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Aims: Papillary thyroid carcinoma, tall cell subtype (PTC‐TC) is a potentially aggressive histotype. The latest World Health Organisation (WHO) classification introduced a novel class of tumours; namely, high‐grade differentiated thyroid carcinoma (HGDTC), characterised by elevated mitotic count and/or necrosis, which can exhibit a tall cell phenotype (HGDTC‐TC). Methods and results: We analysed the clinical outcomes in a large retrospective cohort of 1456 consecutive thyroid carcinomas with a tall cell phenotype, including PTC‐TC and HGDTC‐TC. HGDTC‐TC is uncommon, accounting for 5.3% (77 of 1379) of carcinomas with tall cell morphology. HGDTC‐TC was associated with significantly older age, larger tumour size, angioinvasion, gross extrathyroidal extension, higher AJCC pT stage, positive resection margin and nodal metastasis (P < 0.05). Compared with PTC‐TC, HGDTC was associated with a significantly decreased DSS, LRDFS and distant metastasis‐free survival (DMFS; P < 0.001). The 10‐year DSS was 72 and 99%, the 10‐year LRDFS was 61 and 92% and the 10‐year DMFS was 53 and 97%, respectively, for HGDTC‐TC and PTC‐TC. On multivariate analysis, the classification (HGDTC‐TC versus PTC‐TC) was an independent adverse prognostic factor for DSS, LRDF, and DMFS when adjusted for sex, age, angioinvasion, margin status, AJCC pT and pN stage. Conclusions: Compared with PTC‐TC, HGDTC‐TC is associated with adverse clinicopathological features, a higher frequency of TERT promoter mutations (59% in HGDTC‐TC versus 34% in PTC‐TC) and incurs a significantly worse prognosis. HGDTC‐TC is an independent prognostic factor for carcinoma with tall cell morphology. This validates the concept of HGDTC and the importance of tumour necrosis and high mitotic count for accurate diagnosis and prognosis of differentiated thyroid carcinomas. [ABSTRACT FROM AUTHOR]

Aims: Recently, HMGA2::WIF1 fusion has been reported in pleomorphic adenoma (PAs) originating from the parotid gland with a characteristic canalicular adenoma (CAA)‐like pattern. However, it is unclear whether HMGA2::WIF1 fusion may occur in salivary gland carcinoma or tumours originating from the minor salivary glands. We herein conducted a detailed clinicopathological review of eight salivary gland tumours harbouring HMGA2::WIF1 fusions. Methods and results: The reviewed diagnoses of salivary gland neoplasms with HMGA2::WIF1 fusion were PA (n = four), myoepithelioma (n = one), myoepithelial carcinoma ex PA (n = two) and high‐grade carcinoma with basaloid features (n = one). Two tumours originated from the minor salivary glands. Six tumours (80%) contained areas reminiscent of CAA characterised by interconnected trabeculae/canaliculi of monotonous oncocytic or cuboidal tumour cells associated with a hypocellular, hyalinised to myxoid stroma. Areas typical of PA were seen in four (50%) cases. All tumours showed diffuse S100 and CK7 immunopositivity. Adverse events were detected in two cases, including local recurrence in a patient with PA, and local and distant recurrences and disease‐related death in a patient with a high‐grade carcinoma of the minor salivary gland of the buccal space, showing tumour necrosis and perineural invasion. Conclusion: Salivary gland neoplasms with HMGA2::WIF1 fusion are predominantly characterised by CAA/striated duct adenoma‐like histology and a S100+/CK7+ immunoprofile. These tumours are not always benign, as among all reported cases approximately 20% showed malignancy (six of 28) and adverse outcome (three of 15), including recurrence, distant metastasis and disease‐specific mortality. [ABSTRACT FROM AUTHOR]

Aims: The diagnosis of thyroid neoplasms relies upon the demonstration of histological parameters that can be focal and prone to subjective interpretation. We evaluated the utility of NRAS Q61R immunohistochemistry (IHC) in the diagnosis of thyroid lesions after determining its specificity and sensitivity as a surrogate marker for RAS Q61R mutation. Method and results: NRAS Q61R IHC was performed on 282 primary or metastatic thyroid lesions from 256 patients. RAS mutation status was collected from patients' charts. Sensitivity and specificity of NRAS Q61R IHC for detecting a RAS Q61R mutation was calculated. IHC‐positive cases were reviewed to determine the diagnostic utility of NRAS Q61R IHC. NRAS Q61R immunopositivity was seen in non‐neoplastic, benign and malignant thyroid lesions. NRAS Q61R antibody cross‐reactivity led to the detection of NRAS Q61R, KRAS Q61R and HRAS Q61R proteins. Among primary thyroid carcinomas, immunopositivity was most frequent in papillary thyroid carcinomas, follicular variant (48.0%). The sensitivity and specificity of NRAS Q61R IHC in detecting RAS Q61R mutation was 90.6% and 92.3%, respectively. When positive, the NRAS Q61R stain was determined to be helpful in demonstrating infiltration, tumour size, capsular and/or vascular invasion and multifocality. Conclusion: NRAS Q61R IHC is highly sensitive and specific for the detection of RAS Q61R mutations in thyroid pathology and is particularly relevant in follicular‐patterned neoplasms. When evaluated alongside histological features, NRAS Q61R immunoreactivity can be instrumental in the diagnosis and classification of thyroid nodules. [ABSTRACT FROM AUTHOR]

Objective: Polymorphous adenocarcinoma of salivary gland (PAC) is rare. Despite being described as a low risk histology, some patients develop regional and distant metastasis. More aggressive behavior has been attributed to a PAC subcategory called cribriform adenocarcinoma of minor salivary glands (CAMSG). We examined oncological outcomes of PAC.Patients and Methods: Fifty-seven patients with PAC were identified from an institutional database of 884 patients surgically treated for salivary gland malignancies from 1985 to 2015. Detailed histopathological analysis was performed. Survival outcomes were calculated using the Kaplan-Meier method. Factors predictive of recurrence were identified using the Cox proportional hazard method.Results: Fifty-four (95%) had tumors of minor salivary gland origin; the most frequent location was the oral cavity in 41 (76%), specifically the hard palate in 32 (55%). Forty-six patients (81%) were clinical T1-T2; 3 (5%) had a clinically positive neck. Thirty-two patients (56%) were classified as PAC and 14 (25%) as CAMSG. Forty-four patients (77%) had surgery alone; 13 (23%) had surgery and postoperative radiotherapy. The 5- and 10-year overall survival and disease-specific survival were 88% and 79% and 98% and 94%, respectively (median follow up 84 [1-159] months); 5- and 10-year recurrence-free survival were 93% and 88%, respectively. Univariate analysis showed male sex, III/IV stage, and CASMG variant had increased incidence of recurrence but were not statistically significant.Conclusion: PAC of the salivary glands is an indolent disease with good survival outcomes. Recurrence is uncommon and tends to occur late. Long-term follow-up is indicated in patients with this disease. [ABSTRACT FROM AUTHOR]

Aims Pleomorphic adenoma gene 1 ( PLAG1) gene rearrangement is the most common genetic abnormality in pleomorphic adenoma (PA), resulting in overexpression of PLAG1 protein. PA and carcinoma ex pleomorphic adenoma (CA ex-PA) can mimic various benign and malignant salivary gland tumours. The aims of this study are to evaluate the sensitivity and specificity of PLAG1 immunohistochemistry (IHC) in the differential diagnosis of PA and CA ex-PA and to compare the PLAG1 immunohistochemical results to PLAG1 gene abnormalities as detected by fluorescence in-situ hybridisation (FISH). Methods and results PLAG1 immunostaining was performed on 83 salivary gland tumours, including 23 PA, 15 CA ex-PA and 45 other salivary gland tumours. In addition, PLAG1 FISH was performed in 44 cases for the presence of gene rearrangements/amplifications. The results showed high sensitivity of PLAG1 IHC in 96% of PA; however, discordant results between PLAG1 FISH abnormalities and IHC were noted in 15 of 44 cases (34%). Seven PA, four de-novo myoepithelial carcinomas and one basal cell adenocarcinoma had negative FISH results, but were positive for IHC; while three salivary duct carcinomas (SDC) ex-PA were positive for FISH but negative for IHC. PLAG1 IHC can differentiate CA ex-PA from de-novo SDC ( P = 0.02), but not from de-novo myoepithelial carcinoma. PLAG1 IHC is a sensitive marker for PA. This could be due to PLAG1 gene abnormalities beyond FISH resolution. Conclusions A negative PLAG1 IHC might be helpful in excluding a PA diagnosis. Interestingly, in the context of CA ex-PA, FISH is more sensitive than IHC in detecting PLAG1 abnormalities. [ABSTRACT FROM AUTHOR]

Autonomous functioning thyroid nodules (AFTNs) are generally considered to be benign entities, with malignancy found in about 1 per cent considered to be rare in the general population. Because of this low rate, fine needle aspiration is generally not recommended, and these lesions are most often treated with radioactive iodine, medication, or surgery. However, AFTNs are exceedingly rare in the pediatric population and the optimal treatment is not defined. We present a 14-year-old female patient with an AFTN treated with surgical resection and found to contain a follicular carcinoma with capsular invasion. [ABSTRACT FROM AUTHOR]

Aims To compare the different grading systems of mucoepidermoid carcinoma ( MEC) and identify the most reliable and objective histopathologic features predictive of outcome. Methods and results Seventy-two cases diagnosed as MEC were subjected to a meticulous histopathologic re-review. 20 of 72 (28%) cases were originally misdiagnosed as MEC including 16 as high grade ( HG). Among the 52 confirmed MEC, median follow up ( FU) was 59 months. Mitosis (≥4/10 High Power Fields), necrosis, pleomorphism, focal keratinization, desmoplasia, and lymph node metastasis were associated with adverse disease specific survival ( DSS) and recurrence free survival ( RFS) ( P < 0.002). In all grading systems, low and intermediate grade had similar DSS and RFS but much better outcome than HG ( P < 0.007). All patients with tumour harboring low mitotic rate and no necrosis did not recur except for one patient with a positive margin. All cases with high mitotic rate and necrosis died or recurred. Conclusions The majority of previously diagnosed HG MEC cases are misclassified. There is no difference in outcome between low and intermediate grade in all grading schemes. Consideration should be given to stratify MEC based on relatively objective criteria such as mitosis and necrosis. [ABSTRACT FROM AUTHOR]

