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Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma is increasing in incidence and is often first diagnosed on a cytology fine needle aspiration (FNA) specimen of metastatic nodal disease of the neck. In the setting of oropharyngeal squamous cell carcinoma, HPV status defines the disease with HPV-associated tumors having better overall prognosis than those that are HPV negative. Furthermore, metastatic squamous cell carcinoma of the neck of unknown origin requires testing for HPV as a positive result suggests an oropharyngeal primary. As a result, HPV testing in aspirate samples is increasingly important for the proper diagnosis and treatment of patients with head and neck squamous cell carcinoma. Although HPV testing in cervicovaginal cytology specimens is common and well-established, testing in head and neck FNA samples remains challenging. p16 immunohistochemistry is an excellent surrogate marker for HPV in tumors of known or suspected oropharyngeal origin, but the criteria used in histologic specimens may not be appropriate in cytology samples. FNA samples are more frequently hypocellular, and cytology cell blocks have variable fixation and processing steps, limiting the utility of p16 immunohistochemistry. Other potential testing options have been reported in the literature including staining of aspirate smears and molecular testing of liquid-based samples. The American Society of Cytopathology Clinical Practice Committee recently surveyed the American Society of Cytopathology membership to determine the current state of HPV testing in aspirate samples, and this review article is designed to provide a summary of the current literature on various testing options in FNA samples.

Context Comprehensive genomic analysis of thyroid nodules for multiple classes of molecular alterations detected in a large series of fine needle aspiration (FNA) samples has not been reported. Objective To determine the prevalence of clinically relevant molecular alterations in Bethesda categories III-VI (BCIII-VI) thyroid nodules. Methods This retrospective analysis of FNA samples, tested by ThyroSeq v3 using Genomic Classifier and Cancer Risk Classifier at UPMC Molecular and Genomic Pathology laboratory, analyzed the prevalence of diagnostic, prognostic, and targetable genetic alterations in a total of 50 734 BCIII-VI nodules from 48 225 patients. Results Among 50 734 informative FNA samples, 65.3% were test-negative, 33.9% positive, 0.2% positive for medullary carcinoma, and 0.6% positive for parathyroid. The benign call rate in BCIII-IV nodules was 68%. Among test-positive samples, 73.3% had mutations, 11.3% gene fusions, and 10.8% isolated copy number alterations. Comparing BCIII-IV nodules with BCV-VI nodules revealed a shift from predominantly RAS-like alterations to BRAF V600E-like alterations and fusions involving receptor tyrosine kinases (RTK). Using ThyroSeq Cancer Risk Classifier, a high-risk profile, which typically included TERT or TP53 mutations, was found in 6% of samples, more frequently BCV-VI. RNA-Seq confirmed ThyroSeq detection of novel RTK fusions in 98.9% of cases. Conclusion In this series, 68% of BCIII-IV nodules were classified as negative by ThyroSeq, potentially preventing diagnostic surgery in this subset of patients. Specific genetic alterations were detected in most BCV-VI nodules, with a higher prevalence of BRAF and TERT mutations and targetable gene fusions compared to BCIII-IV nodules, offering prognostic and therapeutic information for patient management.

Sinonasal malignancies constitute 3% of head and neck cancers, with squamous cell carcinoma (SCC) the most common histology. Neuroendocrine carcinomas (NEC) are rare, with a subset showing neuroendocrine carcinoma and a non-neuroendocrine component. The pathogenesis of these combined tumors is largely unknown, and TP53 driver mutations may play a role. A database search for combined NEC was performed across two institutions (UNM and UCSF) spanning 15years. Excluding NUT midline carcinoma, 3 cases met inclusion criteria. All were morphologically NEC + SCC and underwent a comprehensive immunohistochemical evaluation. Tumors demonstrated two components histologically: moderately to poorly differentiated SCC and high-grade NEC. Divergent differentiation was confirmed with lineage-specific markers. Only one patient received neoadjuvant chemotherapy prior to surgery, with a remarkable response (a marked decrease in the size of the primary lesion and resolution of liver metastases). Immunohistochemical staining for p53 was increased in 2 of 3 cases (both components), suggesting a role in the carcinogenesis of these tumors. Aberrant expression of beta-catenin was not identified. One case tested positive for p16, which can be seen in high grade NECs due to inactivation of Rb gene. Additionally, both cases with a small cell NEC component expressed PD-L1, suggesting that immunotherapy may be an effective treatment. Findings in this study support the role of p53 mutation in a subset of combined NEC + SCC of the sinonasal tract. Recognition of this rare entity is essential for optimal management of these aggressive neoplasms.

BACKGROUND: Prior studies evaluating thyroid fine needle aspiration biopsies (FNABs) have limited the calculation of risk of malignancy (ROM) to cytologic specimens with corresponding histologic specimens, and clinical follow-up for those patients who do not undergo immediate surgery has been largely disregarded. Moreover, there is marked variability in how researchers have approached thyroid FNAB statistical analyses. This study addresses the urgent need for information from a large cohort of patients with long-term clinical follow-up to more accurately determine the performance of thyroid FNAB and ROM for each diagnostic category. METHODS: A retrospective review of the University of California, San Francisco (UCSF), pathology database for thyroid FNABs from January 1, 1997, to December 31, 2004, was performed. Diagnoses were coded using the 2017 The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC), and patients were matched to both the UCSF cancer registry and California Cancer Registry. Data were analyzed using the Kaplan–Meier method, and stratified by TBSRTC diagnostic category. Kaplan–Meier curves were used to estimate incidence rates of malignancy, stratified by FNAB category. Cox proportional hazards models were used to determine the instantaneous ROM. RESULTS: Initial FNABs from 2207 patients were included. Median follow-up period after the first thyroid FNAB was 13.9 years (range: 10.5–18.4 years). During follow-up, there were 279 confirmed diagnoses of thyroid malignancy. Estimates derived from Kaplan–Meier curves demonstrated that the risk of having a thyroid malignancy was low for nondiagnostic and benign categories, intermediate for atypia of undetermined significance (AUS), follicular lesion of undetermined significance (FLUS), AUS/FLUS combined, and follicular neoplasm, and high for suspicious and malignant categories. A total of 52/1575 false-negative cases (3.2%) were identified. Excluding papillary microcarcinomas, the false-negative rate was 1.5% (23/1575). No patients with a false-negative diagnosis died of thyroid cancer during the follow-up period. CONCLUSIONS: Asymptomatic patients with low-risk clinical and radiologic features and initially benign or unsatisfactory biopsy are unlikely to develop thyroid malignancy and highly unlikely to die of thyroid cancer. FNAB is highly accurate in detecting malignancy. Additional studies evaluating similar large data sets after the adoption of TBSRTC and the integration of molecular testing are needed.

