OBJECTIVES:The management of oral potentially malignant disorders is primarily guided by the degree of oral epithelial dysplasia (OED) present on incisional biopsy. Despite the universal use of this technique to inform treatment decisions, this method harbours limitations which can result in the under- or overestimating the degree of OED when compared with the fully excised specimen. There is a paucity of published work examining the reliability of incisional biopsy for oral potentially malignant disorders, representing a clear gap in our understanding of the reliability of this diagnostic technique as a mainstay in our management of these conditions. STUDY DESIGN:The current study retrospectively examined the agreement between the histological findings on incisional biopsy and subsequently excised specimens in a cohort of patients with known OED in oral leukoplakia specimens in a single maxillofacial unit between 2021 and 2024. RESULTS:Of 88 total specimens, there was slight overall agreement between the two techniques. On subgroup analysis, for non-PVL OED, agreement was moderate, but agreement for PVL type OED was poor. A total of 31% of specimens were discordant, 41% with a lower degree of OED on biopsy versus excised specimen. The greatest discordance arose for moderate OED. Three factors for discordance were identified. CONCLUSION:This study has contributed to the evidence base by highlighting the discrepancies related to OED grading between incisional biopsy and resection specimens. While incisional biopsy is a dependable method for the diagnosis of non-PVL OED, its use in PVL highlights significant limitations. Reducing discordances requires an understanding of the causative factors and close collaboration between pathologists and clinicians.

Purpose HPV driven oropharyngeal squamous cell carcinoma (OPSCC) proffers a more favorable prognosis in contrast to its HPV negative counterparts. Consequently, studies have analyzed de-intensification measures of current treatment practices to minimize the associated morbidity. However, 25% of patients with HPV positive OPSCC experience a locoregional recurrence (LR) and/or distant metastasis (DM). This study aimed to determine if patient demographics, tumor characteristics and specific HPV genotyping were attributable to HPV positive OPSCC who develop LR and/or DM based on data collated from the largest Head and Neck Cancer center in the Republic of Ireland, with a mean follow up period of 11.16 years. Methods Patient demographics was obtained from HPV positive OPSCC patients from 3 Dublin Hospitals diagnosed over a 10-year period. In addition, HPV genotyping via Ion Torrent Next Generation Sequencing (NGS) and mutations analysis using smMIP panel based NGS was conducted on the cohort archival tumor DNA. Results 67 patients met the criteria for inclusion and had a mean follow-up period of 11.16 years. 28.36% developed LR and/or DM. A statistically significant correlation was identified linking age at diagnosis (p = 0.047), excessive alcohol consumption (p = 0.017) and a higher clinical stage (p = 0.01) with LR and/or DM.HPV 16 was the most prevalent genotype (93.65%), with dual HPV infection illustrated in 4 cases. BRAF, EGFR, ERBB2, KIT, KRAS, NRAS, PDGFRA somatic mutations were not identified in the recurrence cohort. Conclusion With the ongoing focus to reduce treatment for patient with HPV positive OPSCC, upfront recognition of patients at greater risk of LR and/or DM is essential. In the era of personalized medicine, it is hoped that interrogation of archival tumor tissue via similar techniques used in this study may yield pioneering findings with a clinical and prognostic significance.

Sialadenoma papilliferum is a tumor characterized by surface papillary projections and glandular/microcystic proliferation at the lesion base. Cases in which surface involvement is absent have been termed “sialadenoma papilliferum-like intraductal papillary tumor.” Similar tumors that are present in the mandible have been termed “tubulopapillary hidradenoma-like tumor of the mandible.” While previously considered benign, these tumors demonstrate variable clinical behavior and likely exist on a spectrum, rather than as discrete entities. In this study, we present a detailed clinicopathologic and molecular analysis of these lesions and propose a unifying diagnostic term: sialadenopapillary ductal tumor (SDT). Twenty-two cases with similar histologic features were reviewed, with special attention being paid to the clinicopathologic features. Immunohistochemistry for BRAF V600E and molecular testing were performed where material was available. The cases had varying diagnoses, ranging from benign to malignant. Six cases involved bone, 1 of which metastasized to a local lymph node. Of the 20 cases tested for BRAF V600E by immunohistochemistry, 18 were positive. Molecular testing was performed in 5 cases, where BRAF, PTPN11, and PIK3CA mutations were identified, predominantly members of the RAS-RAF-MEK-ERK pathway. In addition, 1 case was reclassified as an intraductal carcinoma after the identification of an NCOA4::RET gene fusion. Tumors on the SDT spectrum all share morphologic and molecular commonalities with unreliable distinguishing features. These tumors demonstrate the potential for aggressive local growth and regional metastasis. We propose a unifying diagnostic term for these lesions to reflect their common morphologic and molecular features and, most importantly, low malignant potential.