Context.--Diagnosis of biliary neoplasia can be challenging but is essential for the appropriate clinical management of patients. Therefore, it is important to recognize the morphologic features of the biliary neoplasms to report a correct diagnosis. Objectives.--(1) To discuss the differential diagnosis of dysplasia in the gallbladder and differentiate dysplasia from reactive atypia and invasive carcinoma, (2) review the histologic features of adenoma and polypoid biliary lesions, (3) highlight the differential diagnosis of adenocarcinoma in liver biopsy, and (4) discuss the differential diagnosis of atypical biliary glandular lesions. Data Sources.--Current English literature related to gallbladder and biliary neoplasia. Conclusions.--Biliary glandular neoplasms show a wide spectrum of morphology and have many mimics. Careful examination of the histologic features of these lesions and familiarity with their morphology can help to achieve the correct diagnosis. [ABSTRACT FROM AUTHOR]

Background and aim Methods Results Conclusions Head and neck nuclear protein of testis carcinoma (HN‐NUT) is a rare form of carcinoma diagnosed by NUT immunohistochemistry positivity and/or NUTM1 translocation. Although the prototype of HN‐NUT is a primitive undifferentiated round cell tumour (URC) with immunopositivity for squamous markers, it is our observation that it may assume variant histology or immunoprofile.We conducted a detailed clinicopathological review of a large retrospective cohort of 30 HN‐NUT, aiming to expand its histological and immunohistochemical spectrum.The median age of patients with HN‐NUT was 39 years (range = 17–86). It affected the sinonasal tract (43%), major salivary glands (20%), thyroid (13%), oral cavity (7%), larynx (7%), neck (7%) and nasopharynx (3%). Although most cases of HN‐NUT (63%) contained a component of primitive URC tumour, 53% showed other histological features and 37% lacked a URC component altogether. Variant histological features included basaloid (33%), differentiated squamous/squamoid (37%), clear cell changes (13%), glandular differentiation (7%) and papillary architecture (10%), which could co‐exist. While most HN‐NUT were positive for keratins, p63 and p40, occasional cases (5–9%) were entirely negative. Immunopositivity for neuroendocrine markers and thyroid transcription factor‐1 was observed in 33 and 36% of cases, respectively. The outcome of HN‐NUT was dismal, with a 3‐year disease specific survival of 38%.HN‐NUT can affect individuals across a wide age range and arise from various head and neck sites. It exhibits a diverse spectrum of histological features and may be positive for neuroendocrine markers, potentially leading to underdiagnosis. A low threshold to perform NUT‐specific tests is necessary to accurately diagnose HN‐NUT. [ABSTRACT FROM AUTHOR]

This article explores the growth rate and safety of observing pleomorphic adenomas (PAs) in pregnant patients. The study reveals that PAs in the parotid gland grow at a median rate of 4.6 mm/year, with potential acceleration during pregnancy and the post-partum period. All patients in the study chose to delay surgery until after pregnancy, and there were no significant complications to the mother or fetus. The study also found no evidence of malignant transformation in any of the cases. The authors conclude that pregnant patients with PAs can be safely monitored until surgery is necessary. The article emphasizes the challenges and considerations in managing benign parotid tumors in pregnant patients, highlighting the importance of comprehensive evaluation, quality imaging, and a reassuring cytologic report in determining the need for surgery. [Extracted from the article]

Background: Recurrent/metastatic adenoid cystic carcinoma (ACC) is a rare, incurable disease. MYB is a putative oncogenic driver in ACC that is often overexpressed through an MYB‐NFIB rearrangement. The authors hypothesized that AKT inhibition with the allosteric inhibitor MK‐2206 could decrease MYB expression and induce tumor regression in patients with incurable ACC (ClinicalTrials.gov identifier NCT01604772). Methods: Patients with progressive, incurable ACC were enrolled and received MK‐2206 150 mg weekly; escalation to 200 mg was allowed. The primary end point was confirmed response. Secondary end points were progression‐free survival, overall survival, and safety. An exploratory analysis evaluating the effect of MK‐2206 on MYB expression was conducted in a subset of patients. Results: Sixteen patients were enrolled, and 14 were evaluable for efficacy. No confirmed responses were observed. Thirteen patients had stable disease, and one had disease progression as their best response. The median progression‐free survival was 9.7 months (95% CI, 3.8–11.8 months), and the median overall survival was 18.0 months (95% CI, 11.8–29.9 months). Nine of 16 patients (56%) had at least one grade 3 treatment‐related adverse event, and the most common were rash (38%), fatigue (19%), decreased lymphocyte count (13%), and hyperglycemia (13%). Twelve of 14 tumors (86%) had detectable MYB expression by immunohistochemistry, and seven of 14 tumors (50%) had an MYB‐NFIB gene rearrangement. Serial biopsies revealed decreased MYB levels with MK‐2206 in four of five patients. Conclusions: MK‐2206 failed to induce clinical responses in patients with incurable ACC. AKT inhibition may diminish MYB protein levels, although the effect was highly variable among patients. Novel approaches to target MYB in ACC are needed. This phase 2 clinical trial demonstrated that the AKT inhibitor MK‐2206 failed to induce clinical responses in patients with recurrent/metastatic adenoid cystic carcinoma. Tumor tissue analyses suggest that MK‐2206 treatment may have diminished intratumoral MYB protein levels. [ABSTRACT FROM AUTHOR]

Aims: Oncogenic FGFR1/2/3 rearrangements are found in various cancers. Reported cases in head and neck (HN) are mainly squamous cell carcinomas (SCCs) with FGFR3::TACC3 fusions, a subset of which also harbour high‐risk human papillomavirus (HPV). However, the knowledge of the clinicopathological spectrum of FGFR‐rearranged head and neck carcinomas (FHNC) is limited. Methods and results: A retrospective MSK‐fusion clinical sequencing cohort 2016–23 was searched to identify malignant tumours in the HN region harbouring FGFR1/2/3 fusion. FHNC were characterised by histological examination, immunohistochemistry and molecular analysis. Electronic medical records were reviewed. Three FHNC were identified. Two cases (cases 1 and 2) involved sinonasal tract and were high‐grade carcinomas with squamous, basaloid, glandular and/or ductal–myoepithelial features. Case 1 arose in a 79‐year‐old man and harboured FGFR2::KIF1A fusion. Case 2 arose in a 58‐year‐old man, appeared as HPV‐related multiphenotypic sinonasal carcinoma (HMSC), and was positive for FGFR2::TACC2 fusion and concurrent high‐risk HPV, non‐type 16/18. Case 3 was FGFR3::TACC3 fusion‐positive keratinising SCCs arising in the parotid of a 60‐year‐old man. All three cases presented at stage T4. Clinical follow‐up was available in two cases; case 1 remained disease‐free for 41 months post‐treatment and case 3 died of disease 2 months after the diagnosis. Conclusions: FHNC include a morphological spectrum of carcinomas with squamous features and may occur in different HN locations, such as parotid gland and the sinonasal tract. Sinonasal cases can harbour FGFR2 rearrangement with or without associated high‐risk HPV. Timely recognition of FHNC could help select patients potentially amenable to targeted therapy with FGFR inhibitors. Further studies are needed (1) to determine if FGFR2 rearranged/HPV‐positive sinonasal carcinomas are biologically distinct from HMSC, and (2) to elucidate the biological and clinical significance of FGFR2 rearrangement in the context of high‐risk HPV. [ABSTRACT FROM AUTHOR]

Background: For oral cavity squamous cell carcinoma (OSCC), extent of extranodal extension (ENE) (minor, ≤2 mm; major, >2 mm) is differentially prognostic, whereas limitations exist with the 8th edition of American Joint Committee on Cancer/International Union Against Cancer TNM N‐classification (TNM‐8‐N). Methods: Resected OSCC patients at four centers were included and extent of ENE was recorded. Thresholds for optimal overall survival (OS) discrimination of lymph node (LN) features were established. After dividing into training and validation sets, two new N‐classifications were created using 1) recursive partitioning analysis (RPA), and 2) adjusted hazard ratios (aHRs) and were ranked against TNM‐8‐N and two published proposals. Results: A total of 1460 patients were included (pN0: 696; pN+: 764). Of the pN+ cases, 135 (18%) had bilateral/contralateral LNs; 126 (17%) and 244 (32%) had minor and major ENE, and two (0.3%) had LN(s) >6 cm without ENE (N3a). LN number (1 and >1 vs. 0: aHRs, 1.92 [95% confidence interval (CI), 1.44–2.55] and 3.21 [95% CI, 2.44–4.22]), size (>3 vs. ≤3 cm: aHR, 1.88 [95% CI, 1.44–2.45]), and ENE extent (major vs. minor: aHR, 1.40 [95% CI, 1.05–1.87]) were associated with OS, whereas presence of contralateral LNs was not (aHR, 1.05 [95% CI, 0.81–1.36]). The aHR proposal provided optimal performance with these changes to TNM‐8‐N: 1) stratification of ENE extent, 2) elimination of N2c and 6‐cm threshold, and 3) stratification of N2b by 3 cm threshold. Conclusion: A new N‐classification improved staging performance compared to TNM‐8‐N, by stratifying by ENE extent, eliminating the old N2c category and the 6 cm threshold, and by stratifying multiple nodes by size. There are several limitations in the most recent TNM N classification system including categories with small sample size and categories that have limited prognostic value. The authors proposed and validated a new N classification system that overcomes these limitations and outperforms the previous iteration of TNM. [ABSTRACT FROM AUTHOR]

