Patterns of recurrence in head and neck squamous cell carcinoma to inform personalized surveillance protocols.

BACKGROUND: Development of evidence-based post-treatment surveillance guidelines in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) is limited by comprehensive documentation of patterns of recurrence and metastatic spread. METHODS: A retrospective analysis of patients diagnosed with R/M HNSCC at a National Cancer Institute-designated cancer center between 1998- 2019 was performed (n = 447). Univariate and multivariate analysis identified patterns of recurrence and predictors of survival. RESULTS: Median overall survival (mOS) improved over time (6.7 months in 1998-2007 to 11.8 months in 2008-2019, p = .006). Predictors of worse mOS included human papillomavirus (HPV) negativity (hazard ratio [HR], 1.8; 95% confidence interval [CI], 1.2-2.6), high neutrophil/lymphocyte ratio (HR, 2.1 [1.4-3.0], disease-free interval (DFI) ≤6 months (HR, 1.4 [1.02-2.0]), and poor performance status (Eastern Cooperative Oncology Group, ≥2; HR, 1.91.1-3.4). In this cohort, 50.6% of recurrences occurred within 6 months of treatment completion, 72.5% occurred within 1 year, and 88.6% occurred within 2 years. Metachronous distant metastases were more likely to occur in patients with HPV-positive disease (odds ratio [OR], 2.3 [1.4-4.0]), DFI >6 months (OR, 2.4 [1.5-4.0]), and body mass index ≥30 (OR, 2.3 [1.1-4.8]). Oligometastatic disease treated with local ablative therapy was associated with improved survival over polymetastatic disease (HR, 0.36; 95% CI, 0.24-0.55). CONCLUSION: These data regarding patterns of distant metastasis in HNSCC support the clinical utility of early detection of recurrence. Patterns of recurrence in this population can be used to inform individualized surveillance programs as well as to risk-stratify eligible patients for clinical trials. PLAIN LANGUAGE SUMMARY: After treatment for head and neck cancer (HNC), patients are at risk of recurrence at prior sites of disease or at distant sites in the body. This study includes a large group of patients with recurrent or metastatic HNC and examines factors associated with survival outcomes and recurrence patterns. Patients with human papillomavirus (HPV)-positive HNC have good survival outcomes, but if they recur, this may be in distant regions of the body and may occur later than HPV-negative patients. These data argue for personalized follow-up schedules for patients with HNC, perhaps incorporating imaging studies or novel blood tests.

Deadly Fungi: Invasive Fungal Rhinosinusitis in the Head and Neck.

Invasive fungal rhinosinusitis (IFRS) is a serious infection that is associated with high morbidity and mortality rates. The incidence of IFRS has been increasing, mainly because of the increased use of antibiotics and immunosuppressive drugs. Rhino-orbital cerebral mucormycosis has recently reemerged among patients affected by COVID-19 and has become a global concern. The detection of extrasinus involvement in its early stage contributes to improved outcomes; therefore, imaging studies are essential in establishing the degree of involvement and managing the treatment properly, especially in immunocompromised patients. The common sites of extrasinus fungal invasion are the intraorbital, cavernous sinus, and intracranial regions. Fungi spread directly to these regions along the blood vessels or nerves, causing devastating complications such as optic nerve ischemia or compression, optic neuritis or perineuritis, orbital cellulitis, cavernous sinus thrombosis, mycotic aneurysm, vasculitis, internal carotid arterial occlusion, cerebral infarction, cerebritis, and brain abscess. IFRS has a broad imaging spectrum, and familiarity with intra- and extrasinonasal imaging features, such as loss of contrast enhancement of the affected region, which indicates tissue ischemia due to angioinvasion of fungi, and the surrounding anatomy is essential for prompt diagnosis and management. The authors summarize the epidemiology, etiology, risk factors, and complications of IFRS and review the anatomy and key diagnostic imaging features of IFRS beyond the sinonasal regions. ©RSNA, 2022.

Secretory Carcinoma in Children and Young Adults: A Case Series.