Sialadenoma papilliferum is a tumor characterized by surface papillary projections and glandular/microcystic proliferation at the lesion base. Cases in which surface involvement is absent have been termed "sialadenoma papilliferum-like intraductal papillary tumor." Similar tumors that are present in the mandible have been termed "tubulopapillary hidradenoma-like tumor of the mandible." While previously considered benign, these tumors demonstrate variable clinical behavior and likely exist on a spectrum, rather than as discrete entities. In this study, we present a detailed clinicopathologic and molecular analysis of these lesions and propose a unifying diagnostic term: sialadenopapillary ductal tumor (SDT). Twenty-two cases with similar histologic features were reviewed, with special attention being paid to the clinicopathologic features. Immunohistochemistry for BRAF V600E and molecular testing were performed where material was available. The cases had varying diagnoses, ranging from benign to malignant. Six cases involved bone, 1 of which metastasized to a local lymph node. Of the 20 cases tested for BRAF V600E by immunohistochemistry, 18 were positive. Molecular testing was performed in 5 cases, where BRAF, PTPN11, and PIK3CA mutations were identified, predominantly members of the RAS-RAF-MEK-ERK pathway. In addition, 1 case was reclassified as an intraductal carcinoma after the identification of an NCOA4::RET gene fusion. Tumors on the SDT spectrum all share morphologic and molecular commonalities with unreliable distinguishing features. These tumors demonstrate the potential for aggressive local growth and regional metastasis. We propose a unifying diagnostic term for these lesions to reflect their common morphologic and molecular features and, most importantly, low malignant potential.

Cytological specimens play a pivotal role in head and neck nodule/mass work up and diagnoses. The specimens´ importance has grown with the onset of personalized medicine and the routine use of molecular markers in the diagnostic work up. The Updates in Head and Neck Cytopathology Short Course ran during the 35th European Congress of Pathology held in Dublin, Ireland, in 2023 and brought together experts in cytopathology, pathology, and related fields to share their expertise and experience in the field of head and neck cytopathology and its future directions. Topics such as a one-stop clinic, the Milan System for Reporting Salivary Gland Cytopathology, next generation sequencing, and human papilloma virus detection in the head and neck area were covered during the short course. These topics are briefly summarized in the present review.