Aims: The 8th edition of the American Joint Committee on Cancer (AJCC) Staging introduced depth of invasion (DOI) into the pT category of oral cavity squamous cell carcinoma. However, we noted multiple practical obstacles in accurately measuring DOI histologically in our daily practice. Methods and results: To compare the prognostic effects of DOI and tumour thickness (TT), a meticulous pathology review was conducted in a retrospective cohort of 293 patients with AJCC 7th edition pT1/T2 oral tongue squamous cell carcinoma. Overall survival (OS) and nodal metastasis rate at initial resection were the primary and secondary outcomes, respectively. We found that TT and DOI were highly correlated with a correlation coefficient of 0.984. The upstage rate was only 6% (18 of 293 patients) when using TT in the pT stage compared with using DOI. More importantly, DOI and TT, as well as pT stage using DOI and pT stage using TT, performed identically in predicting risk of nodal metastasis and OS. Conclusions: We therefore propose to replace DOI, a complicated measurement with many challenges, with TT in the pT staging system. [ABSTRACT FROM AUTHOR]

Aims: Programmed death‐ligand 1 (PD‐L1) expression by tumour cells (TC) is a mechanism for tumour immune escape through down‐regulation of antitumour T cell responses and is a target for immunotherapy. PD‐L1 status as a predictor of treatment response has led to the development of multiple biomarkers with different reference cut‐offs. We assessed pathologist consistency in evaluating PD‐L1 immunopositivity by examining the inter‐ and intraobserver agreement using various antibody clones and different cancer types. Methods and results: PD‐L1 expression in TC and immune cells (IC) was manually scored in 27 head and neck squamous cell carcinoma (HSCC), 30 urothelial carcinoma (UC) and breast carcinoma (BC) using three commercial clones (SP263, SP142, 22C3) and one platform‐independent test (E1L3N). For interobserver agreement, PD‐L1 status was evaluated blindly by three pathologists. For intraobserver agreement, PD‐L1 expression was re‐evaluated following a wash‐out period. Intraclass correlation coefficient (ICC), overall percentage agreement (OPA) and κ‐values were calculated. Using clinical algorithms, the percentage of PD‐L1‐positive cases in HSCC, BC and UC were 15–81%, 47–67% and 7–43%, respectively. The percentage of PD‐L1 positive cases relied heavily on the algorithm/cut‐off values used. Almost perfect interobserver agreement was achieved using SP263 and E1L3N in HSCC, 22C3, SP142 and E1L3N in BC and 22C3 in UC. The SP142 clone in UC and HSCC showed moderate agreement and was associated with lower ICC and decreased intraobserver concordance. Conclusions: Excellent inter‐ and intraobserver agreement can be achieved using SP263, 22C3 and E1L3N, whereas PD‐L1 scoring using SP142 clone is associated with a higher level of subjectivity. [ABSTRACT FROM AUTHOR]

Aims: Programmed death‐ligand 1 (PD‐L1) expression by tumour cells (TC) is a mechanism for tumour immune escape through down‐regulation of antitumour T cell responses and is a target for immunotherapy. PD‐L1 status as a predictor of treatment response has led to the development of multiple biomarkers with different reference cut‐offs. We assessed pathologist consistency in evaluating PD‐L1 immunopositivity by examining the inter‐ and intraobserver agreement using various antibody clones and different cancer types. Methods and results: PD‐L1 expression in TC and immune cells (IC) was manually scored in 27 head and neck squamous cell carcinoma (HSCC), 30 urothelial carcinoma (UC) and breast carcinoma (BC) using three commercial clones (SP263, SP142, 22C3) and one platform‐independent test (E1L3N). For interobserver agreement, PD‐L1 status was evaluated blindly by three pathologists. For intraobserver agreement, PD‐L1 expression was re‐evaluated following a wash‐out period. Intraclass correlation coefficient (ICC), overall percentage agreement (OPA) and κ‐values were calculated. Using clinical algorithms, the percentage of PD‐L1‐positive cases in HSCC, BC and UC were 15–81%, 47–67% and 7–43%, respectively. The percentage of PD‐L1 positive cases relied heavily on the algorithm/cut‐off values used. Almost perfect interobserver agreement was achieved using SP263 and E1L3N in HSCC, 22C3, SP142 and E1L3N in BC and 22C3 in UC. The SP142 clone in UC and HSCC showed moderate agreement and was associated with lower ICC and decreased intraobserver concordance. Conclusions: Excellent inter‐ and intraobserver agreement can be achieved using SP263, 22C3 and E1L3N, whereas PD‐L1 scoring using SP142 clone is associated with a higher level of subjectivity. [ABSTRACT FROM AUTHOR]

Human papilloma virus (HPV)-related oncogenesis in head and neck cancer establishes a local microenvironment rich with immune cells, however the composition of the microenvironment in recurrent disease following definitive treatment is poorly understood. Here, we investigate the composition and spatial relationships between tumor and immune cells in recurrent head and neck cancer following curative intent chemoradiotherapy. Multiplexed immunofluorescence with 12 unique markers, through two multiplex immunofluorescent panels, was performed to evaluate 27 tumor samples including 18 pre-treatment primary and 9 paired recurrent tumors. Tumor and immune cell populations were phenotyped and quantified using a previously validated semi-automated digital pathology platform for cell segmentation. Spatial analysis was conducted by evaluating immune cells within the tumor, peri-tumoral stroma, and distant stroma. Initial tumors in patients with subsequent recurrence were found to be enriched in tumor associated macrophages and displayed an immune excluded spatial distribution. Recurrent tumors after chemoradiation were hypo-inflamed, with a statistically significant reduction in the recently identified stem-like TCF1+ CD8 T-cells, which normally function to maintain HPV-specific immune responses in the setting of chronic antigen exposure. Our findings indicate that the tumor microenvironment of recurrent HPV-related head and neck cancers displays a reduction in stem-like T cells, consistent with an immune microenvironment with a reduced ability to mount T-cell-driven anti-tumor immune responses. [ABSTRACT FROM AUTHOR]

Simple Summary: Smoking is the commonest cause of oral cavity squamous cell carcinoma (OC-SCC), but the cause of OC-SCC in nonsmokers is unknown. Our primary goal was to use metagenomic shotgun sequencing (MSS) to directly define the taxonomic composition and functional potential of oral metagenome in nonsmokers with OC-SCC. We found three bacterial phyla, one genus, and one species were enriched in OC-SCC while two phyla, five genera, and 18 species were enriched in controls. Pathways related to metabolism of flavin, biotin, thiamine, heme, sugars, fatty acids, peptidoglycans, and tRNA were more abundant in OC-SCC while those related to metabolism of nucleotides and essential amino acids were more abundant in controls. The MSS method achieved similar results to the commonly used 16S rRNA gene survey in compositional differentiation but differed greatly from prediction using 16S rRNA genes in functional differentiation of microbiomes in OC-SCC and controls. Objectives: Smoking is the commonest cause of oral cavity squamous cell carcinoma (OC-SCC), but the etiology of OC-SCC in nonsmokers is unknown. Our primary goal was to use metagenomic shotgun sequencing (MSS) to define the taxonomic composition and functional potential of oral metagenome in nonsmokers with OC-SCC. Methods: We conducted a case–control study with 42 OC-SCC case and 45 control nonsmokers. MSS was performed on DNA extracted from mouthwash samples. Taxonomic analysis and pathway analysis were done using MetaPhlAn2 and HUMAnN2, respectively. Statistical difference was determined using the Mann–Whitney test controlling false discovery rate. Results: There was no significant difference in age, sex, race, or alcohol consumption between OC-SCC and control patients. There was a significant difference in beta diversity between OC-SCC and controls. At the phylum level, Bacteroidetes and Synergistetes were overly represented in OC-SCC while Actinobacteria and Firmicutes were overly represented in controls. At the genus level, Fusobacterium was overly represented in OC-SCC compared with controls, while Corynebacterium, Streptococcus, Actinomyces, Cryptobacterium, and Selenomonas were overly represented in controls. Bacterial pathway analysis identified overrepresentation in OC-SCC of pathways related to metabolism of flavin, biotin, thiamin, heme, sugars, fatty acids, peptidoglycans, and tRNA and overrepresentation of nucleotides and essential amino acids in controls. Conclusions: The oral microbiome in nonsmoker patients with OC-SCC is significantly different from that of nonsmoker control patients in taxonomic compositions and functional potentials. Our study's MSS findings matched with previous 16S-based methods in taxonomic differentiation but varied greatly in functional differentiation of microbiomes in OC-SCC and controls. [ABSTRACT FROM AUTHOR]

Background: Secretory carcinoma (SC) is a rare form of salivary carcinoma that was first described in 2010 and is characterized by ETV6::NTRK3 fusion in most cases. In this large retrospective study, we aimed to identify adverse clinicopathologic factors and propose a prognostically relevant grading scheme for SC. Methods: A detailed clinicopathologic review was conducted on 90 SCs from the major and minor salivary glands. Results: The median age at presentation was 50 years (range: 7–93). Sixty-nine (77%) tumours originated from major salivary glands, whereas the remaining 21 involved minor salivary glands.Six cases (7%) had cervical nodal metastasis. Only lymphovascular invasion (LVI) was associated with a risk of nodal metastasis (P < 0.05). The 5-year diseasespecific survival and disease-free survival (DFS) were 98% and 87%, respectively. On univariate survival analysis, adverse prognostic factors associated with decreased DFS included minor salivary gland origin, atypical mitosis, high mitotic index, high-grade transformation (HGT), necrosis, nuclear pleomorphism, infiltrative tumour border, fibrosis at the invasive front, LVI, positive margin, and advanced pT stage (P < 0.05). When adjusted for pT stage and margin status, mitotic index, LVI, nuclear pleomorphism, and HGT remained as independent prognostic factors. Conclusion: We therefore propose a two-tiered grading system for SC. The low-grade SC is defined as those with <5 mitoses /10 high-power fields and no tumour necrosis, and high-grade SC as those with ≥5 mitoses /10 high-power fields and/or necrosis. This proposed grading system can be useful to risk stratify patients with SC for appropriate clinical management. [ABSTRACT FROM AUTHOR]