Secretory carcinoma (SC), previously known as mammary analogue secretory carcinoma, is a rare salivary gland neoplasm that typically presents as a slow-growing painless lesion in the head and neck. SC occurs mainly in adults but has been described in children with the youngest reported patient diagnosed at five years of age. In children the gender distribution has been reported as female to male ratio of 1:1.2. SC is generally considered a low-grade malignancy with characteristic morphological features and immunological profile. SC also harbors ETV6-NTRK3 fusion (t(12;15)(p13:q25)). Surgical resection with or without lymph node dissection is the standard treatment, with generally favorable clinical outcomes. Here we present a single institution case series of six patients (ages 9-21) with SC and a review of the previously described pediatric cases. Our small series showed male predominance in pediatric patients with predominantly low-grade and stage tumors. All cases underwent complete surgical resections and when follow up is available there was no evidence of recurrences or metastases. To the best of our knowledge, this is the only SC case series comprised exclusively of pediatric and youth patients.

Microsecretory Adenocarcinoma of the Ear Canal: Novel Cutaneous Analog of a Salivary Gland Neoplasm.

ABSTRACT: Microsecretory adenocarcinoma (MSA) of the salivary gland is a new entity recently added to the World Health Organization Classification of Head and Neck Tumors. This tumor is characterized by a recurrent MEF2C-SS18 translocation. We present a nodular tumor confined to the dermis of the ear canal of a 44-year-old patient, which demonstrated classic histopathologic features and molecular alteration of MSA. Specifically, the tumor was composed of numerous tubules and microcysts filled with abundant basophilic mucinous secretion and associated with a fibromyxoid stroma. The tumor cells were diffusely positive for CK7 and SOX10 and variably positive for S100 and p63. Breakapart fluorescence in situ hybridization for SS18 confirmed rearrangement of this gene. Together, these findings support a primary cutaneous MSA, presumably arising from ceruminous glands of the ear canal. Based on current knowledge of its salivary gland counterpart, cutaneous MSA is expected to be locally invasive but unlikely to recur or metastasize on complete excision.

Extent of Extranodal Extension in Oral Cavity Squamous Cell Carcinoma is Not Independently Associated With Overall or Disease-Free Survival at a 2.0-mm Threshold.

PURPOSE: The presence of extranodal extension (ENE) conveys a poor prognosis in oral cavity squamous cell carcinoma (OSCC); however, there is no consensus regarding whether the histopathologic extent of ENE (e-ENE) may be a more discriminating prognostic indicator. The purpose of this study was to assess the impact of minor ENE (<2.0 mm) versus major ENE (≥ 2.0 mm) on overall survival (OS) and disease-free survival (DFS) in OSCC. MATERIALS AND METHODS: A single-institution, retrospective cohort study was designed using an electronic medical record review. Inclusion criteria included patients with OSCC and cervical node metastasis. All subjects were treated between the years 2009 and 2017 in the Michigan Medicine Department of Oral and Maxillofacial Surgery (Ann Arbor, Michigan). The primary predictor variable was e-ENE, measured as the maximum distance of tumor invasion into extranodal tissue from the outer aspect of the nodal capsule. Primary outcome variables were OS and DFS. Other covariates included demographic data, tumor staging, and histopathologic data. Descriptive statistics were performed. Kaplan-Meier survival plots for OS and DFS were performed. The data were mined for an alternative threshold at which e-ENE may impact survival using Cox proportional hazards models. RESULTS: One hundred sixty eight subjects were included (91 ENE-negative, 48 minor ENE, and 29 major ENE). Most subjects were male (62%) and the mean age was 62.9 years. Mean follow-up time was 2.97 +/- 2.76 years. There was no statistically significant difference in OS or DFS between minor and major ENE. Five-year OS for minor ENE was 30.4% versus 20.7% for major ENE (P = .28). Five-year DFS for minor ENE was 26.7% versus 18.1% for major ENE (P = .30). Five-year OS and DFS was worse for subjects with ENE-positive disease versus ENE-negative disease (OS: 26.9% vs 63.1%, hazard ratio [HR]: 2.70, 95% confidence interval [CI]: [1.77, 4.10], P < .001; DFS: 23.7% vs 59.7%, HR = 2.55, 95% CI [1.71, 3.79], P < .001). At an alternative threshold of 0.9 mm e-ENE, there was greater DFS in subjects with e-ENE 0.1-0.9 mm versus e-ENE > 0.9 (40.6% vs 18.9%, respectively) (HR = 0.49, 95% CI [0.24, 0.99], P = .047). CONCLUSION: There was no independent association between survival and e-ENE at a 2.0-mm threshold.