Salivary gland secretory carcinoma (SC), previously mammary analog SC, is a low-grade malignancy characterized by well-defined morphology and an immunohistochemical and genetic profile identical to SC of the breast. Translocation t(12;15)(p13;q25) resulting in the ETV6 :: NTRK3 gene fusion is a characteristic feature of SC along with S100 protein and mammaglobin immunopositivity. The spectrum of genetic alterations for SC continues to evolve. The aim of this retrospective study was to collect data of salivary gland SCs and to correlate their histologic, immunohistochemical, and molecular genetic data with clinical behavior and long-term follow-up. In this large retrospective study, we aimed to establish a histologic grading scheme and scoring system. A total of 215 cases of salivary gland SCs diagnosed between 1994 and 2021 were obtained from the tumor registries of the authors. Eighty cases were originally diagnosed as something other than SC, most frequently acinic cell carcinoma. Lymph node metastases were identified in 17.1% (20/117 cases with available data), with distant metastasis in 5.1% (6/117). Disease recurrence was seen in 15% (n=17/113 cases with available data). The molecular genetic profile showed ETV6 :: NTRK3 gene fusion in 95.4%, including 1 case with a dual fusion of ETV6 :: NTRK3 and MYB :: SMR3B . Less frequent fusion transcripts included ETV6 :: RET (n=12) and VIM :: RET (n=1). A 3-tiered grading scheme using 6 pathologic parameters (prevailing architecture, pleomorphism, tumor necrosis, perineural invasion (PNI), lymphovascular invasion (LVI), and mitotic count and/or Ki-67 labeling index) was applied. Grade 1 histology was observed in 44.7% (n=96), grade 2 in 41.9% (n=90), and grade 3 in 13.5% (n=29) of cases. Compared with low-grade and intermediate-grade SC, high-grade tumors were associated with a solid architecture, more prominent hyalinization, infiltrative tumor borders, nuclear pleomorphism, presence of PNI and/or LVI, and Ki-67 proliferative index >30%. High-grade transformation, a subset of grade 2 or 3 tumors, seen in 8.8% (n=19), was defined as an abrupt transformation of conventional SC into high-grade morphology, sheet-like growth, and a tumor lacking distinctive features of SC. Both overall survival and disease-free survival (5 and 10 y) were negatively affected by tumor grade, stage, and TNM status (each P <0.0001). SC is a low-grade malignancy with predominantly solid-microcystic growth patterns, driven by a gene fusion, most commonly ETV6 :: NTRK3 . There is a low risk for local recurrence and a good overall long-term survival, with a low risk for distant metastasis but a higher risk for locoregional lymph node metastasis. The presence of tumor necrosis, hyalinization, PNI and/or LVI, and positive resection margins correlate with higher tumor grade, less favorable prognosis, and increased mortality. The statistical results allowed us to design a 3-tiered grading system for salivary SC.

Human papillomavirus (HPV) infection has been identified as a significant etiological agent in the development of head and neck squamous cell carcinoma (HNSCC). HPV’s involvement has alluded to better survival and prognosis in patients and suggests that different treatment strategies may be appropriate for them. Only some data on the epidemiology of HPV infection in the oropharyngeal, oral cavity, and laryngeal SCC exists in Europe. Thus, this study was carried out to investigate HPV’s impact on HNSCC patient outcomes in the Irish population, one of the largest studies of its kind using consistent HPV testing techniques. A total of 861 primary oropharyngeal, oral cavity, and laryngeal SCC (OPSCC, OSCC, LSCC) cases diagnosed between 1994 and 2013, identified through the National Cancer Registry of Ireland (NCRI), were obtained from hospitals across Ireland and tested for HPV DNA using Multiplex PCR Luminex technology based in and sanctioned by the International Agency for Research on Cancer (IARC). Both overall and cancer-specific survival were significantly improved amongst all HPV-positive patients together, though HPV status was only a significant predictor of survival in the oropharynx. Amongst HPV-positive patients in the oropharynx, surgery alone was associated with prolonged survival, alluding to the potential for de-escalation of treatment in HPV-related OPSCC in particular. Cumulatively, these findings highlight the need for continued investigation into treatment pathways for HPV-related OPSCC, the relevance of introducing boys into national HPV vaccination programs, and the relevance of the nona-valent Gardasil-9 vaccine to HNSCC prevention.

The Human Papilloma Virus (HPV) is an oncogenic virus which is associated with the development of head and neck squamous cell carcinoma (HNSCC), predominantly within the oropharynx. Approximately 25% of oropharyngeal squamous cell carcinoma (OPSCC) cases worldwide are attributable to HPV infection, with an estimated 65% in the United States. Transmission is via exposure during sexual contact, with distinctive anatomical features of the tonsils providing this organ with a predilection for infection by HPV. No premalignant lesion is identifiable on clinical examination, thus no comparative histological features to denote the stages of carcinogenesis for HPV driven HNSCC are identifiable. This is in contrast to HPV-driven cervical carcinoma, making screening a challenge for the head and neck region. However, HPV proffers a favorable prognosis in the head and neck region, with better overall survival rates in contrast to its HPV negative counterparts. This has resulted in extensive research into de-intensifying therapies aiming to minimize the morbidity induced by standard concurrent chemo-radiotherapy without compromising efficacy. Despite the favorable prognosis, cases of recurrence and/or metastasis of HPV positive HNSCC do occur, and are linked with poor outcomes. HPV 16 is the most frequent genotype identified in HNSCC, yet there is limited research to date studying the impact of other HPV genotype with respect to overall survival. A similar situation pertains to genetic aberrations associated in those with HPV positive HNSCC who recur, with only four published studies to date. Somatic mutations in TSC2, BRIP1, NBN, TACC3, NFE2l2, STK11, HRAS, PIK3R1, TP63, and FAT1 have been identified in recurrent HPV positive OPSCC. Finding alternative therapeutic strategies for this young cohort may depend on upfront identification of HPV genotypes and mutations which are linked with worse outcomes, thus ensuring appropriate stratification of treatment regimens.

