Faculty Bibliography

PURPOSE/OBJECTIVE(S): Lacrimal gland cancer is a rare tumor with little data regarding outcomes and optimal management. We performed a large database analysis using the National Cancer Database (NC

PURPOSE/OBJECTIVE(S): Remote training programs have been shown as a cost-effective way to bridge education and training gaps for radiation oncology providers in low- and middle-income countries (LMICs) and could be used to improve contouring skill. Given the expansion of 3D and intensity-modulated radiotherapy and high interest in contouring training in the Philippines, we seek to measure and report the efficacy of a pilot head and neck contouring curriculum. MATERIALS/METHODS: A 13-week, 13-session remote training program on head and neck contouring and plan evaluation was provided at no cost to 8 participating radiation oncology residency programs in the Philippines. The program consisted of weekly 1-hour live video conferencing sessions with interactive didactics and case-based learning through a cloud-based contouring platform. Resident participants were assigned a pre-curriculum and a post-curriculum stage T3N2M0 oropharynx cancer case with 27 OARs. The cases were respectively rated as 2.67/5 and 3.83/5 in difficulty by 6 U.S. educator head and neck radiation oncologists involved in the curriculum. Participants self-rated their confidence in their performance according to a 1-5 Likert scale at the time of each submission regarding three categories: organs at risk (OARs), nodal contouring, and primary target contouring. A team of 4 educators later independently graded contours, according to a 1-5 grading rubric for the same three categories. Cases received 1-2 grades total, which were averaged for analysis. Contour submission was required for a certificate of participation, however no incentives for higher scores were provided.
RESULT(S): 41 residents in the Philippines (10 R1, 12 R2, 11 R3, and 9 R4) participated in the curriculum. Average participation per session was 26 (range 12-39, SD=7.2). 26 (63.4%) participants completed pre-contours for evaluation and 17 (41.5%) post-contours for evaluation. Of these, 14 participants were eligible for paired pre- vs. post-curriculum analysis. Paired pre- and post-curriculum confidence scores (out of 5) were 3.0 and 3.77 for OARs (P=0.003), 3.08 and 3.54 for nodal stations (P=0.056), and 2.85 and 3.31 for primary target contouring (P=0.027), respectively. Overall confidence in contouring the assigned case rose from 2.85 to 3.54 (P < 0.001). Paired pre- and post-curriculum educator grades were 2.96 and 3.38 for OARs (P=0.135), 2.61 and 1.96 for nodal coverage (P=0.019), and 2.54 and 2.73 for primary target contours (P=0.292), respectively. Qualitative observations included greater participant uniformity of left and right parotid glands.
CONCLUSION(S): Longitudinal telehealth training integrating cloud-based tools for radiation oncology professionals is a viable and scalable method for providing head and neck contouring education in a LMIC setting. Our findings suggest that work remains to assess the concordance of confidence with performance, especially in challenging cases, and that further contouring education is needed in LMIC regions.
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Introduction: The prognostic significance of a singular RAS mutation in cytologically indeterminate thyroid nodules (ITN) is unclear. This study aimed to analyze the incidence of malignancy and clinical outcomes of ITNs diagnosed on fine needle aspiration (FNA) cytology with RAS mutations.
Method(s): All FNA ITNs that underwent ThyroSeq testing and thyroidectomy from 2014-2018 were reviewed. ITNs with RAS (N-, H-, or K-RAS) mutations identified on ThyroSeq testing were selected. Demographics, Bethesda classifications, genomic profiles, treatment, final pathology, and clinical outcomes were recorded.
Result(s): During the study period, 93 patients with cytologic diagnosis of ITN and RAS mutations were identified. The mean nodule size was 2.2 cm (range: 0.5-6.6 cm). Most nodules were classified as Bethesda III (77, 82.8%). NRAS mutations were the most common (53, 57%), followed by HRAS (24, 25.8%), and KRAS (16, 17.2%). The majority of patients were treated with thyroid lobectomy (67, 72%). On final pathology, 9 (10%) were diagnosed as malignant (follicular variant of papillary thyroid carcinoma [FVPTC]) and were distributed among all 3 RAS variants (NRAS: 4 [7.5%]; HRAS: 4 [16.7%]; KRAS: 1 [6.3%]; p=0.4). Most FVPTCs were encapsulated (8, 88.9%). With a median follow up of 19 months (interquartile range = 8-35), no recurrences or progression was seen.
Conclusion(s): The risk of malignancy in ITNs with singular RAS mutations is low. All malignancies were low-risk. Our findings demonstrate a low incidence of high-risk malignancy in ITNs with RAS mutations, suggesting that initial management with conservative approaches such as thyroid lobectomy may be justified.
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Introduction: Thyroidectomy is commonly performed in otolaryngology. Complications such as recurrent laryngeal nerve (RLN) injury and severe hypocalcemia have reported incidences in national studies as high as 3% and 8%, respectively. Narcotic pain medications are commonly used for postoperative pain management. Here, we present the long-term results of a thyroidectomy quality and safety improvement program, with an emphasis on reducing narcotic use.
Method(s): All surgeons who perform thyroidectomy established standards for antibiotic administration, postoperative calcium management, and narcotics use. The program was established in 2018 and data on adverse events, length of stay, antibiotic and narcotic use were recorded prospectively from June 2018 to January 2021. Data trends were analyzed throughout the course of the study.
Result(s): During the study period, 542 thyroidectomies were performed by 14 surgeons. The average length of stay was less than 24 hours. Five (0.9%) adverse events were recorded: 1 (0.2%) temporary RLN dysfunction, 3 (0.6%) hematomas, 1 (0.2%) surgical site infection, and 1 (0.2%) temporary hypocalcemia. The average number of narcotics prescribed declined from 18 doses (95%CI: 16.8-18.5) in 2019 to 9 in 2020 (95%CI: 8.5-9.6) (p<0.0001), without an increase in need for refills. No instances of permanent hypocalcemia or permanent RLN injury were identified.
Conclusion(s): By implementing a thyroidectomy quality improvement program, we achieved extremely low rates of adverse events and significantly reduced the use of narcotics without adverse effects. These data can inform practitioners and the public about expected outcomes of thyroid surgery, and establish benchmarks for quality and safety.
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Introduction: Molecular tests such as ThyroSeq are recommended in the workup of cytologically indeterminate thyroid nodules (ITN). While repeat molecular testing is often performed after repeat fine needle aspiration (FNA) yields persistently indeterminate cytology, ThyroSeq's inter-test reliability is unclear. We assessed consistency of initial and repeat ThyroSeq analyses performed on samples from the same thyroid nodules.
Method(s): All thyroid nodules diagnosed as ITN on consecutive FNAs that received ThyroSeq with both biopsies from 2014-2018 at our institution, were reviewed. Initial analysis was ThyroSeq v2 while repeat was v2 or v3. Nodules with gene mutations, fusions, or copy number alterations (CNA) were considered ThyroSeq-positive.
Result(s): During the study period, 30 patients underwent ThyroSeq analysis on initial and repeat FNA samples (median interval=21 months). On initial testing, 27 (90%) nodules were ThyroSeq-negative and 3 (10%) low-risk mutations (RAS, EIF1AX, TSHR) were identified. Repeat ThyroSeq re-identified these 3 nodules and also interpreted 9 initially ThyroSeq-negative nodules as positive (kappa=0.286). All 9 molecular alterations were low-risk, most were identified on v3 (7, 77.8%), and CNA was the most common change (6, 66.7%). Of 12 patients with ThyroSeq-positive nodules, 8 underwent lobectomy. Final pathology identified low-risk malignancy in 3 nodules; the remainder were benign.
Conclusion(s): New findings on repeat ThyroSeq are possible. Whether these findings were detected by expanded panel or are the result of de-novo changes is unknown. The risk of missing high-risk changes appears to be low. More studies are needed to characterize the concordance of ThyroSeq analyses and natural evolution of ITNs.
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INTRODUCTION/BACKGROUND:There is no consensus for interpretation of p16 immunohistochemistry (IHC) in cytology preparations. Our study aims to assess p16 IHC staining in formalin-fixed cytology cell blocks (CBs) from head and neck squamous cell carcinoma (HNSCC) fine-needle aspiration (FNA) specimens in comparison with surgical pathology p16 staining and to determine the reproducibility of p16 IHC scoring in CBs. METHODS:) was calculated to assess inter-rater reliability. RESULTS:= 0.79 (95% CI: 0.61-0.98). CONCLUSION/CONCLUSIONS:p16 IHC performed on cytology CBs can serve as a surrogate marker for the detection of HPV with high sensitivity and specificity levels. Using a threshold lower than that recommended for surgical pathology for the interpretation of p16 positivity may be appropriate for FNA cytology CB preparations. All cytopathologists in our study displayed reproducible high sensitivity and specificity values at the >10% threshold.