TP53 mutations and CDKN2A mutations/deletions are highly recurrent molecular alterations in the malignant progression of sinonasal papillomas.

Sinonasal papillomas are benign epithelial tumors of the sinonasal tract that are associated with a synchronous or metachronous sinonasal carcinoma in a subset of cases. Our group recently identified mutually exclusive EGFR mutations and human papillomavirus (HPV) infection in inverted sinonasal papillomas and frequent KRAS mutations in oncocytic sinonasal papillomas. We also demonstrated concordant mutational and HPV infection status in sinonasal papilloma-associated sinonasal carcinomas, confirming a clonal relationship between these tumors. Despite our emerging understanding of the oncogenic mechanisms driving formation of sinonasal papillomas, little is currently known about the molecular mechanisms of malignant progression to sinonasal carcinoma. In the present study, we utilized targeted next-generation DNA sequencing to characterize the molecular landscape of a large cohort of sinonasal papilloma-associated sinonasal carcinomas. As expected, EGFR or KRAS mutations were present in the vast majority of tumors. In addition, highly recurrent TP53 mutations, CDKN2A mutations, and/or CDKN2A copy-number losses were detected; overall, nearly all tumors (n = 28/29; 96.6%) harbored at least one TP53 or CDKN2A alteration. TERT copy-number gains also occurred frequently (27.6%); however, no TERT promoter mutations were identified. Other recurrent molecular alterations included NFE2L2 and PIK3CA mutations and SOX2, CCND1, MYC, FGFR1, and EGFR copy-number gains. Importantly, TP53 mutations and CDKN2A alterations were not detected in matched sinonasal papillomas, suggesting that these molecular events are associated with malignant transformation. Compared to aerodigestive tract squamous cell carcinomas from The Cancer Genome Atlas (TCGA) project, sinonasal papilloma-associated sinonasal carcinomas have a distinct molecular phenotype, including more frequent EGFR, KRAS, and CDKN2A mutations, TERT copy-number gains, and low-risk human papillomavirus (HPV) infection. These findings shed light on the molecular mechanisms of malignant progression of sinonasal papillomas and may have important diagnostic and therapeutic implications for patients with advanced sinonasal cancer.

Genetic analysis of sinonasal undifferentiated carcinoma discovers recurrent SWI/SNF alterations and a novel PGAP3-SRPK1 fusion gene.

BACKGROUND: Sinonasal Undifferentiated Carcinoma (SNUC) is a rare and aggressive skull base tumor with poor survival and limited treatment options. To date, targeted sequencing studies have identified IDH2 and SMARCB1 as potential driver alterations, but the molecular alterations found in SMARCB1 wild type tumors are unknown. METHODS: We evaluated survival outcomes in a cohort of 46 SNUC patients treated at an NCI designated cancer center and identify clinical and disease variables associated with survival on Kaplan-Meier and Cox multivariate survival analysis. We performed exome sequencing to characterize a series of SNUC tumors (n = 5) and cell line (MDA8788-6) to identify high confidence mutations, copy number alterations, microsatellite instability, and fusions. Knockdown studies using siRNA were utilized for validation of a novel PGAP3-SRPK1 gene fusion. RESULTS: Overall survival analysis revealed no significant difference in outcomes between patients treated with surgery +/- CRT and CRT alone. Tobacco use was the only significant predictor of survival. We also confirmed previously published findings on IDH and SMARC family mutations and identified novel recurrent aberrations in the JAK/STAT and PI3K pathways. We also validated a novel PGAP3-SRPK1 gene fusion in the SNUC cell line, and show that knockdown of the fusion is negatively associated with EGFR, E2F and MYC signaling. CONCLUSION: Collectively, these data demonstrate recurrent alterations in the SWI/SNF family as well as IDH, JAK/STAT, and PI3K pathways and discover a novel fusion gene (PGAP3-SRPK1). These data aim to improve understanding of possible driver mutations and guide future therapeutic strategies for this disease.

