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To present an institution's experience and survival outcomes for patients with head and neck cutaneous squamous cell carcinoma (HNcSCC) and perineural spread (PNS).Retrospective study of patients with HNcSCC and PNS treated between January 2010 and August 2020 from the Sydney Head and Neck Cancer Institute database, Sydney, Australia; a high-volume, tertiary, academic head and neck centre. Patient demographics, primary site, involved cranial nerves, treatment modality, loco-regional failure and survival data were obtained.Forty-five patients were identified, of which 32 patients were male (71%). Mean age at diagnosis was 68.7 years (range 43-90). Median follow-up was 16.1 months (range 1-107). The trigeminal nerve was most frequently involved (n = 30, 66.6%) followed by facial nerve (n = 13, 28.9%). Most patients underwent surgery followed by radiotherapy (n = 33, 73%) and eight received definitive radiotherapy. The median overall survival (OS) was 4.5 years (95% CI 3.71-5.38), median disease-specific survival 5.1 years (95% CI 4.21-5.97) and median disease-free survival (DFS) was 1.7 years (95% CI 1.11-2.22). The estimated 5-year OS and DFS were 45% and 25%, respectively. Patients treated with surgery and adjuvant radiotherapy with a clear proximal nerve margin had favourable DFS (P = 0.035) and trended towards better OS (P = 0.134) compared with patients with an involved nerve margin. Patients treated surgically with involved proximal nerve margins had similar outcomes compared with patients with treated definitive radiotherapy (HR 0.80, 95% CI 0.29-2.22, P = 0.664).The likelihood of achieving a clear proximal nerve margin should be a strong consideration in the selection of appropriate patients for primary surgery.

A small subset of lung adenocarcinomas harbour ROS1 gene arrangements and are amenable to tyrosine kinase inhibitor therapy. Current practice in Australia involves screening for ROS1 rearrangements in adenocarcinomas using ROS1 immunohistochemistry (IHC) followed by confirmatory molecular testing such as fluorescence in situ hybridisation (FISH), if other known genetic driver alterations are absent. The best threshold to determine ROS1 IHC positivity is not well defined, however, and this study aims to determine the optimal threshold for ROS1 IHC screening to identify ROS1-rearranged lung adenocarcinomas. A total of 177 lung adenocarcinomas tested for a ROS1 rearrangement by FISH at our institution between 2017 and 2020 due to presence of ROS1 IHC staining were included in the study. ROS1 IHC staining was assessed by scoring the staining intensity (0, 1, 2, or 3+) and multiplying by the percentage of positive cells to generate an H-score. IHC H-scores were compared with FISH. Of 177 cases, 32 (18%) were ROS1 FISH-positive and 145 (82%) were negative. FISH-positive cases had a median H-score of 300 (range 200-300; mean 290.3) and negative cases had a median H-score of 40 (range 0-300; mean 63). All FISH-positive cases showed strong and diffuse IHC positivity. Using a threshold H-score of 200, the sensitivity of identifying ROS1 rearrangements was 100% and the specificity was 95% amongst cases referred with ROS1 IHC positivity. Adenocarcinomas with a FISH-confirmed ROS1 rearrangement demonstrate diffuse, strong (2-3+) IHC staining. Cases with weak, patchy ROS1 IHC staining are not associated with ROS1 rearrangements and in these cases FISH testing is of little to no utility.

Oral epithelial dysplasia (OED) represents a spectrum of histologic changes in the oral cavity mucosa that has the potential to transform into oral squamous cell carcinoma. Predicting the risk of malignant transformation is predominantly based on clinicopathologic correlation, histologic examination and grading. OED often poses a diagnostic challenge, primarily due to its histologic mimics and a large number of terminologies used in the literature. The grading system for OED is also fraught with significant interobserver variability. This review summarizes the essential clinical and histopathologic features of OED and its mimics. Practical preanalytical, analytical, and postanalytical considerations for anatomic pathologists are discussed to improve the diagnostic accuracy and increase the reproducibility in the grading of OED.