Aims Acinic cell carcinomas (AcCC) of the breast have been reported to constitute the breast counterpart of salivary gland AcCCs, based on the similarities of their histological and immunohistochemical features. Breast AcCC is a vanishingly rare form of triple-negative breast cancer (TNBC). Recent studies have demonstrated that in TNBCs, the two driver genes most frequently mutated are TP53 (82%) and PIK3CA (10%). We sought to define whether breast AcCCs would harbour TP53 and PIK3CA somatic mutations, and if so, whether these would be present in salivary gland AcCCs. Methods and results Sanger sequencing of the entire coding region of TP53 and of PIK3CA hotspot mutation sites of 10 breast and 20 salivary gland microdissected AcCCs revealed eight TP53 (80%) and one PIK3CA (10%) somatic mutations in breast AcCCs. No somatic mutations affecting these genes were found in the 20 salivary gland AcCCs analysed. Conclusions Our findings demonstrate that breast AcCCs display TP53 and PIK3CA mutations at frequencies similar to those of common types of TNBCs, whereas these genes appear not to be altered in salivary gland AcCCs, suggesting that despite their similar histological appearances, AcCCs of the breast and salivary glands probably constitute unrelated diseases. [ABSTRACT FROM AUTHOR]

Aims: We aimed to study the clinicopathological and molecular features of high-grade non-anaplastic thyroid carcinomas (HGTCs), a carcinoma with a prognosis intermediate between those of well-differentiated carcinoma and anaplastic carcinoma. Methods and results: This study included 364 HGTC patients: 200 patients (54.9%) were diagnosed with poorly differentiated thyroid carcinoma (PDTC), based on the Turin consensus (HGTC-PDTC), and 164 were diagnosed with high-grade features that did not meet the Turin criteria (HGTC-nonPDTC). HGTCs are aggressive: the 3-year, 5-year, 10-year and 20-year diseasespecific survival (DSS) rates were 89%, 76%, 60%, and 35%, respectively. Although DSS was similar between HGTC-PDTC and HGTC-nonPDTC patients, HGTC-PDTC was associated with higher rate of radioactive iodine avidity, a higher frequency of RAS mutations, a lower frequency of BRAF V600E mutations and a higher propensity for distant metastasis (DM) than HGTCnonPDTC. Independent clinicopathological markers of worse outcome were: older age, male sex, extensive necrosis and lack of encapsulation for DSS; older age, male sex and vascular invasion for DM-free survival; and older age, necrosis, positive margins and lymph node metastasis for locoregional recurrence-free survival. The frequencies of BRAF, RAS, TERT, TP53 and PTEN alterations were 28%, 40%, 55%, 11%, and 10%, respectively. TP53, PTEN and TERT were independent molecular markers associated with an unfavourable outcome, independently of clinicopathological parameters. The coexistence of BRAF V600E and TERT promoter mutation increased the risk of DM. Conclusions: The above data support the classification of HGTC as a single group with two distinct subtypes based on tumour differentiation: HGTC-PDTC and HGTC-nonPDTC. [ABSTRACT FROM AUTHOR]

Aims: We aimed to study the clinicopathological and molecular features of high‐grade non‐anaplastic thyroid carcinomas (HGTCs), a carcinoma with a prognosis intermediate between those of well‐differentiated carcinoma and anaplastic carcinoma. Methods and results: This study included 364 HGTC patients: 200 patients (54.9%) were diagnosed with poorly differentiated thyroid carcinoma (PDTC), based on the Turin consensus (HGTC‐PDTC), and 164 were diagnosed with high‐grade features that did not meet the Turin criteria (HGTC‐nonPDTC). HGTCs are aggressive: the 3‐year, 5‐year, 10‐year and 20‐year disease‐specific survival (DSS) rates were 89%, 76%, 60%, and 35%, respectively. Although DSS was similar between HGTC‐PDTC and HGTC‐nonPDTC patients, HGTC‐PDTC was associated with higher rate of radioactive iodine avidity, a higher frequency of RAS mutations, a lower frequency of BRAF V600E mutations and a higher propensity for distant metastasis (DM) than HGTC‐nonPDTC. Independent clinicopathological markers of worse outcome were: older age, male sex, extensive necrosis and lack of encapsulation for DSS; older age, male sex and vascular invasion for DM‐free survival; and older age, necrosis, positive margins and lymph node metastasis for locoregional recurrence‐free survival. The frequencies of BRAF, RAS, TERT, TP53 and PTEN alterations were 28%, 40%, 55%, 11%, and 10%, respectively. TP53, PTEN and TERT were independent molecular markers associated with an unfavourable outcome, independently of clinicopathological parameters. The coexistence of BRAF V600E and TERT promoter mutation increased the risk of DM. Conclusions: The above data support the classification of HGTC as a single group with two distinct subtypes based on tumour differentiation: HGTC‐PDTC and HGTC‐nonPDTC. [ABSTRACT FROM AUTHOR]

Objectives: Salivary gland acinic cell carcinoma (AciCC) has recognizable cytomorphologic features that can overlap with benign and malignant entities, creating a diagnostic challenge. AciCC harbors a t(4;9) translocation increasing nuclear receptor subfamily 4 group A member 3 (NR4A3) expression, detectable by immunohistochemistry (IHC) on surgical resection (SR). NR4A3 IHC cytology data are limited. Here, we examine NR4A3 IHC on smears, cell blocks (CBs), and SRs of AciCC and its mimickers.Methods: Our cohort comprised AciCC (including high-grade transformation), secretory carcinoma, mucoepidermoid carcinoma (MEC), Warthin tumor, pleomorphic adenoma (PA), cellular PA, carcinoma ex-PA, oncocytic carcinoma, oncocytoma, and nodular oncocytosis. NR4A3 IHC (Santa Cruz Biotechnology and Origene antibodies) was positive if more than 5% tumor cells showed nuclear staining.Results: Among CBs, 90% of AciCC cases and none of the mimickers expressed NR4A3. Among SRs, 100% of AciCC cases showed diffuse NR4A3, whereas one high-grade MEC expressed focal NR4A3. Concordance was 95% with two antibody clones. Sensitivity, specificity, positive predictive value, and negative predictive value were 90%, 100%, 100%, and 94.7% for CBs and 100%, 98.8%, 92.3%, and 100% for SRs, respectively. NR4A3 immunostaining was demonstrable on smears from an AciCC case.Conclusions: NR4A3 IHC can be a robust diagnostic tool to identify AciCC, especially for cytology specimens. [ABSTRACT FROM AUTHOR]

Background: The risk of local recurrence in the pancreatic remnant after resection of noninvasive intraductal papillary mucinous neoplasm (IPMN) is not well defined.Study Design: We performed a retrospective review of a prospectively maintained pancreatic resection database that identified 78 patients who underwent resection for noninvasive IPMN between 1983 and 2006. Local recurrence was determined radiographically and confirmed either pathologically or clinically.Results: At a median followup of 40 months, 6 patients (7.7%) have recurred locally, with a median interval of 22 months (range 8 to 62 months) from the time of resection. Three patients did not undergo additional operative treatment and died of disease progression. Three patients underwent additional resection and are alive without evidence of disease. The estimated 5-year local recurrence-free survival for all patients with noninvasive IPMN is 87%. One of 50 patients (2%) with margins negative for IPMN recurred versus 4 of 23 patients (17%) with margins positive for IPMN (p=0.02).Conclusions: Patients who have undergone resection for noninvasive IPMN require indefinite surveillance because local recurrences may be identified several years from the initial operation and be resected while still noninvasive. Although the risk of local recurrence appears to increase in the setting of positive margins, the majority of patients with positive margins have not developed local recurrence. Negative margins should be the goal of the operation when achievable with partial pancreatectomy, but the risk of local recurrence is not high enough to mandate total pancreatectomy for microscopic positive margins. [ABSTRACT FROM AUTHOR]

We report a case of a 65-year-old black man with combined Hodgkin lymphoma and T-cell lymphoma. The patient presented with diffuse lymphadenopathy, fever, weight loss, and night sweats. Subsequent biopsy of an axillary lymph node revealed a composite lymphoma composed of classic Hodgkin lymphoma and a peripheral T-cell lymphoma. A needle biopsy of the liver also showed involvement by the composite lymphoma. In situ hybridization studies revealed positive Epstein-Barr virus in Reed-Sternberg cells. Development of T-cell lymphoma following chemotherapy for Hodgkin lymphoma has been reported, but synchronous composite occurrence of both lesions is very rare. Furthermore, this is the first report of such occurrence in a black patient. We present a review of the literature and a discussion of the potential pathophysiologic role of Epstein-Barr virus in the early stages of T-cell lymphomagenesis. [ABSTRACT FROM AUTHOR]

PURPOSE: Telomerase reverse transcriptase (TERT) promoter mutations are prognostic in many cancers and have been observed in human papillomavirus (HPV)–negative head and neck squamous cell carcinomas (HNSCCs). However, the role of TERT promoter mutations in HPV-negative HNSCCs remains poorly understood in these cancers, which have increased risk for locoregional failure (LRF). PATIENTS AND METHODS: We retrospectively identified patients who were diagnosed with HNSCC between July 1, 2004, and October 12, 2017, at Memorial Sloan Kettering Cancer Center and whose tumors underwent next-generation sequencing using the MSK-IMPACT panel. Patients with HPV-positive oropharyngeal squamous cell carcinoma (SCC) were excluded. Cumulative incidence of LRF, patterns of failure, and overall survival were measured. RESULTS: We identified 117 patients with SCC of the oral cavity (OSCC), larynx, hypopharynx, or HPV-negative oropharynx whose tumors underwent next-generation sequencing. Sequencing was performed on 95 tumors that were obtained after recurrence and 22 that were obtained before recurrence. TERT promoter mutations were enriched in OSCC compared with laryngopharyngeal cancers (81.1% v 7.0%; P <.001), which was the largest genetic difference between these anatomic disease subsites. TERT promoter mutations were associated with LRF in OSCCs (Gray's test, P <.001) and in the overall cohort (Gray's test, P <.001). On multivariate analysis, TERT promoter mutations were associated with an increased risk for LRF (subdistribution hazard ratio, 2.82; 95% CI, 1.47 to 5.42; P =.0019), independent of oral cavity primary site and TP53 mutation status. CONCLUSION: TERT promoter status is associated with the cumulative incidence of LRF and patterns of failure. TERT promoter mutations may define a subset of OSCCs with unique pathogenesis that is associated with an increased risk of LRF. Validation in prospective cohorts is warranted. [ABSTRACT FROM AUTHOR]