Pretreatment Dietary Patterns, Serum Carotenoids and Tocopherols Influence Tumor Immune Response in Head and Neck Squamous Cell Carcinoma.

BACKGROUND: Tumor infiltrating lymphocytes (TILs) aid in informing treatment for head and neck squamous cell carcinoma (HNSCC). Nevertheless, little is known about the role of diet on TILs. METHODS: Immunohistologic expression of CD4, CD8, CD68, CD103, CD104 and FOXP3 were assessed in tissue microarrays from 233 previously untreated HNSCC patients. Associations between these markers and pretreatment dietary patterns were evaluated using linear regression. Associations between baseline serum carotenoids, tocopherols and TILs were assessed using logistic regression. Cox models evaluated the association between diet and TILs on overall and recurrence-free survival. RESULTS: Consumption of a Western dietary pattern was associated with lower CD8+ and FOXP3+ infiltrates (p-value:0.03 and 0.02, respectively). Multivariable logistic regression models demonstrated significantly higher CD8+ (OR:2.21;p-value:0.001) and FOXP3+ (OR:4.26;p-value:<0.0001) among patients with high gamma tocopherol. Conversely, high levels of xanthophylls (OR:0.12;p-value:<0.0001), lycopene (OR:0.36;p-value:0.0001) and total carotenoids(OR:0.31;p-value: <0.0001) were associated with significantly lower CD68+. Among those with high CD4+ (HR:1.77;p-value:0.03), CD68+ (HR:2.42;p-value:0.004), CD103+ (HR:3.64;p-value:0.03) and FOXP3+ (HR:3.09;p-value:0.05), having a high Western dietary pattern increased the risk of overall mortality when compared to a low Western dietary pattern. CONCLUSION: Dietary patterns and serum carotenoids may play an important role in modifying TILs, and ultimately, outcome after diagnosis with HNSCC.

Comparison of Early Oral Cancer Depth of Invasion From the American Joint Committe on Cancer 7th to 8th Edition Criteria. Does the Difference Impact the Accuracy of Clinical Decision Making?

PURPOSE: Depth of invasion (DOI) is an independent predictor of regional metastasis in oral squamous cell carcinoma. Measurement criteria for DOI were modified in the American Joint Committee on Cancer (AJCC) eighth edition. The purpose of this study was to compare DOI AJCC seventh (DOI7) and eighth (DOI8) edition criteria on frozen section accuracy for decisions regarding elective neck dissection (END) in cT1N0 oral squamous cell carcinoma. PATIENTS AND METHODS: A blinded, retrospective, comparative study of patients who underwent ablative surgery at the University of Michigan was completed. The predictor variable was criteria for DOI measurement. The outcome variables were concordance between DOI7 and DOI8 measurements and accuracy using thresholds for END. Effect of tumor growth pattern and worst pattern of invasion, and the difference between DOI8 on frozen and permanent specimen were assessed. RESULTS: A total of 30 specimens of T1N0 oral squamous cell carcinoma (16 tongue, 5 alveolus, 5 floor of mouth, 4 buccal mucosa) were included. DOI7 versus DOI8 on frozen and permanent specimen were significantly different (P < .05) but clinically insignificant and highly correlated (r > 0.99, P < .001). One hundred percent concordance between DOI7 and DOI8 was noted on frozen specimen in predicting the need for END when compared with permanent pathology DOI. There was no significant impact of tumor growth pattern or worst pattern of invasion on measurements and no significant difference in DOI on frozen and permanent specimen for DOI8 (P = .68). Excellent agreement between pathologists for all measurements was observed (ICC>0.99, P < 0001). CONCLUSIONS: High concordance between DOI measurements by AJCC seventh and eighth edition criteria suggests that guidelines for DOI thresholds for END in patients with T1N0 tumors developed using the AJCC seventh edition can be safely applied using AJCC eighth edition criteria. DOI measurement by AJCC 8 criteria on frozen specimen can be used to guide decision-making regarding END, given the high correlation to AJCC 8 permanent DOI measurement.