Background pT3/4 head and neck cutaneous squamous cell carcinomas (HNcSCCs) are associated with poor outcomes, including local recurrence, metastasis and death. Whilst surgery remains the standard treatment for advanced HNcSCC, novel systemic therapies, such as immunotherapy, are being used earlier in the treatment paradigm. It is imperative that the clinical outcomes of surgery are clearly described so that conventional and emerging treatment modalities can be better integrated and sequenced in the management of pT3/4 HNcSCC. Methods Patients with confirmed pT3/4 HNcSCC undergoing curative surgical resection between 2014-2020 were identified retrospectively from a prospectively maintained research database. The primary outcomes of interest were locoregional control (LRC), disease-specific survival (DSS), and overall survival (OS). The secondary outcome was surgical complication rate. Results A total of 104 patients (median age 74, range 41–94 years) were included, 90% of which had pT3 tumors; 36.5% received adjuvant radiotherapy. Median follow-up was 24.3 (range 1.0–84.3) months. LRC at 5 years was 62.0%, DSS at 5 years was 83.7%, and OS at 5 years was 71.9%. Median time to recurrence was 8.4 months. LRC was reduced in the presence of margin involvement and previous treatment (radiotherapy/surgery). The major surgical complication rate was 9.6%. Conclusions More than 60% of patients treated surgically for pT3/4 head and neck cSCC were alive and free of disease at 5 years posttreatment. High-risk features such as margin involvement and having had previous treatment (radiotherapy/surgery) should be used to guide adjuvant therapy.

Supplementary Figure from High-Dimensional and Spatial Analysis Reveals Immune Landscape–Dependent Progression in Cutaneous Squamous Cell Carcinoma

Purpose:The tumor immune microenvironment impacts the biological behavior of the tumor, but its effect on clinical outcomes in head and neck cutaneous squamous cell carcinomas (HNcSCC) is largely unknown.Experimental Design:We compared the immune milieu of high-risk HNcSCC that never progressed to metastasis with those that metastasized using multiparameter imaging mass cytometry. The cohort included both immunosuppressed patients (IS) and patients with an absence of clinical immune-suppression (ACIS). Spatial analyses were used to identify cellular interactions that were associated with tumor behavior.Results:Nonprogressing primary HNcSCC were characterized by higher CD8+ and CD4+ T-cell responses, including numerically increased regulatory T cells. In contrast, primary lesions from HNcSCC patients who progressed were largely devoid of T cells with lower numbers of innate immune cells and increased expression of checkpoint receptors and in the metastatic lesions were characterized by an accumulation of B cells. Spatial analysis reveals multiple cellular interactions associated with nonprogressing primary tumors that were distinct in primary tumors of disease-progressing patients. Cellular regional analysis of the tumor microenvironment also shows squamous cell–enriched tumor regions associated with primary nonprogressing tumors.Conclusions:Effective responses from both CD8+ and CD4+ T cells in the tumor microenvironment are essential for immune control of primary HNcSCC. Our findings indicate that the early events that shape the immune responses in primary tumors dictate progression and disease outcomes in HNcSCC.

Supplementary Table from High-Dimensional and Spatial Analysis Reveals Immune Landscape–Dependent Progression in Cutaneous Squamous Cell Carcinoma

Targeted therapy (BRAF inhibitor plus MEK inhibitor) is now among the possible treatment options for patients with BRAF mutation-positive stage III or stage IV melanoma. This makes prompt BRAF mutation testing an important step in the management of patients diagnosed with stage III or IV melanoma; one that can help better ensure that the optimal choice of systemic treatment is initiated with minimal delay. This article offers guidance about when and how BRAF mutation testing should be conducted when patients are diagnosed with melanoma in Australia. Notably, it recommends that pathologists reflexively order BRAF mutation testing whenever a patient is found to have American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) stage III or IV melanoma (i.e., any metastatic spread beyond the primary tumour) and that patient's BRAF mutation status is hitherto unknown, even if BRAF mutation testing has not been specifically requested by the treating clinician (in Australia, Medicare-subsidised BRAF

Background The eighth edition of the American Joint Committee on Cancer Staging Manual includes a staging system for head and neck cutaneous squamous cell carcinoma for the first time. The pN categories for head and neck cutaneous squamous cell carcinoma and mucosal squamous cell carcinoma are identical, despite the vastly different biological behavior of these diseases. This study aimed to survey head and neck cancer specialists’ views regarding the clinical utility of the American Joint Committee on Cancer Staging Manual for head and neck cutaneous squamous cell carcinoma and to identify avenues for improvement. Design An electronic survey of 19 questions relating to the prognostic utility of the staging system was designed based on the findings of a literature review. The survey was distributed internationally to specialists managing head and neck cutaneous squamous cell carcinoma. Results Literature review identified 9 articles describing primary research relevant to the performance of the American Joint Committee on Cancer Staging Manual for head and neck cutaneous squamous cell carcinoma, which recognized a lack of homogeneity, monotonicity, and distinctiveness in the pN staging system. One hundred and five survey responses were received: 71% indicated that mucosal and head and neck cutaneous squamous cell carcinoma require different nodal staging categories; 63% indicated that immunosuppression should be included in the staging system; 70% thought that soft tissue metastases portend a worse prognosis compared with extranodal extension; 38% almost never saw pN3a tumors; and 40% felt that the N stage is a poor predictor of survival. Conclusion The views of head and neck cancer specialists across disciplines and countries align with evidence suggesting that head and neck cutaneous squamous cell carcinoma merits a staging system distinct from mucosal squamous cell carcinoma, that immunosuppression should be considered in prognostication, and that the use of extranodal extension should be modified.