Signal transducers and activator of transcription (STAT)-3 is activated in cancers, where it promotes growth, inflammation, angiogenesis, and inhibits apoptosis. Tissue microarrays were generated using tissues from 154 patients, with oesophageal adenocarcinoma (OAC) (n = 116) or squamous cell carcinoma (SCC) (n = 38) tumours. The tissues were stained for pSTAT3 and IL-6R using immunohistochemistry. The OE33 (OAC) and OE21 (SCC) cell lines were treated with the STAT3 inhibitor, STATTIC. The Univariate cox regression analysis revealed that a positive pSTAT3 in SCC was adversely associated with survival (Hazard ratio (HR) 6.382, 95% CI 1.266–32.184), while a protective effect was demonstrated with the higher pSTAT3 levels in OAC epithelium (HR 0.74, 95% CI 0.574–0.953). The IL-6R intensity levels were higher in the SCC tumours compared with the OAC tumours for the core and leading edge tumour tissue. The pSTAT3 levels correlated positively with the IL-6R levels in both the OAC and SCC. The treatment of OE21 and OE33 cells with the STAT3 inhibitor STATTIC in vitro resulted in decreased survival, proliferation, migration, and increased apoptosis. The pSTAT3 expression was associated with adverse survival in SCC, but not in the OAC patients. The inhibition of STAT3 in both of the tumour subtypes resulted in alterations in the survival, proliferation, migration, and apoptosis, suggesting a potential role for therapeutically targeting STAT3.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Background: Human papillomavirus (HPV)–related oropharyngeal squamous cell carcinoma (SCC) represents a distinct subgroup of head and neck tumors. We analyze the expression of cytokeratin 7, a junctional biomarker with a SEQIKA fragment, which stabilizes HPV-16 E7 transcripts, in oropharyngeal SCCs. Methods: Archived tumor specimens and epidemiologic data were collected from patients with oropharyngeal SCCs over 10 years. Briefly, DNA was extracted from tissue blocks, and HPV testing was carried out using SPF10 HPV PCR and INNO-LiPA HPV Genotyping. Immunohistochemical staining for CK7 and p16ink4a was performed on the Ventana BenchMark Ultra Immunostainer. Analysis was by light microscopy using the H-score. CK7 expression was correlated with epidemiologic data, p16ink4a positivity, and HPV status using SPSS. Results: CK7 expression was observed specifically and uniformly in the tonsillar crypt epithelium of normal tonsils and tumor specimens. There were 226 cases of oropharyngeal SCCs, with 70 demonstrating both HPV and p16 positivity. Of 216 cases evaluated for CK7, 106 demonstrated some positivity, whereas H-score > 60 was seen in 55 of these. CK7 H-score > 60 was significantly associated with tonsillar subsite and HPV and p16 positivity. Conclusions: An association between CK7 and HPV has been demonstrated. CK7-expressing tonsillar crypt cells potentially represent an oropharyngeal subsite susceptible to HPV-related SCC. Impact: Along with the cervix and anorectum, specific oropharyngeal expression of CK7 in a site predisposed to HPV-related tumors may suggest a role for CK7 in the pathogenesis of this subgroup of tumors. Further research is warranted to characterize the association between CK7 and HPV-related head and neck SCC. Cancer Epidemiol Biomarkers Prev; 26(5); 702–10. ©2017 AACR.