Synovial Biopsy in the Diagnosis of Crystal-Associated Arthropathies.

BACKGROUND/ OBJECTIVE: This study seeks to assess the utility of synovial biopsy in the diagnosis of crystal-associated arthropathies (CAAs) in a clinical setting. METHODS: In this retrospective study, we reviewed biopsy reports involving synovial tissue between 1988 and 2015. We then reviewed the records of patients where the biopsy was performed for a clinical suspicion of CAA-the clinical group-and calculated the frequency of a positive diagnosis. The t test, Mann-Whitney-Wilcoxon test, and Fisher test were used to compare clinical characteristics of patients with and without a tissue diagnosis of CAA. We also reviewed cases of unexpected detection of crystalline disease involving synovial tissue-the incidental group. RESULTS: Among 2786 biopsies involving the synovium, we identified 65 cases in the clinical group and 33 cases in the incidental group. In the clinical group, a relevant diagnosis was obtained from synovial tissue in 36.9%, and a CAA was diagnosed in 20%. Restricting analysis to clinical biopsies performed for a primary suspicion of CAA, a relevant diagnosis was obtained in 61.3%, and a CAA was diagnosed in 38.7%. The incidental group comprised 1.2% of all synovial biopsies and included 7 mass lesions. Basic calcium phosphate was not reported on any biopsy in the study period. CONCLUSIONS: Synovial biopsy is a diagnostic option when suspected CAA is resistant to conventional modes of diagnosis. Crystalline diseases should be considered in the differential diagnosis of musculoskeletal mass lesions mimicking neoplasms.

Analysis of tumor-infiltrating CD103 resident memory T-cell content in recurrent laryngeal squamous cell carcinoma.

BACKGROUND: Recurrent laryngeal squamous cell carcinomas (LSCCs) are associated with poor outcomes, without reliable biomarkers to identify patients who may benefit from adjuvant therapies. Given the emergence of tumor-infiltrating lymphocytes (TIL) as a biomarker in head and neck squamous cell carcinoma, we generated predictive models to understand the utility of CD4+, CD8+ and/or CD103+ TIL status in patients with advanced LSCC. METHODS: Tissue microarrays were constructed from salvage laryngectomy specimens of 183 patients with recurrent/persistent LSCC and independently stained for CD4+, CD8+, and CD103+ TIL content. Cox proportional hazards regression analysis was employed to assess combinations of CD4+, CD8+, and CD103+ TIL levels for prediction of overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) in patients with recurrent/persistent LSCC. RESULTS: High tumor CD103+ TIL content was associated with significantly improved OS, DSS, and DFS and was a stronger predictor of survival in recurrent/persistent LSCC than either high CD8+ or CD4+ TIL content. On multivariate analysis, an "immune-rich" phenotype, in which tumors were enriched for both CD103+ and CD4+ TILs, conferred a survival benefit (OS hazard ratio: 0.28, p = 0.0014; DSS hazard ratio: 0.09, p = 0.0015; DFS hazard ratio: 0.18, p = 0.0018) in recurrent/persistent LSCC. CONCLUSIONS: An immune profile driven by CD103+ TIL content, alone and in combination with CD4+ TIL content, is a prognostic biomarker of survival in patients with recurrent/persistent LSCC. Predictive models described herein may thus prove valuable in prognostic stratification and lead to personalized treatment paradigms for this patient population.

Intraoperative Depth of Invasion Is Accurate in Early-Stage Oral Cavity Squamous Cell Carcinoma.