Introduction This study aims to improve understanding of the cytopathology community’s perspective regarding the value of rapid onsite evaluation (ROSE) in clinical practice. Materials and methods The American Society of Cytopathology membership was surveyed in 2019 to obtain subjective data on the cytopathology community’s perceptions regarding ROSE. Comments were categorized by major themes and attitudes and analyzed by respondent’s role in laboratory, practice size, and practice setting (Fisher’s exact and χ2 tests). Results A total of 541 responses were received from 255 cytopathologists/pathologists, 261 cytotechnologists, 19 trainees, and 6 others (as previously reported). Reasons for which cytopathology personnel provide this service aligned with their perceptions of why clinicians request ROSE. A minority of respondents, disproportionally from high volume centers, felt ROSE is unnecessary. Overall attitude regarding ROSE was generally positive. There were no significant differences in attitude regarding ROSE according to role in laboratory or practice size, but respondents from academic centers provided a significantly higher percentage of positive comments than those in private or community practice. Although survey respondents generally felt that ROSE is valuable to patient care, they also highlighted several challenges, including staffing, time commitment, and inadequate reimbursement. Implementation of telecytology was felt to potentially alleviate some of these challenges. Conclusions Survey results show that the cytology community views ROSE favorably, practices vary considerably, and there is a perceived need for improved reimbursement. Data from this study may be used to identify areas that warrant additional research to clarify the clinical value of ROSE.

To compare the outcomes of Sinonasal Mucosal Melanomas (SNMM) treated with endoscopic and open resection. A retrospective case review of 20 patients with SNMM treated surgically at UCSF. Kaplan–Meier analyses were calculated to determine outcome differences in endoscopic vs. open resections. From 2005 to 2014, 20 cases of SNMM were confirmed and treated at UCSF. All cases underwent surgical resection, with 10 cases by open resection and 10 cases by endoscopic resection. Using Kaplan–Meier analyses, the open resection group had a 1-year survival of 30% whereas endoscopic resection group was 80% (p = 0.032). Endoscopic resection showed improved survival at all time points after surgery compared to open resection. SNMM is a rare and aggressive tumor that is associated with low survival rates. In this small case series, endoscopic resection had improved survival outcomes compared to open resection.

High-risk human papillomavirus (HR-HPV) status is critical in the diagnosis of oropharyngeal squamous cell carcinoma, informing prognosis and choice of therapy. HR-HPV status additionally plays a key role in the evaluation of squamous cell carcinoma of unknown origin metastatic to cervical lymph nodes. Thus, HR-HPV testing of fine needle aspirate (FNA) specimens from the head and neck is invaluable for accurate diagnosis, prognostication, and treatment planning.American Society of Cytopathology members were surveyed to understand the current state of HR-HPV testing on FNA samples from the head and neck. The survey focused on 3 main topic areas: practice setting of respondents, methods of collection and processing of aspirate specimens for HR-HPV testing, and validation of HR-HPV testing methodologies on aspirate samples.The survey reveals that laboratories employ various methods to detect HR-HPV in FNA samples, most commonly p16 immunohistochemical staining of cell block sections. Although some laboratories have independently validated their HR-HPV detection method, such validation is not universal. Finally, not all respondents currently have HR-HPV testing available, but approximately half of those without a testing method desire to make HR-HPV testing of FNA samples available.Survey responses highlight that various testing modalities are utilized for HR-HPV detection in aspirate samples. However, internal laboratory validation of HR-HPV testing for FNA specimens is not ubiquitous despite professional society recommendations.

Importance Understanding patient-specific risk of adverse histopathologic findings after primary surgery for human papillomavirus (HPV)-positive oropharynx squamous cell carcinoma (OPSCC) may help guide patient consultations. Objective To determine the likelihood of adverse histopathologic features that may indicate adjuvant radiotherapy or chemoradiotherapy after primary surgery for HPV-positive OPSCC according to 2021 National Comprehensive Cancer Network guidelines. Design, Setting, and Participants This retrospective cohort study was performed at a single academic tertiary care center. Of 258 patients who underwent transoral robotic surgery (TORS) from March 1, 2012, to March 1, 2021, 136 consecutive, treatment-naive patients with HPV-positive OPSCC without obvious clinical extranodal extension (ENE) who underwent definitive TORS and neck dissection were included in the analysis. Indications for surgical treatment included non–deeply infiltrative oropharynx tumors, minimal soft palate involvement, and low suspicion for pathologic ENE. Exposures Primary site TORS with neck dissection. Main Outcomes and Measures The primary outcomes were the adverse histopathologic features of pathologic ENE and positive surgical margins (PSM) that are indications for possible adjuvant chemoradiotherapy. Outcomes were compared among varying American Joint Committee on Cancer 7th edition (AJCC-7) T and N categories and patient clinical characteristics. Results Of the 136 patients included in the analysis (113 men [83.1%]; median age, 63 [interquartile range, 55-70] years), 109 (80.1%) had at least 1 indication for possible adjuvant radiotherapy. Twenty-seven patients (19.9%) had pathologic ENE and 10 (7.3%) had PSM. Thirty-four patients (25.0%) had pathologic ENE and/or PSM, whereas 3 (2.2%) had both. Age, smoking history, history of alcohol consumption, and clinical T category were not associated with pathologic ENE, PSM, lymphovascular invasion, perineural invasion, or pN2 category or greater. The proportion of pathologic ENE varied by clinical N category: 0 of 16 for cN0, 8 of 48 (16.7%) for cN1, 3 of 23 (13.0%) for cN2a, and 16 of 45 (35.6%) for cN2b. Compared with patients with cN1-cN2a disease, patients with cN2b disease had higher odds of pathologic ENE (odds ratio, 3.01; 95% CI, 1.14-8.10). Clinical and pathologic N category were concordant in 77 patients (56.6%), whereas 42 (30.9%) were upstaged and 17 (12.5%) were downstaged. Conclusions and Relevance In this cohort study, approximately one-quarter of carefully selected patients with HPV-positive OPSCC without obvious clinical ENE undergoing primary surgery had pathologic ENE and/or PSM. Patients with AJCC-7 cT0-cT2 cN0-cN2b disease, especially cN0-cN2a, without signs of clinical ENE may represent appropriate candidates for primary surgery when avoidance of adjuvant chemotherapy and/or reduction of adjuvant radiotherapy dose/extent are the goals.