Circumorificial plasmacytosis is a rare plasma cell proliferative disorder of the orificial mucous membranes. The etiology is unknown, and there are no reported effective treatments to date. We report three cases of idiopathic circumorificial plasmacytosis with varying clinical presentations and responses to treatment, including a first reported case of resolution with adalimumab therapy.

Human papillomavirus (HPV) has been implicated in the pathogenesis of a subset of oropharyngeal squamous cell carcinoma. As a result, traditional paradigms in relation to the management of head and neck squamous cell carcinoma have been changing. Research into HPV-related oropharyngeal squamous cell carcinoma is rapidly expanding, however many molecular pathological and clinical aspects of the role of HPV remain uncertain and are the subject of ongoing investigation. A detailed search of the literature pertaining to HPV-related oropharyngeal squamous cell carcinoma was performed and information on the topic was gathered. In this article, we present an extensive review of the current literature on the role of HPV in oropharyngeal squamous cell carcinoma, particularly in relation to epidemiology, risk factors, carcinogenesis, biomarkers and clinical implications. HPV has been established as a causative agent in oropharyngeal squamous cell carcinoma and biologically active HPV can act as a prognosticator with better overall survival than HPV-negative tumours. A distinct group of younger patients with limited tobacco and alcohol exposure have emerged as characteristic of this HPV-related subset of squamous cell carcinoma of the head and neck. However, the exact molecular mechanisms of carcinogenesis are not completely understood and further studies are needed to assist development of optimal prevention and treatment modalities.

Background: Induction chemotherapy is a common therapeutic option for patients with locoregionally-advanced head and neck cancer (HNC), but it remains unclear which patients will benefit. In this study, we searched for biomarkers predicting the response of patients with locoregionally-advanced HNC to induction chemotherapy by evaluating the expression pattern of DNA repair proteins.Methods: Expression of a panel of DNA-repair proteins in formalin-fixed paraffin embedded specimens from a cohort of 37 HNC patients undergoing platinum-based induction chemotherapy prior to definitive chemoradiation were analyzed using quantitative immunohistochemistry.Results: We found that XPF (an ERCC1 binding partner) and phospho-MAPKAP Kinase 2 (pMK2) are novel biomarkers for HNSCC patients undergoing platinum-based induction chemotherapy. Low XPF expression in HNSCC patients is associated with better response to induction chemoradiotherapy, while high XPF expression correlates with a worse response (p = 0.02). Furthermore, low pMK2 expression was found to correlate significantly with overall survival after induction plus chemoradiation therapy (p = 0.01), suggesting that pMK2 may relate to chemoradiation therapy.Conclusions: We identified XPF and pMK2 as novel DNA-repair biomarkers for locoregionally-advanced HNC patients undergoing platinum-based induction chemotherapy prior to definitive chemoradiation. Our study provides insights for the use of DNA repair biomarkers in personalized diagnostics strategies. Further validation in a larger cohort is indicated.

Objective To examine the role of RET in renal malignancy, in particular papillary renal cell carcinoma (RCC). Materials and methods A cohort of 111 archival renal samples was used consisting of 94 renal cancers (66 papillary RCC, 18 conventional clear cell carcinoma, 10 chromophobe RCC), 4 benign oncocytomas, and 13 normal kidney tissues. RET protein expression was examined by immunohistochemistry and expression levels were correlated with clinicopathologic and patient survival data. Results Positive RET staining was seen in 34/66 (52%) papillary RCCs, 4/10 (40%) chromophobe carcinomas, 4/4 (100%) oncocytomas, and 11/13 (85%) normal kidney samples. All 18 cases of conventional clear cell carcinoma had negative RET staining. RET expression was associated with low Fuhrman nuclear grade. Conclusions RET protein may be contributing in part to an adaptation of a papillary growth pattern in certain renal malignancies. Given the possible therapeutic benefit of small molecule inhibitors of RET activation, further work needs to be done to highlight the functional relevance of RET protein expression in papillary RCC.