PURPOSE: Depth of invasion (DOI) is one predictor of nodal metastasis in oral cavity squamous cell carcinoma (OCSCC) and can facilitate the decision to complete an elective neck dissection (END) in early-stage disease with a clinically negative neck. The purpose of this study was to investigate the accuracy of DOI in intraoperative frozen specimens for T1N0 oral OCSCC. MATERIALS AND METHODS: To compare the accuracy of DOI in frozen versus permanent specimens, we completed a prospective, blinded study of 30 patients with cT1N0 OCSCC who presented between October 2016 and December 2017. RESULTS: DOI in frozen specimens was 96.8% accurate in predicting the need for END with a sensitivity of 90.9%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 95.2%. A strong correlation was found between DOIs in frozen and permanent specimens measured by head and neck (HN) pathologists (r = 0.96; 95% confidence interval [CI], 0.93 to 0.97), between HN pathologists using frozen specimens (r = 0.98; 95% CI, 0.95 to 0.99) and permanent specimens (r = 0.95; 95% CI, 0.91 to 0.98), and in DOIs in frozen specimens communicated intraoperatively versus measured by HN pathologist 1 (r = 0.93; 95% CI, 0.86 to 0.97) and HN pathologist 2 (r = 0.95; 95% CI, 0.89 to 0.98). Only 1 patient who did not undergo an END based on frozen specimens was undertreated owing to upgrading of the DOI in permanent specimens. CONCLUSIONS: DOI in intraoperative frozen sections has an accuracy of 96.8% and may be reliably used as a clinical tool to determine the need for END in early-stage OCSCC.

The utility of ETV1, ETV4 and ETV5 RNA in-situ hybridization in the diagnosis of CIC-DUX sarcomas.

AIMS: A recently characterized group of undifferentiated small round cell sarcomas harbours fusions of the genes CIC and DUX4. Studies report a distinctive gene expression profile for these sarcomas, including expression of E26 transformation-specific (ETS) family proto-oncogenic transcription factors ETV1, ETV4 and ETV5. To test the utility of an ancillary diagnostic technique for these tumours, we evaluated chromogenic RNA in-situ hybridization assays for ETV1, ETV4 and ETV5 as diagnostic adjuncts for this emerging group of highly malignant sarcomas. METHODS AND RESULTS: We tested six confirmed CIC-DUX4 sarcomas and 105 lesions in the differential, including 48 Ewing sarcomas for expression of ETV1, ETV4 and ETV5, scoring expression utilizing a previously validated scale. ETV1 and ETV4 were positive in five of six cases, while ETV5 was positive in six of six. No Ewing sarcoma or other sarcoma tested showed coexpression of these transcripts, while one ETV1/ETV4/ETV5 triple positive previously unclassified round cell sarcoma was identified as harbouring a CIC rearrangement by break-apart fluorescence in-situ hybridization (FISH). CONCLUSION: We identified overexpression of ETV1, ETV4 and ETV5 transcripts in situ in CIC-DUX4 sarcomas using a robust assay in routine archival sections. One previously unclassified round cell sarcoma showed ETV1/4/5 positivity, and was proved to harbour a CIC rearrangement by break-apart FISH. The sensitivity and specificity observed with our in-situ hybridization assay implies potential utility as an ancillary diagnostic technique, particularly when faced with limited biopsy samples.

A distinctive, low-grade oncocytic fumarate hydratase-deficient renal cell carcinoma, morphologically reminiscent of succinate dehydrogenase-deficient renal cell carcinoma.

AIMS: Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is a high-grade, aggressive tubulopapillary carcinoma, arising predominantly in the setting of the hereditary leiomyomatosis-RCC syndrome of familial uterocutaneous leiomyomatosis and deficiency of FH. In contrast, succinate dehydrogenase (SDH)-deficient RCC is a lower-grade oncocytic carcinoma with cytoplasmic flocculence/vacuolation and inclusions, arising mostly in individuals harbouring germline mutations of subunit B of the SDH complex (SDHB). Herein we aim to report the clinicopathologic features of a novel form of FH-deficient RCC showing a low grade oncocytic morphology, reminiscent of SDH-deficient RCC. METHODS AND RESULTS: These distinctive, low-grade oncocytic neoplasms, with solid, nested and focally tubular architecture (2-90 mm), arose in four males (aged 11-41 years). Uniform cytology of polygonal cells, with flocculent, vacuolated eosinophilic cytoplasm with scattered inclusions, fine chromatin, and inconspicuous nucleoli, was apparent. Despite these features suggestive of SDH-deficient RCC, each tumour was confirmed as an FH-deficient carcinoma with retained SDHB expression. One case showed a synchronous, anatomically separate, typical high-grade FH-deficient RCC; one other showed such a tumour at nephrectomy 4 years later. No progression has been noted at 3 and 7 years in the cases with only the SDH-like lesions; the two cases with separate, typical FH-deficient RCCs progressed. CONCLUSIONS: In summary, we characterize a novel oncocytic type of FH-deficient RCC with a striking resemblance to SDH-deficient RCC, posing a diagnostic challenge and raising concerns about sampling and multifocality for syndrome-associated cases under surveillance protocols.