Introduction Rapid on-site evaluation (ROSE) is a service provided by cytologists that helps ensure specimen adequacy and appropriate triage for ancillary testing. However, data on the current usage patterns across different practice settings have been lacking. Materials and methods To obtain an accurate and timely assessment of the current state of practice of ROSE, a 14-question online survey was constructed by the Clinical Practice Committee of the American Society for Cytopathology. The survey was available to the membership of the American Society for Cytopathology for a 3-week period in early 2019. Results A total of 541 responses were received, including from 255 cytopathologists/pathologists, 261 cytotechnologists, 19 cytology resident/fellow trainees, and 6 others. ROSE was offered as a clinical service by 95.4% of the respondents, with telecytology for ROSE used in 21.9% of the practices. Endobronchial ultrasound-guided transbronchial needle aspiration was the procedure most frequently reported to use ROSE (mean, 59.1%; median, 70%). Cytotechnologists were involved in ROSE in most practices. The number of daily ROSE procedures correlated with the annual nongynecologic cytology volumes. Approximately 70% of ROSE procedures were reported to require >30 minutes, on average, for the cytologist. Conclusions The results from our survey of cytologists have shown that the reported practice patterns for the usage of ROSE vary considerably. The presented data can help inform future guideline recommendations and the implementation of ROSE in different clinical settings.

Purpose/Objectives: The human tumor microenvironment (TME) has a dramatic impact on cancer prognosis and therapeutic response, but accurate models of the native TME do not exist. The Comparative In Vivo Oncology (CIVO) platform was developed as a means to assess the effect of investigational agents on the native TME in a Phase 0 microdosing study. CIVO was clinically validated using approved agents and is used for the first time here to assess the impact of an investigational agent - the SUMOylation inhibitor TAK-981 - on the native human TME in HNSCC. Materials/Methods: Eligible subjects have a confirmed HNSCC diagnosis, ECOG 0-2, and planned surgical resection. Injectable tumors were at the primary site or within cervical lymph nodes but had to be surface-accessible and ≥ 2cm. TAK-981 or control microdoses were simultaneously administered via a CIVO device and co-injected with a fluorescent tracking marker for injection site identification and visualization. Tumors were resected 24 or 72 hours after injection, processed, and then analyzed at a central site. Multiplexed biomarker staining and molecular profiling via GeoMx Digital Spatial Profiling were performed to capture pharmacodynamic responses in the native TME. Results: As of January 2022, 8 subjects provided informed consent and were enrolled, and no adverse events associated with the injection procedure or microdoses have been reported. Biomarker analysis demonstrated TAK-981 distribution around the injection site accompanied by reduction of SUMOylation. Dose-dependent elevation of IFN1 signaling was also observed in TAK-981-exposed areas within the TME. Elevated IFN1 signaling was accompanied by TME reconfiguration, with increased macrophage M1 polarization and activation of dendritic cells, NK cells, and CD8+ T cells. TAK-981 exposure was also associated with upregulation of CXCL10, PD-L1, and an IFNγ gene expression signature predictive of response to immune checkpoint blockade. Conclusion: IT microdosing with CIVO provided early insights into complex functional responses induced by the investigational agent TAK-981 that can only be accurately evaluated in the intact, native TME of a patient’s tumor. SUMO pathway inhibition in HNSCC tumors following TAK-981 exposure led to functional activation of multiple immune cell types, effectively shifting the local TME toward an inflamed “hot” state, highlighting TAK-981’s potential as an immune stimulating agent for treating patients with solid tumors. These data were generated while TAK-981 was still in Phase I dose escalation trials (via IV administration), highlighting CIVO’s ability to safely study investigational agents. Further evaluation of TAK-981 alone and in combination with other agents is ongoing in this Phase 0 CIVO microdosing trial. Citation Format: Jeffrey Houlton, Harrison Cash, Haodong Xu, Paul L. Swiecicki, Keith Casper, Steven B. Chinn, Daniel R. Clayburgh, Ryan J. Li, Robert J. Christian, Aaron Halfpenny, Annemieke van Zante, Beryl A. Hatton, Kimberly Sottero, Marc O. Grenley, Connor Burns, Jason Frazier, Jonathan Derry, Gloria Kung, Emily Beirne, Nathan J. Schauer, Atticus Turner, Wendy Jenkins, Kirsten Anderson, Richard A. Klinghoffer, Dennis Huszar, Allison Berger, Karuppiah Kannan. Intratumoral (IT) microdosing of the investigational SUMOylation Inhibitor TAK-981 in a phase 0 CIVO trial demonstrates the reactivation of type I Interferon (IFN1) signaling in head and neck squamous cell carcinoma (HNSCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT139.