Background: Patients with human papillomavirus-related oropharyngeal cancers have excellent outcomes but experience clinically significant toxicities when treated with standard chemoradiotherapy (70 Gy). We hypothesized that functional imaging could identify patients who could be safely deescalated to 30 Gy of radiotherapy.Methods: In 19 patients, pre- and intratreatment dynamic fluorine-18-labeled fluoromisonidazole positron emission tomography (PET) was used to assess tumor hypoxia. Patients without hypoxia at baseline or intratreatment received 30 Gy; patients with persistent hypoxia received 70 Gy. Neck dissection was performed at 4 months in deescalated patients to assess pathologic response. Magnetic resonance imaging (weekly), circulating plasma cell-free DNA, RNA-sequencing, and whole-genome sequencing (WGS) were performed to identify potential molecular determinants of response. Samples from an independent prospective study were obtained to reproduce molecular findings. All statistical tests were 2-sided.Results: Fifteen of 19 patients had no hypoxia on baseline PET or resolution on intratreatment PET and were deescalated to 30 Gy. Of these 15 patients, 11 had a pathologic complete response. Two-year locoregional control and overall survival were 94.4% (95% confidence interval = 84.4% to 100%) and 94.7% (95% confidence interval = 85.2% to 100%), respectively. No acute grade 3 radiation-related toxicities were observed. Microenvironmental features on serial imaging correlated better with pathologic response than tumor burden metrics or circulating plasma cell-free DNA. A WGS-based DNA repair defect was associated with response (P = .02) and was reproduced in an independent cohort (P = .03).Conclusions: Deescalation of radiotherapy to 30 Gy on the basis of intratreatment hypoxia imaging was feasible, safe, and associated with minimal toxicity. A DNA repair defect identified by WGS was predictive of response. Intratherapy personalization of chemoradiotherapy may facilitate marked deescalation of radiotherapy. [ABSTRACT FROM AUTHOR]

PURPOSE: Telomerase reverse transcriptase (TERT) promoter mutations are prognostic in many cancers and have been observed in human papillomavirus (HPV)–negative head and neck squamous cell carcinomas (HNSCCs). However, the role of TERT promoter mutations in HPV-negative HNSCCs remains poorly understood in these cancers, which have increased risk for locoregional failure (LRF). PATIENTS AND METHODS: We retrospectively identified patients who were diagnosed with HNSCC between July 1, 2004, and October 12, 2017, at Memorial Sloan Kettering Cancer Center and whose tumors underwent next-generation sequencing using the MSK-IMPACT panel. Patients with HPV-positive oropharyngeal squamous cell carcinoma (SCC) were excluded. Cumulative incidence of LRF, patterns of failure, and overall survival were measured. RESULTS: We identified 117 patients with SCC of the oral cavity (OSCC), larynx, hypopharynx, or HPV-negative oropharynx whose tumors underwent next-generation sequencing. Sequencing was performed on 95 tumors that were obtained after recurrence and 22 that were obtained before recurrence. TERT promoter mutations were enriched in OSCC compared with laryngopharyngeal cancers (81.1% v 7.0%; P <.001), which was the largest genetic difference between these anatomic disease subsites. TERT promoter mutations were associated with LRF in OSCCs (Gray's test, P <.001) and in the overall cohort (Gray's test, P <.001). On multivariate analysis, TERT promoter mutations were associated with an increased risk for LRF (subdistribution hazard ratio, 2.82; 95% CI, 1.47 to 5.42; P =.0019), independent of oral cavity primary site and TP53 mutation status. CONCLUSION: TERT promoter status is associated with the cumulative incidence of LRF and patterns of failure. TERT promoter mutations may define a subset of OSCCs with unique pathogenesis that is associated with an increased risk of LRF. Validation in prospective cohorts is warranted. [ABSTRACT FROM AUTHOR]

The aim of this study was to carry out a case control study comparing the HPV genome in patients with oral cavity squamous cell carcinoma (OC-SCC) to normal patients using metagenomic shotgun sequencing. We recruited 50 OC-SCC cases which were then matched with a control patient by age, gender, race, smoking status and alcohol status. DNA was extracted from oral wash samples from all patients and whole genome shotgun sequencing performed. The raw sequence data was cleaned, reads aligned with the human genome (GRCH38), nonhuman reads identified and then HPV genotypes identified using HPViewer. In the 50 patients with OC-SCC, the most common subsite was tongue in 26 (52%). All patients were treated with primary resection and neck dissection. All but 2 tumors were negative on p16 immunohistochemistry. There were no statistically significant differences between the cases and controls in terms of gender, age, race/ethnicity, alcohol drinking, and cigarette smoking. There was no statistically significant difference between the cancer samples and control samples in the nonhuman DNA reads (medians 4,228,072 vs. 5,719,715, P value = 0.324). HPV was detected in 5 cases (10%) of OC-SCC (genotypes 10, 16, 98) but only 1 tumor sample (genotype 16) yielded a high number of reads to suggest a role in the etiology of OC-SCC. HPV was detected in 4 control patients (genotypes 16, 22, 76, 200) but all had only 1–2 HPV reads per human genome. Genotypes of HPV are rarely found in patients with oral cancer. [ABSTRACT FROM AUTHOR]

Background: Anaplastic thyroid carcinoma (ATC) is nearly always fatal. Large studies on ATC are exceedingly rare. We aimed to study the clinical, genotypic, and histologic characteristics of ATC in the largest retrospective cohort of ATC to date. Methods: Three hundred sixty patients with ATC from two tertiary centers were studied. Molecular testing was performed in 126 cases including 107 using next-generation sequencing. Results: The median patients' age was 68 years. Differentiated thyroid carcinoma (DTC) was present in 208 cases (58%), the most common being papillary carcinoma (n = 150). The 1-, 2-, 3-, and 5-year overall survival (OS) was 36%, 17%, 13%, and 11%, respectively. On univariate analysis, age, resectability, chemotherapy, radiotherapy, margin status, encapsulation, gross residual disease, gross extrathyroidal extension, percentage, and size of ATC in the primary tumor predicted OS (p < 0.05). Age, resectability, chemotherapy, and gross residual disease were independent prognostic factors in the entire cohort, while gross residual disease was the only independent predictor of OS in patients who had resection of their tumor. BRAF, RAS, TERT promoter, TP53, PIK3CA, E1F1AX, and PTEN mutations were detected in 45%, 24%, 75%, 63%, 18%, 14%, and 14% of ATC, respectively. Concomitant BRAF/RAS and TERT mutations were associated with worse outcome than mutation in only one of the genes. BRAF-mutated and RAS-mutated ATCs had similar frequency of nodal and distant metastasis. Twelve cases were pure squamous cell carcinoma, 60% of which carried BRAFV600E mutation and showed a similar OS to other ATCs. Conclusions: (i) Gross residual disease remains the most crucial indicator of outcome in ATC. (ii) Encapsulation, margin status, percentage, and size of ATC in the primary were prognostically relevant. (iii) Pure thyroid squamous cell carcinoma may be considered as ATC given a BRAFV600E genotype and similar outcome. (iv) In contrast to DTC, BRAF-mutated and RAS-mutated ATCs have similar metastatic spread. (v) Concomitant mutations of BRAF or RAS with TERT confer a worse prognosis. [ABSTRACT FROM AUTHOR]

Purpose: Activation of the PI3K/mTOR signaling pathway is common in head and neck squamous cell carcinoma (HNSCC). BYL719 is an α-specific PI3K inhibitor that is synergistic and efficacious when combined with cetuximab, a Food and Drug Administration-approved radiosensitizing agent in the treatment of HNSCC. The agent independently has been shown to enhance radiosensitivity. This study evaluates the addition of BYL719 to cetuximab and radiation in the treatment of locally advanced HNSCC.Methods and Materials: This is a single-institution, phase 1 study. Patients with American Joint Committee on Cancer seventh edition stage III to IVB HNSCC received standard cetuximab (400 mg/m2 intravenous loading dose) before intensity modulated radiation therapy (IMRT) followed by 250 mg/m2 weekly infusions during IMRT. BYL719 was given orally during IMRT in 3 dose levels: (1) 200 mg/d, (2) 250 mg/d, or (3) 300 mg/d in a standard 3 + 3 dose-escalation design.Results: Eleven patients were evaluable. Dose level 2 was the maximum tolerated dose for BYL719. Two patients on dose level 3 had dose-limiting toxicities of oral mucositis that required a dose reduction of BYL719. One patient on dose level 2 had a dose-limiting toxicity of nausea that led to withdrawal of on-study treatment. Related grade 3 or higher adverse events consisted of decreased lymphocyte count, oral mucositis, dysphagia, hyperglycemia, maculopapular rash, and palmar-plantar erythrodysesthesia syndrome. All 11 patients had a complete response on posttreatment imaging, and 10 remain disease free. Of the 8 patients with mutational analysis, 1 had an activating PIK3CA mutation associated with a rapid response on serial intratreatment magnetic resonance imaging scans.Conclusions: The recommended phase 2 dose of BYL719 is 250 mg/d in combination with cetuximab and IMRT in patients with locally advanced HNSCC. Further evaluation of the addition of BYL719 to the platinum-sparing regimen of cetuximab and IMRT in the treatment of locally advanced HNSCC is warranted. [ABSTRACT FROM AUTHOR]