Activating KRAS mutations are characteristic of oncocytic sinonasal papilloma and associated sinonasal squamous cell carcinoma.

Oncocytic sinonasal papillomas (OSPs) are benign tumours of the sinonasal tract, a subset of which are associated with synchronous or metachronous sinonasal squamous cell carcinoma (SNSCC). Activating EGFR mutations were recently identified in nearly 90% of inverted sinonasal papillomas (ISPs) - a related tumour with distinct morphology. EGFR mutations were, however, not found in OSP, suggesting that different molecular alterations drive the oncogenesis of these tumours. In this study, tissue from 51 cases of OSP and five cases of OSP-associated SNSCC was obtained retrospectively from six institutions. Tissue was also obtained from 50 cases of ISP, 22 cases of ISP-associated SNSCC, ten cases of exophytic sinonasal papilloma (ESP), and 19 cases of SNSCC with no known papilloma association. Using targeted next-generation and conventional Sanger sequencing, we identified KRAS mutations in 51/51 (100%) OSPs and 5/5 (100%) OSP-associated SNSCCs. The somatic nature of KRAS mutations was confirmed in a subset of cases with matched germline DNA, and four matched pairs of OSP and concurrent associated SNSCC had concordant KRAS genotypes. In contrast, KRAS mutations were present in only one (5%) SNSCC with no known papilloma association and none of the ISPs, ISP-associated SNSCCs, or ESPs. This is the first report of somatic KRAS mutations in OSP and OSP-associated SNSCC. The presence of identical mutations in OSP and concurrent associated SNSCC supports the putative role of OSP as a precursor to SNSCC, and the high frequency and specificity of KRAS mutations suggest that OSP and OSP-associated SNSCC are biologically distinct from other similar sinonasal tumours. The identification of KRAS mutations in all studied OSP cases represents an important development in our understanding of the pathogenesis of this disease and may have implications for diagnosis and therapy. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Establishing quality indicators for neck dissection: Correlating the number of lymph nodes with oncologic outcomes (NRG Oncology RTOG 9501 and RTOG 0234).

BACKGROUND: Prospective quality metrics for neck dissection have not been established for patients with head and neck squamous cell carcinoma. The purpose of this study was to investigate the association between lymph node counts from neck dissection, local-regional recurrence, and overall survival. METHODS: The number of lymph nodes counted from neck dissection in patients treated in 2 NRG Oncology trials (Radiation Therapy Oncology Group [RTOG] 9501 and RTOG 0234) was evaluated for its prognostic impact on overall survival with a multivariate Cox model adjusted for demographic, tumor, and lymph node data and stratified by the postoperative treatment group. RESULTS: Five hundred seventy-two patients were analyzed at a median follow-up of 8 years. Ninety-eight percent of the patients were pathologically N+. The median numbers of lymph nodes recorded on the left and right sides were 24 and 25, respectively. The identification of fewer than 18 nodes was associated with worse overall survival in comparison with 18 or more nodes (hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.09-1.74; P = .007). The difference appeared to be driven by local-regional failure (HR, 1.46; 95% CI, 1.02-2.08; P = .04) but not by distant metastases (HR, 1.08; 95% CI, 0.77-1.53; P = .65). When the analysis was limited to NRG Oncology RTOG 0234 patients, adding the p16 status to the model did not affect the HR for dissected nodes, and the effect of nodes did not differ with the p16 status. CONCLUSIONS: The removal and identification of 18 or more lymph nodes was associated with improved overall survival and lower rates of local-regional failure, and this should be further evaluated as a measure of quality in neck dissections for mucosal squamous cell carcinoma. Cancer 2016;122:3464-71. © 2016 American Cancer Society.