Background Adenoid cystic carcinoma (ACC) is the second most common malignancy of the salivary glands, accounting for ~ 1% of malignant tumors of the head and neck region and 10% of salivary gland neoplasms. Predicting the long-term outcomes of patients with ACC is still challenging, as reliable prognostic biomarkers are not available. Among salivary gland tumors, Myb overexpression is highly specific for ACC. In addition, the MYB-NF1B fusion translocation is a hallmark of ACC, and although the detection of this translocation does not appear to impact prognosis, the MYB-NF1B fusion is also implicated in MYB upregulation. Myb has recently been identified as an activator of the Wnt/β-catenin signaling pathway, and aberrant cytoplasmic expression of β-catenin has been observed in many salivary gland malignancies. In this study, we aim to analyze the impact of Myb and β-catenin expression on prognosis in ACC. Methods A tissue microarray constructed from archival tissue from 64 patients with ACC was stained for Myb and β-catenin; both localization and intensity were evaluated. In parallel, we abstracted demographic data, tumor characteristics, survival data, and outcomes, including local recurrence, regional recurrence, and distant metastasis from the medical record. Statistical analysis was performed. Results Our analysis supports that ACC patients negative for Myb by immunohistochemical methods have a higher risk of developing metastasis than patients with Myb staining (HR: 4.06, 95% CI: 1.02–14.96, p-value: 0.03). Although not statistically significant, cytoplasmic localization of β-catenin is may suggest a diminished rate of relapse-free survival (HR 2.45, 95%CI: 0.9–6.7, p = 0.08). Furthermore, Myb expression correlated with β-catenin expression, increasing 1.69 in staining intensity units with each increase in β-catenin staining intensity (p-value: 0.04). Conclusions Our study suggests that Myb expression is protective; Myb positive patients have diminished risk of distant metastasis. In contrast, there is a trend towards increased hazard of death in ACC patients with cytoplasmic β-catenin expression. Additional analyses will be necessary to establish Myb and β-catenin as independent protective and adverse biomarkers, respectively.

Human papillomavirus (HPV) is a principal driver for most oropharyngeal squamous cell carcinomas (OPSCCs), where it is strongly associated with improved survival. HPV is much less frequently detected in squamous cell carcinomas arising in nonoropharyngeal sites (non-OPSCCs), and its pathogenic role and prognostic value in these tumors is unclear. We evaluated the clinicopathologic features of 52 non-OPSCCs considered HPV-positive based upon p16 immunohistochemistry and direct HPV detection using RNA in situ hybridization (ISH), DNA ISH, or real-time DNA polymerase chain reaction. The HPV-positive non-OPSCCs were from the larynx (n = 27), oral cavity (n = 21), and hypopharynx (n = 4). While most cases (n = 34, 65%) showed classic histologic features of HPV-positive OPSCC, including endophytic growth, minimal keratinization, and hyperchromatic nuclei without koilocytic changes, a subset (n = 13, 25%) were characterized by exophytic growth, exuberant surface hyperkeratosis and parakeratosis, marked nuclear pleomorphism, and prominent koilocytic atypia. These antithetical features were highly reminiscent of the warty variant of HPV-positive squamous cell carcinoma described in anogenital sites. Compared with tumors without warty features, the warty tumors presented at lower stage and were not associated with lymph node metastasis, local recurrence, or distant spread (4 y disease-free survival of 100% vs. 66%, P = 0.069). The presence of transcriptionally active HPV as detected by RNA ISH suggests a pathogenic role for HPV in these nonoropharyngeal sites. While most HPV-positive non-OPSCCs are morphologically similar to their tonsillar counterparts, this study highlights a previously unrecognized warty variant that may be associated with a highly favorable clinical outcome.

BACKGROUND Head and neck squamous cell carcinoma of unknown primary site (HNSCCUP) is a diagnostic challenge. Identification of an ultraviolet (UV) light-related DNA damage signature using next-generation sequencing (NGS) can classify the primary site of origin as cutaneous. METHODS A 62-year-old male was seen with 2 months of left neck swelling. He was a lifetime nonsmoker but had a history of cutaneous squamous cell carcinoma (SCC) of the left helix. He was also found to have left hilar adenopathy. He had a p16-negative HNSCCUP on fine needle aspiration (FNA) biopsy of the left neck. RESULTS NGS of the FNA specimen revealed a high number of somatic mutations that were mostly C to T transitions, indicating a UV mutation signature and confirming the diagnosis of cutaneous SCC. CONCLUSIONS Identification of a UV DNA damage signature with NGS distinguishes HNSCCUP of cutaneous vs mucosal or other squamous cell carcinoma origin.

We present a case of a 61-year-old man with history of prostate cancer and rising PSA levels referred for restaging. Ga-PSMA-11 PET/CT identified 2 lung nodules with low and moderate PSMA uptake. Subsequent F-FDG PET/CT showed high hypermetabolism in the nodule with low PSMA uptake, and low hypermetabolism in the nodule with moderate PSMA uptake. The isolated pulmonary findings and metabolic appearance is an atypical presentation of prostate cancer metastases and raised concern for a second primary malignancy. Fine-needle aspiration of the F-FDG active lung nodule confirmed metastatic prostatic adenocarcinoma that subsequently responded to androgen deprivation therapy and abiraterone acetate.

Aims Mucoepidermoid carcinomas (MEC) are the most common malignant neoplasms of salivary glands, but are uncommon in other sites. Salivary gland MEC are most frequently associated with CRTC1-MAML2 translocations. Exceedingly rare MEC of the breast demonstrate a basal-like and often triple (oestrogen and progesterone receptor, HER2)-negative immunophenotype, with a single case previously reported to show MAML2 rearrangement, although the fusion partner was not known. Comprehensive genomic studies of breast MEC are lacking. In this study, we analysed the immunophenotype and molecular landscape of two breast MEC to elucidate the pathogenesis of these rare tumours. Methods and results Two breast MEC were subjected to capture-based next-generation DNA sequencing of 479 cancer-related genes. The presence of the CRTC1-MAML2 fusion transcript was interrogated by reverse transcriptase-polymerase chain reaction. In addition, the immunoprofiles of breast MEC were compared to salivary gland MEC. Both breast MEC harboured CRTC1-MAML2 fusions. In contrast to most triple-negative breast carcinomas of no special type, the mutational burden of MEC was very low, with one case demonstrating only an inactivating SETD2 mutation, and the other harbouring no somatic variants in genes on the panel. No copy number alterations were identified. The immunoprofiles of breast and salivary gland MEC were overlapping, but not identical. Conclusions The findings highlight MEC as a breast cancer subtype more closely related to its salivary gland counterpart than to basal-like/triple-negative breast cancers of no special type.