Aims: Secretory carcinoma (SC) of the salivary gland typically harbours ETV6–NTRK3 fusion, which can be utilised clinically to assist with diagnosis. Pan‐Trk inhibitor therapy has demonstrated drastic responses in patients with NTRK‐translocated tumours, including SC. Pan‐Trk immunohistochemistry (IHC) is emerging as a sensitive and specific tool for detecting NTRK1, NTRK2 and NTRK3 fusions in various cancers. We aimed to establish the specificity and sensitivity of pan‐Trk IHC in diagnosing SC and detecting ETV6–NTRK3 fusion. A literature review on the utility of pan‐Trk IHC was conducted. Methods and results: Pan‐Trk IHC was performed on 83 salivary gland neoplasms (29 SCs and 54 non‐SCs). ETV6–NTRK3 fusion status was established in 25 cases. With any staining (nuclear or cytoplasmic) as a positive threshold, the sensitivity and specificity of pan‐Trk IHC were 90% and 70% in diagnosing SC, and 100% and 0% in detecting NTRK3 fusion. When only pan‐Trk nuclear staining was considered as positive, the sensitivity and specificity were 69% and 100% in diagnosing SC, and 92% and 100% in detecting NTRK3 fusion. Conclusions: Nuclear pan‐Trk IHC is highly specific for SC diagnosis, with a specificity approaching 100%, making it a useful and precise diagnostic tool for differentiating SC from its histological mimics. On the other hand, any pan‐Trk staining (nuclear or cytoplasmic) is highly sensitive for SC, and can serve as an attractive, cheap, fast and accessible screening tool for selecting patients to undergo confirmative molecular testing for clinical trials using TRK inhibitors. [ABSTRACT FROM AUTHOR]

Background: The percentage of papillae is a crucial criterion in differentiating noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) from papillary thyroid carcinomas (PTCs) and in subclassifying PTC into classic and follicular variant. Since the description of NIFTP, three studies have shown that the presence of any papillae may be associated with nodal metastasis, which led to modification of the NIFTP criterion from <1% papillae to no true papillae allowed. We aim at providing clinical evidence-based data on the impact that papillary growth has on nodal spread and tumor genotype in tumors previously diagnosed as encapsulated unifocal PTC. Methods: A meticulous histopathologic examination was performed on 235 cases previously diagnosed as unifocal encapsulated PTC (U-EPTC). One hundred of these cases were subjected to BRAFV600E and NRASQ61R immunohistochemistry. Results: In our cohort, 27 patients (12%) had lymph node metastasis (N1) at the time of initial resection. Overall, 89% of the tumors in the N1 group contained ≥50% papillae, compared with 13% in the N0/Nx group. Nodal metastases were only present in tumors with ≥1% papillae. In noninvasive U-EPTC (n = 161), N1 disease was seen only in tumors with ≥10% papillae. A higher percentage of papillae within the tumor also correlated with an increased frequency of BRAFV600E and decreased rate of NRASQ61R. None of the 26 NRAS-positive cases had nodal disease, including the invasive tumors. Among 216 patients with follow-up (median: 5.2 years), 3 patients (1.5%) had distant metastases, all detected at the initial presentation. All three tumors displayed 100% follicular growth, and capsular or vascular invasion. There was no locoregional recurrence in the entire cohort. Conclusion: In U-EPTC, there is a strong correlation between high percentage of papillary growth, presence of nodal metastasis, and BRAF+/RAS− genotype regardless of invasive status. Nodal metastases were not seen in tumors with <1% papillae irrespective of invasive status. These findings indicate that the initial criterion of <1% papillae is still valid for the diagnosis of NIFTP. Reinstituting this criterion will spare a carcinoma diagnosis and unnecessary therapy with its side effects on patients who have negligible clinical risk. [ABSTRACT FROM AUTHOR]

Aims: Salivary duct carcinoma (SDC) is an aggressive salivary malignancy that results in high mortality rates and is often resistant to chemotherapy. Anti‐programmed death‐1 (PD‐1)/programmed death ligand‐1 (PD‐L1) checkpoint inhibitors have led to dramatic improvements in patients with various cancers. Other immunotherapeutic approaches, e.g. cancer vaccines, have shown promising results. Cancer testis antigens, e.g. preferentially expressed antigen in melanoma (PRAME), are regarded as promising vaccine targets because of their tumour‐specific expression pattern. Methods and results: We analysed the immunoexpression of PD‐L1, PD‐1, major histocompatibility complex class I (MHC I) and PRAME in 53 SDCs. The immunoexpression levels of PD‐L1 in tumour cells (TCs) and immune cells (ICs), PD‐1 in ICs, PRAME in TCs and MHC I in TCs were analysed, and were correlated with outcome. PRAME expression was seen in 83% of SDCs. No PRAME staining was present in normal salivary gland tissue. With the three established diagnostic algorithms proposed for head and neck squamous cell carcinoma, the criteria being a combined positive score of ≥1, TC% ≥1%, and TC% ≥25%, 35 (66%), 17 (32%) and three cases (6%), respectively, were deemed to be positive for PD‐L1. PD‐1‐positive ICs were seen in 35 (66%) cases. MHC I down‐regulation was seen in 82% of SDCs. There was a significant correlation among PD‐L1 expression in ICs, PD‐1 expression in ICs, and PRAME expression in TCs. PD‐L1 expression in TCs and lack of PD‐1 expression in ICs were associated with decreased disease‐specific survival in SDC patients. Conclusions: Alterations of the tumour immune microenvironment are common in SDCs, including expression of PD‐1/PD‐L1 and PRAME, which opens the way to potential novel immune therapies, such as cancer vaccination and PD‐1/PD‐L1 blockade, in these tumours. [ABSTRACT FROM AUTHOR]

BACKGROUNDAdenoid cystic carcinoma (ACC) is a rare malignancy arising in salivary glands and other sites, characterized by high rates of relapse and distant spread. Recurrent/metastatic (R/M) ACCs are generally incurable, due to a lack of active systemic therapies. To improve outcomes, deeper understanding of genetic alterations and vulnerabilities in R/M tumors is needed.METHODSAn integrated genomic analysis of 1,045 ACCs (177 primary, 868 R/M) was performed to identify alterations associated with advanced and metastatic tumors. Intratumoral genetic heterogeneity, germline mutations, and therapeutic actionability were assessed.RESULTSCompared with primary tumors, R/M tumors were enriched for alterations in key Notch (NOTCH1, 26.3% vs. 8.5%; NOTCH2, 4.6% vs. 2.3%; NOTCH3, 5.7% vs. 2.3%; NOTCH4, 3.6% vs. 0.6%) and chromatin-remodeling (KDM6A, 15.2% vs. 3.4%; KMT2C/MLL3, 14.3% vs. 4.0%; ARID1B, 14.1% vs. 4.0%) genes. TERT promoter mutations (13.1% of R/M cases) were mutually exclusive with both NOTCH1 mutations (q = 3.3 × 10-4) and MYB/MYBL1 fusions (q = 5.6 × 10-3), suggesting discrete, alternative mechanisms of tumorigenesis. This network of alterations defined 4 distinct ACC subgroups: MYB+NOTCH1+, MYB+/other, MYBWTNOTCH1+, and MYBWTTERT+. Despite low mutational load, we identified numerous samples with marked intratumoral genetic heterogeneity, including branching evolution across multiregion sequencing.CONCLUSIONThese observations collectively redefine the molecular underpinnings of ACC progression and identify further targets for precision therapies.FUNDINGAdenoid Cystic Carcinoma Research Foundation, Pershing Square Sohn Cancer Research grant, the PaineWebber Chair, Stand Up 2 Cancer, NIH R01 CA205426, the STARR Cancer Consortium, NCI R35 CA232097, the Frederick Adler Chair, Cycle for Survival, the Jayme Flowers Fund, The Sebastian Nativo Fund, NIH K08 DE024774 and R01 DE027738, and MSKCC through NIH/NCI Cancer Center Support Grant (P30 CA008748). [ABSTRACT FROM AUTHOR]

Aims: Polymorphous adenocarcinoma (PAC) usually follows an indolent course, but some cases may show recurrences and high‐grade features. The genetic events associated with recurrences and high‐grade versions are yet to be defined. Our aim was to determine the genetic underpinning of recurrent PACs of the salivary gland and the repertoire of somatic genetic alterations in cases with high‐grade histology. Methods and results: Four PACs from three patients, including one case with matching primary and recurrent tumours, one de‐novo high‐grade PAC, and a PAC that transformed to a high‐grade tumour following multiple recurrences, were subjected to targeted sequencing (Memorial Sloan Kettering Mutation Profiling of Actionable Cancer Targets assay) or whole‐exome sequencing. Both matching primary and recurrent tumours, and the de‐novo high‐grade PAC, harboured clonal PRKD1 E710D hotspot mutations, whereas the PAC that underwent high‐grade transformation upon recurrence, which was wild‐type for PRKD1, harboured a PRKD2 rearrangement. The PACs analysed here also harboured mutations targeting cancer genes such as PIK3CA, SETD2, ARID1A, and NOTCH2. A clonal decomposition analysis of the matching primary and recurrent PACs revealed that a minor subclone from the primary tumour became dominant in the recurrent tumour following a clonal selection evolutionary pattern. Conclusions: Our findings demonstrate that recurrent and high‐grade PACs are underpinned by PRKD1 E710D hotspot mutations or PRKD2 rearrangements, and that recurrences of PACs may stem from the selection of pre‐existing subclones in the primary tumour. [ABSTRACT FROM AUTHOR]

PURPOSE: A circulating tumor DNA (ctDNA) test to detect plasma Epstein-Barr viral DNA can be used to screen for early nasopharyngeal cancers; however, the reported sensitivity of viral ctDNA tests to detect human papillomavirus (HPV)–associated cancers is modest. We assessed the utility of droplet digital polymerase chain reaction (ddPCR) to detect early-stage HPV-associated cancers using sequential HPV16 and HPV33 assays that account for HPV subtype distribution and subtype sequence variants. PATIENTS AND METHODS: We collected plasma specimens from 97 HPV-positive patients with oropharyngeal squamous cell carcinoma and eight patients with HPV-positive anal squamous cell carcinoma, each with locoregionally confined disease. Negative controls included samples from seven patients with HPV-negative head and neck cancers and 20 individuals without cancer. RESULTS: Of 97 patients with nonmetastatic, locoregionally confined oropharyngeal squamous cell carcinoma, 90 patients had detectable HPV16 ctDNA and three patients had HPV33 ctDNA, indicating an overall sensitivity of 95.6%. Seven of eight patients with early anal cancer were HPV16 ctDNA positive. No HPV ctDNA was detected in 27 negative controls, indicating 100% specificity. HPV16 ctDNA was detected in 19 of 19 patients with low-volume disease, defined as patients with a single, asymptomatic positive lymph node (N1) or an isolated T1-2 asymptomatic primary tumor. HPV16 ctDNA levels directly corresponded to tumor responses to chemoradiation and surgery. CONCLUSION: With an updated understanding of HPV subtypes and sequence variation, HPV ctDNA by ddPCR is highly sensitive and specific, identifying HPV16 and HPV33 subtypes in a similar distribution as reported in major genomic profiling studies. The detection of small tumors indicates that HPV16 and HPV33 ctDNA ddPCR could be readily used in early detection screening trials and in disease response monitoring, analogous to Epstein-Barr virus DNA. [ABSTRACT FROM AUTHOR]