Large-scale molecular profiling studies in recent years have shown that central nervous system (CNS) tumors display a much greater heterogeneity in terms of molecularly distinct entities, cellular origins and genetic drivers than anticipated from histological assessment. DNA methylation profiling has emerged as a useful tool for robust tumor classification, providing new insights into these heterogeneous molecular classes. This is particularly true for rare CNS tumors with a broad morphological spectrum, which are not possible to assign as separate entities based on histological similarity alone. Here, we describe a molecularly distinct subset of predominantly pediatric CNS neoplasms (n = 60) that harbor PATZ1 fusions. The original histological diagnoses of these tumors covered a wide spectrum of tumor types and malignancy grades. While the single most common diagnosis was glioblastoma (GBM), clinical data of the PATZ1-fused tumors showed a better prognosis than typical GBM, despite frequent relapses. RNA sequencing revealed recurrent MN1:PATZ1 or EWSR1:PATZ1 fusions related to (often extensive) copy number variations on chromosome 22, where PATZ1 and the two fusion partners are located. These fusions have individually been reported in a number of glial/glioneuronal tumors, as well as extracranial sarcomas. We show here that they are more common than previously acknowledged, and together define a biologically distinct CNS tumor type with high expression of neural development markers such as PAX2, GATA2 and IGF2. Drug screening performed on the MN1:PATZ1 fusion-bearing KS-1 brain tumor cell line revealed preliminary candidates for further study. In summary, PATZ1 fusions define a molecular class of histologically polyphenotypic neuroepithelial tumors, which show an intermediate prognosis under current treatment regimens.

