catheters. Soft tissue reconstruction was performed as necessary. The technical aspects of IBT were reviewed, and the overall and disease free survival rates and the recurrence rates were determined. Results All patients had received external beam radiation (EBRT) as part of their initial treatment to a median dose of 66 Gy; 40 and 68% of the patients also had a neck dissection or chemotherapy, respectively. The cumulative regional recurrence probability is 28 and 38% at 5 years and 10 years. All of the patients underwent salvage neck dissection and IBT, with 81% also undergoing soft tissue reconstruction. The median dose delivered to the tumor bed was 60 Gy over a median duration of 4.5 days. There were 21 early adverse events, 8 of which were severe, and 19 late adverse events, 6 of which were severe. The most common early and late adverse events due to surgery and brachytherapy were dysphagia (7.1%) and true vocal cord paralysis (17.9%), respectively. There were no perioperative deaths or carotid hemorrhages. Nineteen patients developed recurrence including regional recurrence and distinct metastasis. The median time to recurrence is 130 months using Kaplan-Meier product limit method. The 2-year disease-free survival rate was 58%. The 2-year, 5-year, and 10-year overall survival rates were 69, 56, and 46%, respectively. Conclusions Regional recurrences in previously irradiated tissues after the definitive treatment of primary head and neck cancers represent a challenging problem. We demonstrated that salvage neck dissection with IBT provided encouraging regional control and survival rates, while maintaining relatively low acute and long-term toxicity rates.

Background The current study was performed to assess the efficacy of surveillance imaging in patients with head and neck cancer (HNC) who are treated definitively with radiotherapy. Methods Eligible patients included those with a demonstrable disease-free interval (≥1 follow-up imaging procedure without evidence of disease and a subsequent visit/imaging procedure) who underwent treatment of HNC from 2000 through 2010. Results A total of 1508 patients were included. The median overall survival was 99 months, with a median imaging follow-up period of 59 months. Of the 1508 patients, 190 patients (12.6%) experienced disease recurrence (107 patients had locoregional and 83 had distant disease recurrence). A total of 119 patients (62.6%) in the group with disease recurrence were symptomatic and/or had an adverse clinical finding associated with the recurrence. Approximately 80% of patients with locoregional disease recurrences presented with a clinical finding, whereas 60% of distant disease recurrences were detected by imaging in asymptomatic patients. Despite the earlier detection of disease recurrence via imaging, those patients in the group of patients with clinically detected disease recurrence were significantly more likely to undergo salvage therapy compared with those whose recurrence was detected on imaging (odds ratio, 0.35). There was no difference in overall survival noted between those patients with disease recurrences that were detected clinically or with imaging alone. Approximately 70% of disease recurrences occurred within the first 2 years. In those patients who developed disease recurrence after 2 years, the median time to recurrence was 51 months. After 2 years, the average number of imaging procedures per patient for the detection of a salvageable recurrence for the imaging-detected group was 1539. Conclusions Surveillance imaging in asymptomatic patients with HNC who are treated definitively with radiotherapy without clinically suspicious findings beyond 2 years has a low yield and a high cost. Physicians ordering these studies must use judicious consideration and discretion.

Enhanced Recovery After Surgery (ERAS) pathways in head and neck cancer (HNC) have shown to improve perioperative outcomes and reduce complications. The longer term implications on adjuvant treatment and survival have not been studied. We hereby report the first study on the impact of an ERAS pathway on return to intended oncologic treatment (RIOT) and overall survival (OS) in HNC.200 patients undergoing head and neck oncologic surgery on an ERAS pathway between March 1, 2016 and March 31, 2019 were matched to controls over the same interval. Demographic, tumor and adjuvant therapy-related data were collected, including time to adjuvant therapy(TAT) and treatment package time(TPT). Risk factors for TAT 42 days and TPT ≥ 85 days were assessed. OS was compared and risk factors for inferior OS determined.Baseline characteristics including co-morbidities and tumor stage were similar. Of 179 patients planned for adjuvant treatment, there was no difference in RIOT rate (89.0% vs 87.5%, p = 0.753), proportion of TAT 42 days of surgery (55.6% vs 59.7%, p = 0.642), or TPT ≥ 85 days (48.1% vs 57.1, p = 0.258), for the ERAS and control groups, respectively. On multivariate analysis, alcohol use (OR 3.58; 95 %CI 1.11-11.52) and recurrent disease status (OR 2.88; 95 %CI 1.40-5.93) were independently associated with prolonged TAT. Three-year OS was similar between the ERAS and control groups (73% vs 76%, p = 0.521).ERAS has not shown to improve RIOT or OS in the current study. However, its benefit for perioperative outcomes is undeniable and further studies are required on longer term quality and survival outcomes.

9519 Background: In a pilot phase II trial, we investigated the use of neoadjuvant immunotherapy to induce a pathologic response in patients with stage III/IV (M0) cutaneous squamous cell carcinoma of the head and neck (CSCC-HN). Here, we report the long-term outcomes according to pathologic response. Methods: Patients with newly diagnosed or recurrent stage III/IV (M0) (AJCC 8th Ed) CSCC-HN were treated with 2 doses of cemiplimab 350 mg intravenously every 3 weeks prior to surgery. The primary endpoint was overall response rate (ORR) per RECIST v1.1. Secondary endpoints included safety, pathologic response, disease-free and overall survival. Results: Of 20 patients enrolled, 7 (35%) had recurrent disease and 12 (60%) were stage IV on presentation. Neoadjuvant immunotherapy was generally well-tolerated and there were no surgical delays. Adverse events (AEs) were observed in 7 (35%) patients; 1 (5%) grade 3 diarrhea, 6 (30%) ≤ grade 2 AEs. ORR by RECIST was 30%. However, 85% (17/20) achieved a pathologic response (≤50% viable tumor), with pathologic complete response (pCR) in 11 (55%), major pathologic response (MPR, ≤10% viable tumor) in 4 (20%) and pathologic partial response (pPR, >10% and ≤50% viable tumor) in 2 (10%). Patients with a pCR did not receive planned radiotherapy after surgery. Patients who did not have a pathologic response (> 50% viable tumor) either progressed and died (1, 5%) or developed recurrence (2, 10%) despite surgery and adjuvant radiation or chemoradiation. At a median follow up of 34.5 months (range: 7.7-42.7), none of the patients who achieved a pathologic response have recurred. Conclusions: Consistent with other cancer types, pathologic response to neoadjuvant immunotherapy is durable in patients with advanced, resectable CSCC-HN. Adjuvant radiation therapy may be spared in patients who achieve a pCR and warrants further investigation. Clinical trial information: NCT03565783.

Background The 8th edition of the American Joint Committee on Cancer's (AJCC) staging system for oral cavity cancer incorporates pathological features. We aimed to assess whether these changes results in better risk stratification of patients with early oral tongue squamous cell carcinoma (OTSCC). Methods Overall survival (OS) and disease-specific survival (DSS) of 244 patients were calculated using the Kaplan-Meier method. Multivariate analysis with stepwise selection was performed using Cox proportional hazards regression. Results Sixty-two patients (25%) were upstaged using the 8th edition. Multivariate analysis revealed that overall stage using the 8th edition of the AJCC staging system but not using the 7th edition was a significant predictor for both OS and DSS. The 8th edition had lower Akaike information criterion and improved concordance index values compared with the 7th edition. Conclusion The 8th edition of AJCC allows better risk stratification and more precise counseling of patients with OTSCC who were previously considered at low risk.