Standardized, synoptic pathologic reporting for tumors greatly improves communication among clinicians, patients, and researchers, supporting prognostication and comparison about patient outcomes across institutions and countries. The International Collaboration on Cancer Reporting is a nonprofit organization whose mission is to develop evidence-based, universally available surgical pathology reporting data sets. Within the head and neck region, lymph node excisions and neck dissections are frequently performed as part of the management of head and neck cancers arising from the mucosal sites (sinonasal tract, nasopharynx, oropharynx, hypopharynx, oral cavity, and larynx) along with bone tumors, skin cancers, melanomas, and other tumor categories. The type of specimen, exact location (lymph node level), laterality, and orientation (by suture or diagram) are essential to accurate classification. There are significant staging differences for each anatomic site within the head and neck when lymph node sampling is considered, most importantly related to human papillomavirus-associated oropharyngeal carcinomas and mucosal melanomas. Number, size, and site of affected lymph nodes, including guidelines on determining the size of tumor deposits and the presence of extranodal extension and soft tissue metastasis, are presented in the context of prognostication. This review elaborates on each of the elements included in the data set for Nodal Excisions and Neck Dissection Specimens for Head & Neck Tumours. [ABSTRACT FROM AUTHOR]

Perineural invasion (PNI), the neoplastic invasion of nerves, is a common pathologic finding in head and neck cancer that is associated with poor clinical outcomes. PNI is a histologic finding of tumor cell infiltration and is distinct from perineural tumor spread (PNTS), which is macroscopic tumor involvement along a nerve extending from the primary tumor that is by definition more advanced, being radiologically or clinically apparent. Despite widespread acknowledgment of the prognostic significance of PNI and PNTS, the mechanisms underlying its pathogenesis remain largely unknown, and specific therapies targeting nerve invasion are lacking. The use of radiation therapy for PNI and PNTS can improve local control and reduce devastating failures at the skull base. However, the optimal volumes to be delineated with respect to targeting cranial nerve pathways are not well defined, and radiation can carry risks of major toxicity secondary to the location of adjacent critical structures. Here we examine the pathogenesis of these phenomena, analyze the role of radiation in PNI and PNTS, and propose guidelines for radiation treatment design based on the best available evidence and the authors' collective experience to advance understanding and therapy of this ominous cancer phenotype. [ABSTRACT FROM AUTHOR]

Aims In the current study, we aimed to examine primary parotid squamous cell carcinoma (Par SCC) for the presence of high-risk human papillomavirus ( HR- HPV) and associated molecular alterations. Methods and results Eight cases of Par SCC were retrieved after a detailed clinicopathological review to exclude the possibility of metastasis and/or extension from another primary site. HR- HPV status was determined on the basis of immunohistochemistry ( IHC) for p16 expression and chromogenic in-situ hybridization ( CISH) for HR- HPV. All cases were genotyped with a multiplexed mass spectrometry assay interrogating 91 hotspot mutations in eight cancer-related genes ( EGFR, KRAS, NRAS, BRAF, PIK3 CA, AKT1, MEK1 and ERBB2), and studied by fluorescence in-situ hybridization for PTEN copy number alteration. Three of eight cases (37.5%) were positive for the presence of HR- HPV by CISH and p16 IHC. One of three (33%) HR- HPV-positive cases harboured a PTEN hemizygous deletion, and one (33%) HR- HPV-positive case harboured a PIK3 CA E545K somatic mutation. No alteration of the PTEN- PI3K pathway was detected in HR- HPV-negative tumours. Over a median follow-up period of 66.2 months, only the patient with the HR- HPV-positive PIK3 CA-mutated tumour died of his disease, the remaining seven patients being disease-free. Conclusions Given the established aetiological role of HR- HPV in other head and neck squamous cell carcinomas, it is likely that HR- HPV represents an oncogenic driver in the pathogenesis of more than one-third of Par SCCs. The presence of HR- HPV in Par SCC may be coupled with alterations in the PTEN- PI3K pathway. Further studies on HR- HPV and the molecular characterization of a larger number of Par SCCs are needed to determine the clinical significance of these findings. [ABSTRACT FROM AUTHOR]

Purpose: To report a small substudy of an ongoing large, multi-arm study using functional imaging to assess pre-/intratreatment hypoxia for all head and neck cancer, in which we hypothesized that pre- and early-treatment hypoxia assessment using functional positron emission tomography (PET) imaging may help select which human papillomavirus (HPV)-positive (HPV(+)) oropharyngeal cancer (OPC) patients can safely receive radiation de-escalation without jeopardizing treatment outcomes.Methods and Materials: Patients with HPV(+) oropharyngeal carcinoma were enrolled on an institutional review board-approved prospective study of which de-escalation based on imaging response was done for node(s) only. Pretreatment (18)F-fluorodeoxyglucose and dynamic (18)F-FMISO (fluoromisonidazole) positron emission tomography (PET) scans were performed. For patients with pretreatment hypoxia on(18)F-FMISO PET (defined as a >1.2 tumor to muscle standard uptake value ratio), a repeat scan was done 1 week after chemoradiation. Patients without pretreatment hypoxia or with resolution of hypoxia on repeat scan received a 10-Gy dose reduction to metastatic lymph node(s). The 2-year local, regional, distant metastasis-free, and overall survival rates were estimated using the Kaplan-Meier product-limit method. A subset of patients had biopsy of a hypoxic node done under image guidance.Results: Thirty-three HPV(+) OPC patients were enrolled in this pilot study. One hundred percent showed pretreatment hypoxia (at primary site and/or node[s]), and among these, 48% resolved (at primary site and/or node[s]); 30% met criteria and received 10-Gy reduction to the lymph node(s). At the median follow-up of 32 months (range, 21-61 months), the 2-year locoregional control rate was 100%. One patient failed distantly with persistence of hypoxia on (18)F-FMISO PET. The 2-year distant metastasis-free rate was 97%. The 2-year OS rate was 100%. Hypoxia on imaging was confirmed pathologically.Conclusions: Hypoxia is present in HPV(+) tumors but resolves within 1 week of treatment in 48% of cases either at the primary site and/or lymph node(s). Our 100% locoregional control rate suggests that intratreatment functional imaging used to selectively de-escalate node(s) to 60 Gy was confirmed safe using our stringent imaging criteria. Intratreatment functional imaging warrants further study to determine its ultimate role in de-escalation treatment strategies. [ABSTRACT FROM AUTHOR]

Aims Polymorphous low-grade adenocarcinoma ( PLGA) is the second most common intra-oral salivary gland malignancy. The vast majority of PLGAs harbour a PRKD1 E710D hot-spot somatic mutation or somatic rearrangements of PRKD1, PRKD2 or PRKD3. Given the kinase domain homology among PRKD1, PRKD2 and PRKD3, we sought to define whether PLGAs lacking PRKD1 somatic mutations or PRKD gene family rearrangements would be driven by somatic mutations affecting the kinase domains of PRKD2 or PRKD3. Methods and results DNA was extracted from eight microdissected PLGAs lacking PRKD1 somatic mutations or PRKD gene family rearrangements. Samples were thoroughly centrally reviewed, microdissected and subjected to Sanger sequencing of the kinase domains of the PRKD2 and PRKD3 genes. None of the PLGAs lacking PRKD1 somatic mutations or PRKD gene family rearrangements harboured somatic mutations in the kinase domains of the PRKD2 or PRKD3 genes. Conclusion PLGAs lacking PRKD1 somatic mutations or PRKD gene family rearrangements are unlikely to harbour somatic mutations in the kinase domains of PRKD2 or PRKD3. Further studies are warranted to define the driver genetic events in this subgroup of PLGAs. [ABSTRACT FROM AUTHOR]

Background Due to the rarity of adenoid cystic carcinoma (ACC), information on outcome is based upon small retrospective case series. The aim of our study was to create a large multiinstitutional international dataset of patients with ACC in order to design predictive nomograms for outcome. Methods ACC patients managed at 10 international centers were identified. Patient, tumor, and treatment characteristics were recorded and an international collaborative dataset created. Multivariable competing risk models were then built to predict the 10 year recurrence free probability (RFP), distant recurrence free probability (DRFP), overall survival (OS) and cancer specific mortality (CSM). All predictors of interest were added in the starting full models before selection, including age, gender, tumor site, clinical T stage, perineural invasion, margin status, pathologic N-status, and M-status. Stepdown method was used in model selection to choose predictive variables. An external dataset of 99 patients from 2 other institutions was used to validate the nomograms. Findings Of 438 ACC patients, 27.2% (119/438) died from ACC and 38.8% (170/438) died of other causes. Median follow-up was 56 months (range 1–306). The nomogram for OS had 7 variables (age, gender, clinical T stage, tumor site, margin status, pathologic N-status and M-status) with a concordance index (CI) of 0.71. The nomogram for CSM had the same variables, except margin status, with a concordance index (CI) of 0.70. The nomogram for RFP had 7 variables (age, gender, clinical T stage, tumor site, margin status, pathologic N status and perineural invasion) (CI 0.66). The nomogram for DRFP had 6 variables (gender, clinical T stage, tumor site, pathologic N-status, perineural invasion and margin status) (CI 0.64). Concordance index for the external validation set were 0.76, 0.72, 0.67 and 0.70 respectively. Interpretation Using an international collaborative database we have created the first nomograms which estimate outcome in individual patients with ACC. These predictive nomograms will facilitate patient counseling in terms of prognosis and subsequent clinical follow-up. They will also identify high risk patients who may benefit from clinical trials on new targeted therapies for patients with ACC. Funding None. [ABSTRACT FROM AUTHOR]