Objectives/hypothesis Human papillomavirus (HPV)-positive and HPV-negative oropharyngeal squamous cell carcinoma (OPSCC) are distinct disease entities. Prognostic factors specific to each entity have not been adequately explored. Goals for this study were: 1) to determine whether HPV-positive and HPV-negative OPSCCs have distinct prognostic factors, and 2) to explore the prognostic significance of sex and race in OPSCC after HPV stratification STUDY DESIGN: Retrospective case series. Methods A retrospective review of 239 incident OPSCC patients from 1995 to 2012, treated at Johns Hopkins and University of California-San Francisco was conducted. Women and nonwhite races were oversampled. All analyses were stratified by tumor HPV in situ hybridization status. The effects of sex and race on survival were considered in Kaplan-Meier and unadjusted and adjusted Cox regression models. Results One hundred thirty-four (56.1%) OPSCC patients were HPV positive. On univariate analysis, women had better overall survival than men among HPV-positive (hazard ratio [HR]: 0.47, 95% confidence interval [CI]: 0.20-1.07; P = .06) but not HPV-negative (HR: 0.73, 95% CI: 0.43-1.24; P = .24) OPSCCs. On multivariate analysis, women with HPV-positive OPSCCs remained at lower risk of death (adjusted hazard ratio [aHR]: 0.34, 95% CI: 0.12-0.96; P = .04). Survival did not vary significantly by race among HPV-positive patients. Among HPV-negative patients, Hispanic patients had significantly better survival in unadjusted (HR: 0.27, 95% CI: 0.08-0.91; P = .04) but not adjusted (aHR: 0.93, 95% CI: 0.11-7.36; P = .94) analysis. Conclusions Women with HPV-positive OPSCC may have improved overall survival compared to men. Sex does not play a prognostic role in HPV-negative OPSCC. There are no differences in prognosis by race among HPV-positive or HPV-negative patients. Level of evidence 4 Laryngoscope, E287-E295, 2018.

OBJECTIVE To quantify the rate of late intracranial recurrences among esthesioneuroblastoma patients treated with surgical resection and postoperative radiation. STUDY DESIGN Retrospective review. METHODS All patients receiving definitive-intent therapy for esthesioneuroblastoma between March 1995 and September 2015 were reviewed. Presenting disease extent was categorized based on radiologic, operative, and pathologic findings. Between-group survival differences were assessed using Kaplan-Meier method and log-rank test. Multivariate analyses were performed using Cox proportional hazards model. RESULTS Of 38 patients initially treated at our institution, 53% (20 of 38) presented with intracranial extension. At a median follow-up of 90 months (range, 6-199), 37% (14 of 38) recurred; 5- and 8-year disease-free survival rates were 69% and 54%; and overall survival rates were 81% and 72%, respectively. Among these patients, the dura was the most commonly involved site of relapse (8), followed by local (6), regional (5), and distant extracranial (3) sites; and five patients had ≥ two categories of failure. Eight-year dural disease-free survival was 57% versus 90% (P = 0.017) and 0% versus 87% (P

Objective The rising incidence of oral tongue squamous cell carcinoma (OTSCC) in patients who have never smoked and the paucity of knowledge of its biological behavior prompted us to develop a new cell line originating from a never-smoker. Materials and methods Fresh tumor tissue of keratinizing OTSCC was collected from a 44-year-old woman who had never smoked. Serum-free media with a low calcium concentration were used in cell culture, and a multifaceted approach was taken to verify and characterize the cell line, designated UCSF-OT-1109. Results UCSF-OT-1109 was authenticated by STR DNA fingerprint analysis, presence of an epithelial marker EpCAM, absence of human papilloma virus (HPV) DNA, and SCC-specific microscopic appearance. Sphere-forming assays supported its tumorigenic potential. Spectral karyotype (SKY) analysis revealed numerical and structural chromosomal abnormalities. Whole-exome sequencing (WES) identified 46 non-synonymous and 13 synonymous somatic single-nucleotide polymorphisms (SNPs) and one frameshift deletion in the coding regions. Specifically, mutations of CDKN2A, TP53, SPTBN5, NOTCH2, and FAM136A were found in the databases. Copy number aberration (CNA) analysis revealed that the cell line loses chromosome 3p and 9p, but lacks amplification of 3q and 11q (as does HPV-negative, smoking-unrelated OTSCC). It also exhibits four distinctive focal amplifications in chromosome 19p, containing 131 genes without SNPs. Particularly, 52 genes showed >3- to 4-fold amplification and could be potential oncogenic drivers. Conclusion We have successfully established a novel OTSCC cell line from a never-smoking patient. UCSF-OT-1109 is potentially a robust experimental model of OTSCC in never-smokers.

To compare the outcomes of Sinonasal Mucosal Melanomas (SNMM) treated with endoscopic and open resection.A retrospective case review of 20 patients with SNMM treated surgically at UCSF. Kaplan-Meier analyses were calculated to determine outcome differences in endoscopic vs. open resections.From 2005 to 2014, 20 cases of SNMM were confirmed and treated at UCSF. All cases underwent surgical resection, with 10 cases by open resection and 10 cases by endoscopic resection. Using Kaplan-Meier analyses, the open resection group had a 1-year survival of 30% whereas endoscopic resection group was 80% (p = 0.032). Endoscopic resection showed improved survival at all time points after surgery compared to open resection.SNMM is a rare and aggressive tumor that is associated with low survival rates. In this small case series, endoscopic resection had improved survival outcomes compared to open resection.

The escalating incidence of squamous cell carcinoma of the oropharynx and base of the tongue (OPC) is associated with remote exposure to hrHPV and thereby indicates that the increasing numbers of these cancers will be seen in the clinical setting. HPV status in OPC impacts a range of clinical factors including primary site determination, extent of surgery, adjuvant treatment, and prognosis. Thus, accurate and reproducible methods to determine HPV status will be needed for an increasing volume of patients. For OPC, p16 is now considered to be a reliable surrogate for detection of hrHPV, but its use will likely wane as molecular testing such as in situ hybridization becomes more widespread and laboratories become more comfortable with application and interpretation of these methodologies.