OBJECTIVES:Sinonasal mucosal melanoma (SNMM) is an aggressive cancer usually managed with surgical resection. This study evaluates the impact of treatment modality and positive surgical margin (PSM) on survival following resection of SNMM. STUDY DESIGN:Retrospective study of a national cancer registry. METHODS:The National Cancer Database was queried for cases of SNMM from 2010 to 2015. Data regarding patient demographics, tumor staging, and treatment modality were obtained. Survival rates were compared by margin status: PSM, negative (NSM), and no operation (0SM) using Kaplan-Meier analysis and log rank test. RESULTS:A total of 446 patients met inclusion criteria. Most cases were elderly (>66 years-old) (67.3%), female (54.3%), and white (89.5%). Cases of SNMM most commonly involved the nasal cavity (81.6%), were Stage 3 (60.0%), and underwent surgical resection at an academic center (65.0%). NSM and PSM were present in 59.0% and 26.9% of cases, respectively, while 14.1% of cases did not undergo surgical resection (0SM). Factors predictive of PSM included resection at a community hospital (OR 2.47) and Stage 4 disease (OR 2.07). The 2-year survival rates were 72.1% (95% CI 69.4-75.4%), 36.3% (95% CI 22.0-48.9), and 16.0% (95% CI 8.2-25.4%) for NSM, PSM and 0SM, respectively. Survival was statistically significant between NSM and PSM (Log rank <0.001) but not between 0SM and PSM (Log rank = 0.062). CONCLUSION:Our study emphasizes the need for NSM for SNMM as PSM did not demonstrate any significant improvement in survival when compared to 0SM. Our findings suggest that cases of SNMM are best managed at academic centers. LEVEL OF EVIDENCE:4 Laryngoscope, 131:2429-2435, 2021.

In contrast to adults, meningiomas are uncommon tumors in childhood and adolescence. Whether adult and pediatric meningiomas differ on a molecular level is unclear. Here we report detailed genomic analyses of 37 pediatric meningiomas by sequencing and DNA methylation profiling. Histologically, the series was dominated by meningioma subtypes with aggressive behavior, with 70% of patients suffering from WHO grade II or III meningiomas. The most frequent cytogenetic aberrations were loss of chromosomes 22 (23/37 [62%]), 1 (9/37 [24%]), 18 (7/37 [19%]), and 14 (5/37 [14%]). Tumors with NF2 alterations exhibited overall increased chromosomal instability. Unsupervised clustering of DNA methylation profiles revealed separation into three groups: designated group 1 composed of clear cell and papillary meningiomas, whereas group 2A comprised predominantly atypical meningiomas and group 2B enriched for rare high-grade subtypes (rhabdoid, chordoid). Meningiomas from NF2 patients clustered exclusively within groups 1 and 2A. When compared with a dataset of 105 adult meningiomas, the pediatric meningiomas largely grouped separately. Targeted panel DNA sequencing of 34 tumors revealed frequent NF2 alterations, while other typical alterations found in adult non-NF2 tumors were absent. These data demonstrate that pediatric meningiomas are characterized by molecular features distinct from adult tumors.

Oral potentially malignant disorders (OPMDs) are associated with an increased risk of occurrence of cancers of the lip or oral cavity. This paper presents an updated report on the nomenclature and the classification of OPMDs, based predominantly on their clinical features, following discussions by an expert group at a workshop held by the World Health Organization (WHO) Collaborating Centre for Oral Cancer in the UK. The first workshop held in London in 2005 considered a wide spectrum of disorders under the term "potentially malignant disorders of the oral mucosa" (PMD) (now referred to as oral potentially malignant disorders: OPMD) including leukoplakia, erythroplakia, proliferative verrucous leukoplakia, oral lichen planus, oral submucous fibrosis, palatal lesions in reverse smokers, lupus erythematosus, epidermolysis bullosa, and dyskeratosis congenita. Any new evidence published in the intervening period was considered to make essential changes to the 2007 classification. In the current update, most entities were retained with minor changes to their definition. There is sufficient evidence for an increased risk of oral cancer among patients diagnosed with "oral lichenoid lesions" and among those diagnosed with oral manifestations of 'chronic graft-versus-host disease'. These have now been added to the list of OPMDs. There is, to date, insufficient evidence concerning the malignant potential of chronic hyperplastic candidosis and of oral exophytic verrucous hyperplasia to consider these conditions as OPMDs. Furthermore, due to lack of clear evidence of an OPMD in epidermolysis bullosa this was moved to the category with limited evidence. We recommend the establishment of a global research consortium to further study the natural history of OPMDs based on the classification and nomenclature proposed here. This will require multi-center longitudinal studies with uniform diagnostic criteria to improve the identification and cancer risk stratification of patients with OPMDs, link them to evidence-based interventions, with a goal to facilitate the prevention and management of lip and oral cavity cancer.