Objectives: Ribavirin inhibits eukaryotic translation initiation factor 4E (eIF4E), thereby decreasing cap-dependent translation. In this two-part study, we assessed the pharmacodynamic effects and therapeutic potential of ribavirin in human papillomavirus (HPV)-related malignancies.Methods: In the pharmacodynamic study, ribavirin (400 mg BID for 14 days) was evaluated in 8 patients with HPV-positive localized oropharyngeal carcinoma with phosphorylated-eIF4E (p-eIF4E) ≥ 30%. In the therapeutic study, ribavirin (1400 mg BID in 28-day cycles, continuously dosed) was evaluated in 12 patients with recurrent and/or metastatic HPV-related cancer. Dose interruptions or reductions were allowed according to prespecified criteria. Toxicities were assessed in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events version 4; response was assessed using Response Evaluation Criteria in Solid Tumors version 1.1. Patients remained on study until disease progression or unacceptable toxicity.Results: Six patients were evaluable in the pharmacodynamic study: 4 had decreased p-eIF4E after 14 days of ribavirin. In the therapeutic study, 12 patients were evaluable for toxicity, and 9 were evaluable for response. Among these, median follow-up was 3.5 months, and best overall response was stable disease in 5 patients and progression of disease in 4 patients. Median progression-free survival was 1.8 months. The most common treatment-related adverse events (grade > 2) were anemia, dyspnea, and hyperbilirubinemia. All patients had anemia (grades 1-3), with 33% having at least 1 dose reduction.Conclusion: Oral ribavirin decreases p-eIF4E levels and is well-tolerated. However, a clear signal of efficacy in patients with recurrent and/or metastatic HPV-related cancers was not observed. (NCT02308241, NCT01268579). [ABSTRACT FROM AUTHOR]

Background: Vascular invasion (VI) is an important predictor of distant metastasis and possible radioactive iodine (RAI) benefit in follicular, Hürthle cell, and poorly differentiated thyroid carcinomas, but its role in well-differentiated papillary thyroid cancer (WDTC) remains unclear. Methods: Archived pathological material of all differentiated thyroid carcinoma patients undergoing primary surgical treatment at Memorial Sloan-Kettering Cancer Center between 1986 and 2003 was reviewed by two dedicated thyroid pathologists. Only WDTCs were included in the present study. Standard statistical methods were used to assess the relationship between VI and outcomes of interest, including 10-year disease-specific survival (DSS), regional recurrence-free survival (RRFS), and distant recurrence-free survival (DRFS). Results: VI was present in 47 of 698 WDTC (6.7%). VI was significantly associated with tumor size >4.0 cm, extrathyroidal extension, distant metastasis, and RAI treatment. On univariate analysis, VI was predictive of decreased 10-year DRFS, but not DSS or RRFS. On multivariate analysis, VI was not an independent predictor of DRFS. Univariate survival analysis of 422 RAI-naïve WDTC showed that both size >4 cm and VI were predictors of outcome, but only size remained independently predictive on multivariate analysis. Conclusion: The presence of VI is not an independent predictor of outcome in WDTC. [ABSTRACT FROM AUTHOR]

Purpose: Phosphatidylinositol-3-kinase I (PI3K) inhibition sensitizes a wide range of cancer cell lines to platinum/taxane-based chemotherapy. This phase I study combines buparlisib, a pan-class 1A PI3K inhibitor, with two schedules of carboplatin and paclitaxel for patients with advanced solid tumors (ClinicalTrials.gov, NCT01297452). Methods: There were two regimens: Group 1 received carboplatin AUC 5 and paclitaxel 175 mg/m, on day 1 of a 21-day cycle with pegfilgrastim support; Group 2 received carboplatin AUC 5 (day 1) and paclitaxel 80 mg/m (days 1, 8, and 15) on a 28-day cycle without growth factor support. In both groups, three dose levels of buparlisib were explored: 50, 80, and 100 mg/day. Primary endpoint was to identify recommended phase II doses of buparlisib in both groups. Results: Thirty subjects enrolled, 16 in Group 1 and 14 in Group 2. The DLTs were elevated alkaline phosphatase ( n = 1) and uncomplicated neutropenia ( n = 2). The median numbers of cycles were 5 (Group 1) and 6 (Group 2). The MTDs for buparlisib were 100 mg/day in Group 1 and 80 mg/day in Group 2. Among 25 patients with measurable disease, the confirmed objective response rate was 20 % (one complete response, four partial responses). Among three patients with known loss of PTEN expression, all derived clinical benefit from treatment. Conclusion: The addition of buparlisib to carboplatin + paclitaxel was well tolerated, and preliminary activity was notable against tumors with loss of PTEN expression. [ABSTRACT FROM AUTHOR]

Purpose: Elevated expression of eukaryotic protein synthesis initiation factor 4E (eIF4E) in histologically cancer-free margins of resected head and neck squamous cell carcinomas (HNSCCs) is mediated by mammalian target of rapamycin complex 1 (mTORC1) and has been associated with increased risk of disease recurrence. Preclinically, inhibition of mTORC1 with everolimus sensitizes cancer cells to cisplatin and radiation. Methods and Materials: This was single-institution phase 1 study to establish the maximum tolerated dose of daily everolimus given with fixed dose cisplatin (30 mg/m2 weekly × 6) and concurrent intensity modulated radiation therapy for patients with locally and/or regionally advanced head-and-neck cancer. The study had a standard 3 + 3 dose-escalation design. Results: Tumor primary sites were oral cavity (4), salivary gland (4), oropharynx (2), nasopharynx (1), scalp (1), and neck node with occult primary (1). In 4 of 4 cases in which resected HNSCC surgical pathology specimens were available for immunohistochemistry, elevated expression of eIF4E was observed in the cancer-free margins. The most common grade ≥3 treatment-related adverse event was lymphopenia (92%), and dose-limiting toxicities (DLTs) were mucositis (n=2) and failure to thrive (n=1). With a median follow up of 19.4 months, 2 patients have experienced recurrent disease. The maximum tolerated dose was everolimus 5 mg/day. Conclusions: Head-and-neck cancer patients tolerated everolimus at therapeutic doses (5 mg/day) given with weekly cisplatin and intensity modulated radiation therapy. The regimen merits further evaluation, especially among patients who are status post resection of HNSCCs that harbor mTORC1-mediated activation of eIF4E in histologically negative surgical margins. [ABSTRACT FROM AUTHOR]

Mucoepidermoid carcinoma (MEC) is one of the most common salivary gland malignancies. Our aim was to evaluate the prognostic impact of primary tumor site in patients with MEC.Material and Methods: This cohort identified 308 patients with MEC who underwent primary surgery between 1985 and 2015. Survival outcomes were determined using the Kaplan-Meier method. Hazard ratios for primary site were determined using the Cox proportional-hazards model.Results: One hundred eighty (58%) patients were diagnosed with minor and 128 (42%) with major salivary gland cancer. Primary site in the minor salivary gland group included 137 (44%) oral cavity, 38 (12%) pharynx, 3 (0.9%) nasal cavity, and 2 (0.6%) trachea and larynx. The major salivary gland group included 118 (38%) parotid, 8 (3%) submandibular, and 2 (0.6%) sublingual. With a median follow-up of 73 months, 5-year overall survival and disease-specific survival were 84% and 91%, respectively. Patients with tumors located in the hard palate and retromolar trigone had the best survival, while patients with tumors located in the paranasal sinuses and submandibular gland had the poorest survival. After controlling for tumor grade and stage, MEC primary site was not predictive of survival or recurrence. On multivariate analysis, worse DSS was associated with stage III-IV tumors (HR: 7,11; 95% CI: 1.19-26.43; p = 0.0034) and high-grade tumors (HR: 19.12; 95% CI: 2.26-162.77; p = 0.0068).Conclusions: While high grade and advanced overall stage were found to be independent predictors of worse survival, primary tumor site was not predictive of poor outcome. [ABSTRACT FROM AUTHOR]

Host immune microenvironment is a key component of anti-tumoral immune response, influencing tumor progression, regression, and treatment responses. There is a need for simple and reliable histologic measurements of host immune response in routine histopathologic diagnosis. The prognostic value of lymphocytic host response (LHR), a qualitative histologic grading scheme, was compared to stromal/intratumoral TIL (sTIL/iTIL) percentage, a quantitative measurement in a retrospective study of 329 patients with oral tongue squamous cell carcinoma (OTSCC) of 4 cm or less in size. High sTIL predicted improved distant recurrence free survival on univariate survival analysis and was an independent prognostic factor for better overall survival on multivariate analysis. LHR and iTIL were not associated with the risk of nodal metastasis or outcome. sTIL appears to be a superior quantitative histologic measurement for the host immune microenvironment compared with the qualitative LHR grading scheme. sTIL is an independent prognostic factor for overall survival in OTSCC. [ABSTRACT FROM AUTHOR]

Adenoid cystic carcinomas (ACCs) are among the most enigmatic of human malignancies. These aggressive salivary gland cancers frequently recur and metastasize despite definitive treatment, with no known effective chemotherapy regimen. Here we determined the ACC mutational landscape and report the exome or whole-genome sequences of 60 ACC tumor-normal pairs. These analyses identified a low exonic somatic mutation rate (0.31 non-silent events per megabase) and wide mutational diversity. Notably, we found mutations in genes encoding chromatin-state regulators, such as SMARCA2, CREBBP and KDM6A, suggesting that there is aberrant epigenetic regulation in ACC oncogenesis. Mutations in genes central to the DNA damage response and protein kinase A signaling also implicate these processes. We observed MYB-NFIB translocations and somatic mutations in MYB-associated genes, solidifying the role of these aberrations as critical events in ACC. Lastly, we identified recurrent mutations in the FGF-IGF-PI3K pathway (30% of tumors) that might represent new avenues for therapy. Collectively, our observations establish a molecular foundation for understanding and exploring new treatments for ACC. [ABSTRACT FROM AUTHOR]