Background Thyroid-stimulating hormone (TSH)-secreting pituitary adenomas are rare, accounting for up to 3% of all pituitary tumors. Ectopic TSH-secreting tumors are even rarer and can be difficult to detect. We report the first use of 68Gallium (Ga)-DOTA-TATE PET/CT to diagnose an ectopic TSH-secreting tumor located in the nasopharynx. Clinical case A 48-year-old woman presented to clinic for evaluation of hyperthyroidism. Three years prior to presentation, the patient complained of typical hyperthyroid symptoms. Thyroid function tests showed TSH 3.57 uIU/ml (ref 0.34-4.82); fT4 2.37 ng/dL (0.76-1.8); TT4 24 ug/dL (4.7-13.3); fT3 5.18 pg/mL (2.3-4.2); TT3 260 ng/dL (87-167). Over the next three years, she had persistently elevated T4 and T3 with normal TSH, despite treatment with thionamides. A RAIU scan showed diffuse thyroid gland uptake without any evidence of a focal hyper- or hypofunctioning nodule and a thyroid ultrasound revealed heterogeneous echogenicity and a 1.9 x 0.8 x 1.3 cm hypoechoic solid nodule within the isthmus. On her initial evaluation, physical examination was notable for an enlarged thyroid gland and resting tremor in bilateral hands. Thyroid function tests remained similar to prior; Tg antibodies

BACKGROUND Human papillomavirus (HPV) is a well-established prognostic marker for oropharyngeal squamous cell cancer (OPSCC). Because of the limited numbers of women and nonwhites in studies to date, sex and racial/ethnic differences in prognosis have not been well explored. In this study, survival differences were explored by the tumor HPV status among 1) patients with OPSCCs by sex and race and 2) patients with nonoropharyngeal (non-OP) head and neck squamous cell cancers (HNSCCs). METHODS This retrospective, multi-institution study included OPSCCs and non-OP HNSCCs of the oral cavity, larynx, and nasopharynx diagnosed from 1995 to 2012. Race/ethnicity was categorized as white non-Hispanic, black non-Hispanic, Asian non-Hispanic, and Hispanic of any race. Tumors were centrally tested for p16 overexpression and the presence of HPV by HPV16 DNA and high-risk HPV E6/E7 messenger RNA in situ hybridization. Kaplan-Meier and Cox proportional hazards models were used to evaluate overall survival (OS). RESULTS The study population included 239 patients with OPSCC and 621 patients with non-OP HNSCC with a median follow-up time of 3.5 years. After adjustments for the tumor HPV status, age, current tobacco use, and stage, the risk of death was lower for women versus men with OPSCC (adjusted hazard ratio, 0.55; P = .04). The results were similar with p16. In contrast, for non-OP HNSCCs, HPV positivity, p16 positivity, and sex were not associated with OS. CONCLUSIONS For OPSCC, there are differences in survival by sex, even after the tumor HPV status has been taken into account. For non-OP HNSCC, the HPV status and the p16 status are not of prognostic significance. Cancer 2017;123:1566–1575. © 2017 American Cancer Society.

PurposeRadiofrequency ablation (RFA) effectively treats esophageal high-grade dysplasia, but its efficacy in treating anal canal high-grade squamous intraepithelial lesions (HSILs) is unsubstantiated. This prospective study assessed the safety and efficacy of applying hemi-circumferential RFA to anal canal HSIL.MethodsTwenty-one HIV-negative participants with HSIL occupying ≤half the anal canal circumference were treated with hemi-circumferential anal canal RFA. Participants were assessed every 3months for 12months with high-resolution anoscopy; recurrence in the treatment zone was re-treated with focal RFA.ResultsTwenty-one participants with a mean of 1.7 lesions (range 1-4) enrolled and completed the trial. Six (29%) participants had recurrent HSIL within the treated hemi-circumference within 1year. Four participants (19%) had persistence of an index lesion at 3months. One (2.9%) index HSIL persisted again at 12months. No participants had more than two RFA treatments. KM curve-predicted HSIL-free survival within the treatment zone at 1year was 76% (95% CI 52-89%). Comparing the first 7 and last 14 participants, the predicted 1-year HSIL-free survivals are 43% (95% CI 10-73%) and 93% (95% CI 59-99%), respectively (p=0.008), suggesting a learning curve with the treating physician. Multivariable analysis showed decreased recurrence in the last 14 participants (HR 0.02; 95% CI 0.001-0.63) while increasing BMI increased recurrence (HR 1.43, 95% CI 1.01-2.01). No participants had device or procedure-related serious adverse events, anal stricture, or heavy bleeding.ConclusionsHemi-circumferential RFA yielded a high rate of anal HSIL eradication in HIV-negative patients at 1year with minimal adverse events. Lesion persistence was probably related to incomplete initial ablation.

Background Ectopic thyroid-secreting hormone (TSH)–secreting pituitary adenomas are rare, with only 9 cases reported in the literature. Case Description We describe a case of an ectopic TSH-secreting pituitary adenoma located in the nasopharynx in a patient initially presenting with signs and symptoms of hyperthyroidism that persisted despite treatment with antithyroid medications. Magnetic resonance imaging of the pituitary gland was normal, although subsequent review by a neuroradiologist revealed a nodule attached to the posterior septum in the nasopharynx that was, in retrospect, seen on several other magnetic resonance imaging scans. Gallium 68 (68Ga) DOTATATE positron emission tomography/computed tomography showed increased uptake in the nasopharyngeal nodule. The patient underwent resection of the nasopharyngeal mass with remission of hyperthyroidism. On pathology, the resected mass stained positive for TSH and prolactin. Conclusions This is the first report of use of 68Ga-DOTATATE positron emission tomography/computed tomography to aid in localizing an ectopic TSH-secreting tumor. Prior studies have shown that 68Ga-DOTATATE positron emission tomography/computed tomography improves detection of small lesions with shorter imaging times and lower radiation doses compared with other modalities. Our case emphasizes the importance of using 68Ga-DOTATATE PET/CT in the diagnosis of ectopic pituitary adenomas, as these tumors can be challenging to diagnose radiographically.

Author(s): Goldstone, Stephen E; Lensing, Shelly Y; Stier, Elizabeth A; Darragh, Teresa; Lee, Jeannette Y; van Zante, Annemieke; Jay, Naomi; Berry-Lawhorn, J Michael; Cranston, Ross D; Mitsuyasu, Ronald; Aboulafia, David; Palefsky, Joel M; Wilkin, Timothy | Abstract: BackgroundAnal high-grade squamous intraepithelial lesions (HSILs) ablation may reduce the incidence of invasive cancer, but few data exist on treatment efficacy and natural regression without treatment.MethodsAn open-label, randomized, multisite clinical trial of human immunodeficiency virus (HIV)-infected adults aged ≥27 years with 1-3 biopsy-proven anal HSILs (index HSILs) without prior history of HSIL treatment with infrared coagulation (IRC). Participants were randomized 1:1 to HSIL ablation with IRC (treatment) or no treatment (active monitoring [AM]). Participants were followed every 3 months with high-resolution anoscopy. Treatment participants underwent anal biopsies of suspected new or recurrent HSILs. The AM participants underwent biopsies only at month 12. The primary end point was complete clearance of index HSIL at month 12.ResultsWe randomized 120 participants. Complete index HSIL clearance occurred more frequently in the treatment group than in the AM (62% vs 30%; risk difference, 32%; 95% confidence interval [CI], 13%-48%; P l .001). Complete or partial clearance (clearance of ≥1 index HSIL) occurred more commonly in the treatment group (82% vs 47%; risk difference, 35%; 95% CI, 16%-50%; P l .001). Having a single index lesion, compared with having 2-3 lesions, was significantly associated with complete clearance (relative risk, 1.96; 95% CI, 1.22-3.10). The most common adverse events related to treatment were mild or moderate anal pain and bleeding. No serious adverse events were deemed related to treatment or study participation.ConclusionIRC ablation of anal HSILs results in more clearance of HSILs than observation alone.

Background Management of locoregional recurrence (LRR) and distant metastasis (DM) in adenoid cystic carcinoma (ACC) is guided by limited data. We investigated mortality risks in patients diagnosed and treated for recurrent ACC. Methods A retrospective review of ACC patients treated from 1989 to 2016 identified 36 patients with LRR or DM. High-risk disease was defined as skull base involvement (for LRR) or International Registry of Lung Metastases Group III/IV or extrapulmonary site of metastasis (for DM). Kaplan-Meier method, log-rank tests, and Cox proportional hazards were used for time-to-event analysis. Results Among 20 LRR and 16 DM patients, the median times to recurrence were 51 and 50 months, respectively. The median follow-up post-recurrence was 37.5 months (interquartile range (IQR)16.5–56.5). Post-recurrence 3-year overall survival (OS) was 78.5%, 73.3% for LRR and 85.1% for DM (p = 0.62). High-risk recurrences were associated with worse 3-year OS (68.8% for high-risk and 92.3% for low-risk, χ2 = 10.4, p = 0.001). Among LRR patients, 90% had surgery as part of their treatment. Multimodality therapy, age, and histopathologic features (size, margins, solid histology, lymphovascular or perineural invasion) were not associated with PFS or OS. High-risk LRR was the only variable associated with OS (χ2 = 5.9, p = 0.01). Among DM patients, six were initially managed with observation and ten received surgery, RT, or systemic therapy. Upfront therapy was not associated with improved PFS or OS. High-risk DM was the only variable associated with OS (χ2 = 4.7, p = 0.03). Conclusions High-risk LRR and DM were associated with decreased 3-year OS. More effective therapies are needed for high-risk ACC recurrences.

Oncocytic lipoadenoma is an extremely rare benign salivary gland tumor with few reported cases. We provide a comprehensive description of key radiographic features suggesting the diagnosis of oncocytic lipoadenoma and review its clinical and pathologic features. We present a case of a 70-year-old woman with a slowly enlarging submandibular mass. Magnetic resonance imaging showed a heterogeneous fat-containing lesion without aggressive features. The solid components enhanced with gadolinium. Fine needle aspiration biopsy showed oncocytic cells. After surgical resection, histology showed a well-encapsulated mass with a mixture of oncocytes and adipocytes consistent with oncocytic lipoadenoma. While the usual differential diagnosis of oncocytes in a salivary gland aspirate includes oncocytoma, Warthin’s tumor, oncocytic carcinoma, and oncocytic metaplasia/hyperplasia, specific radiographic features on MRI of a well-circumscribed soft tissue and fat-containing mass, can direct preoperative diagnosis a...

Adenoid cystic carcinoma (ACC) can arise in several organs, and prognosis is highly dependent on the primary tumor site. Primary cutaneous ACC has an excellent prognosis compared with salivary or lacrimal ACC. Activation of MYB by gene fusion or other mechanisms has been found in salivary, breast, and lacrimal ACCs but has not been described in cutaneous ACC. We analyzed the histopathologic and immunohistochemical features of 19 primary cutaneous ACCs, 2 periorbital ACCs, and 12 salivary gland ACCs and assessed for MYB activation in primary cutaneous ACC by immunohistochemistry and molecular methods. The presence of perineural invasion differed significantly among ACCs of various sites (83% salivary, 50% eyelid, 11% skin, P=0.0002). Over 90% of all ACCs were grade 1 or 2 and exhibited diffuse (>50%) positivity with CD117, SOX-10, and smooth muscle actin immunostains. CK15 and vimentin showed diffuse positivity in 36% and 57% of cutaneous ACCs, respectively, and were negative or only focally positive in all salivary ACCs (P=0.04 and 0.002). Six of the 11 cutaneous and periorbital ACCs tested with reverse transcriptase polymerase chain reaction and/or fluorescence in situ hybridization had MYB rearrangements including 2 cases that expressed MYB-NFIB fusion transcripts. Diffuse expression of MYB protein assessed by immunostaining was present in 8 of 9 cutaneous ACCs, including cases both with and without MYB rearrangements. These results indicate that cutaneous ACCs possess the same types of MYB alterations as ACCs of other anatomic sites. Vimentin and CK15 appear to have some discriminatory value in differentiating between primary cutaneous and salivary gland ACCs.

To quantify the rate of late intracranial recurrences among esthesioneuroblastoma patients treated with surgical resection and postoperative radiation.Retrospective review.All patients receiving definitive-intent therapy for esthesioneuroblastoma between March 1995 and September 2015 were reviewed. Presenting disease extent was categorized based on radiologic, operative, and pathologic findings. Between-group survival differences were assessed using Kaplan-Meier method and log-rank test. Multivariate analyses were performed using Cox proportional hazards model.Of 38 patients initially treated at our institution, 53% (20 of 38) presented with intracranial extension. At a median follow-up of 90 months (range, 6-199), 37% (14 of 38) recurred; 5- and 8-year disease-free survival rates were 69% and 54%; and overall survival rates were 81% and 72%, respectively. Among these patients, the dura was the most commonly involved site of relapse (8), followed by local (6), regional (5), and distant extracranial (3) sites; and five patients had ≥ two categories of failure. Eight-year dural disease-free survival was 57% versus 90% (P = 0.017) and 0% versus 87% (P 0.0001), with and without intracranial extension and subtotal resection, respectively. Of six patients treated at recurrence, five (83%) experienced dural-based failure such that, among all 44 patients, 13 (65%) of 20 recurrences involved the dura. After dural recurrence, the median survival time was 42 months (range, 12-125); salvage treatments were effective in rare cases of isolated low-volume recurrence.Esthesioneuroblastoma patients presenting with intracranial extension are at substantial and unique risk for long-term dural-based relapse.4. Laryngoscope, 128:2226-2233, 2018.

The incidence of oropharyngeal squamous cell carcinoma (OPSCC) is increasing among older adults. It is unknown whether these trends can be explained by human papillomavirus (HPV) and whether HPV-related tumors remain associated with an improved prognosis among older patients.In a retrospective study of OPSCCs diagnosed from 1995 to 2013 at 2 National Comprehensive Cancer Network-designated cancer centers, p16 immunohistochemistry and in situ hybridization (ISH) for HPV-16, high-risk DNA, and/or E6/E7 RNA were performed. The median age at diagnosis was compared by p16 and ISH tumor status. Trends in age were analyzed with nonparametric trends. Survival was analyzed with the Kaplan-Meier method and Cox proportional hazards models.Among 239 patients, 144 (60%) were p16-positive. During 1998-2013, the median age increased among p16-positive patients (PThe median age at diagnosis for HPV-related OPSCC is increasing as the proportion of OPSCCs caused by HPV rises among older adults. The favorable survival conferred by an HPV-positive tumor status persists in older adults. Cancer 2018;124:2993-9. © 2018 American Cancer Society.

BACKGROUND Treatment for squamous cell carcinoma (SCC) of unknown primary consists of radiotherapy (RT) +/- chemotherapy or neck dissection +/- adjuvant RT/chemoradiotherapy (CRT). We compared these strategies and identified prognostic factors. METHODS From 1993 to 2015, 75 patients with SCC of unknown primary had RT-based or surgery-based treatment. Primary endpoints were overall survival (OS) and disease-free survival (DFS). Event-time distributions were estimated using the Kaplan-Meier method. RESULTS Five-year OS and DFS for RT-based and surgery-based treatments were similar (OS 73% vs 68%, respectively; DFS 65% vs 64%, respectively). Among 38 patients with p16 data, 76% were p16 positive and showed improved 5-year DFS (90% vs 33%; P = .001) and OS (96% vs 33%; P < .001). Smoking history ≤10 pack-years conferred better 5-year DFS (88% vs 49%; P < .001) and OS (91% vs 59%; P < .001). CONCLUSION RT-based and surgery-based treatments produced similar outcomes. Patients with p16-positive disease with ≤10 pack-years of smoking history and limited nodal stage constitute a "low-risk" group in SCC of unknown primary similar to that in oropharyngeal cancer.

Fine needle aspiration (FNA) biopsy is a useful diagnostic tool in the management of salivary gland pathology. FNA cytology for salivary disease can influence management decisions and inform counseling on therapeutic options. Compared to other forms of biopsy, FNA is simple, cost-effective, and safe while providing rapid information (Majewski et al. J Med Genet 48:580–589, 2011; Service Science 311:1544–1546, 2006). However, the large number of benign and malignant salivary tumors and inflammatory diseases with potential overlapping morphologies makes salivary cytology particularly challenging. There is a relative paucity of specific immunohistochemical stains and readily available molecular markers to accurately subtype salivary gland neoplasms. These factors can confound even experienced cytopathologists. Thus, both the imperfect accuracy of cytologic analysis and the confidence level of the pathologist need to be considered in the context of the clinical and imaging findings prior to any surgical intervention. This chapter explores the technique, utility, and limitations associated with FNA of salivary glands.

Objectives/Hypothesis To determine the incidence and clinical significance of TP53 and CDKN2a somatic mutations in never smokers with oral tongue squamous cell carcinoma (OTSCC). Study Design Case series. Methods Fifty-one paraffin-embedded tumors from never smokers with OTSCC were obtained. p53 and p16 expression was determined by immunohistochemical (IHC) staining. Tumor DNA was amplified by polymerase chain reaction, and direct sequencing and mutation analysis was performed. Statistical relationships among p53 and p16 IHC findings, TP53 and CDKN2a mutation status, and clinicopathologic characteristics were determined. Univariate and multivariate Cox models for survival were performed. Results Sixteen tumors (31.4%) showed strong expression of p53 by IHC. There was no correlation between p53 status and clinicopathologic variables or survival outcomes. TP53 mutations were seen in 10 tumors (19.6%). Patients with TP53 mutations had higher tumor-node-metastasis (TNM) stage (P = 0.049), worse tumor differentiation (P = 0.025), earlier recurrence (P = 0.024), and more often died from their disease (P = 0.043) than those without mutations. Five tumors (9.8%) showed p16 positivity by IHC. There was no correlation between p16 status and clinicopathologic variables or survival. CDKN2a mutations were seen in four tumors (7.8%). Patients with CDKN2a mutations had earlier recurrence (P = 0.019) and more often died from their disease (P = 0.010) than those without mutations. Kaplan-Meier curves show worse disease-free survival (P = 0.0162, P = 0.0025) and overall survival (P = 0.0095, P = 0.0001) for TP53 and CDKN2a mutations, respectively. Multivariate analysis demonstrated that TP53 and CDKN2a mutations were independent predictors of disease-free survival (P = 0.038 and P = 0.039, respectively). Conclusions TP53 and CDKN2a mutations in never-smoker OTSCC are associated with worse clinicopathologic characteristics and poorer survival outcomes. Level of Evidence N/A. Laryngoscope, 124:E267–E273, 2014