Context.— There is a global decline in medical graduates pursuing pathology careers, resulting in a broadening gap between workforce demand and supply. Objective.— To determine causes of low popularity of pathology as a career and develop strategies to avoid a workforce crisis. Design.— An online survey was distributed and yielded 1247 responses, including 609 Australian medical students from 10 medical schools, 119 prevocational doctors from 10 major teaching hospitals in New South Wales, 175 residents, and 344 pathologists throughout Australia. Results.— Compared with pathology-uninterested peers, students and prevocational doctors interested in pathology careers were more likely to value research opportunities (57 of 166 [34.3%] pathology-interested respondents versus 112 of 521 [21.5%] pathology-uninterested respondents; odds ratio [OR] = 1.91, P < .001), have children (19 of 165 respondents [11.5%] versus 22 of 522 respondents [4.2%]; OR = 2.96, P < .001), and self-identify as introverted (87 of 167 respondents [52.1%] versus 179 of 526 respondents [34%]; OR = 2.1, P < .001). Those uninterested in pathology were more likely to value patient interaction (363 of 524 respondents [69.3%] versus 71 of 166 respondents [42.8%]; OR = 3.02, P < .001). Lack of exposure to pathology was the most-cited reason for rejecting pathology (after lack of patient interaction). There was poor understanding of the role of pathologists and low confidence in the ability to interpret histopathology reports among medical students and prevocational doctors. Negative stereotypes regarding pathologists were identified. Conclusions.— Active interventions increasing exposure of medical students and prevocational doctors to pathology as a career, as well as promotion of research opportunities and potential for work–life balance, are needed to address pending workforce shortages.

Background Regional metastasis of head and neck cutaneous squamous cell carcinoma (HNcSCC) can be seen in either parotid and/or cervical lymph nodes. The aim of this study was to assess whether there was a difference in prognosis between parotid and cervical nodal metastases. Methods Patients with regional metastasis from HNcSCC were identified from an institutional database. Disease-specific (DSS) and overall survival (OS) were calculated using the Kaplan-Meier method and Cox proportional hazards models. Results Five hundred and thirty-five patients were identified with median follow-up of 26.4 months (3-255 months). Two hundred and thirty-five patients had parotid metastasis, 96 patients had neck metastasis, and 204 patients had both. On multivariable analysis, any regional metastasis to the neck when compared to parotid alone conferred worse DSS (HR 1.8, p = 0.007) and OS (HR 1.3, p = 0.024). Conclusion Regional metastasis of HNcSCC to the neck confers worse outcomes compared to metastasis to the parotid alone.

Viruses are well known drivers of several human malignancies. A causative factor for oral cavity squamous cell carcinoma (OSCC) in patients with limited exposure to traditional risk factors, including tobacco use, is yet to be identified. Our study aimed to comprehensively evaluate the role of viral drivers in OSCC patients with low cumulative exposure to traditional risk factors. Patients under 50 years of age with OSCC, defined using strict anatomic criteria were selected for WGS. The WGS data was interrogated using viral detection tools (Kraken 2 and BLASTN), together examining >700,000 viruses. The findings were further verified using tissue microarrays of OSCC samples using both immunohistochemistry and RNA in situ hybridisation (ISH). 28 patients underwent WGS and comprehensive viral profiling. One 49-year-old male patient with OSCC of the hard palate demonstrated HPV35 integration. 657 cases of OSCC were then evaluated for the presence of HPV integration through immunohistochemistry for p16 and HPV RNA ISH. HPV integration was seen in 8 (1.2%) patients, all middle-aged men with predominant floor of mouth involvement. In summary, a wide-ranging interrogation of >700,000 viruses using OSCC WGS data showed HPV integration in a minority of male OSCC patients and did not carry any prognostic significance.

Background and objectives We performed a critical analysis of the 8th edition American Joint Committee on Cancer (AJCC) staging for head and neck cutaneous squamous cell carcinoma (HNcSCC) with nodal metastases and compared the performance to the N1S3 and ITEM systems. Methods Multicenter study of 990 patients with metastatic HNcSCC treated with curative intent. The end points of interest were disease-specific (DSS) and overall survival (OS). Model fit was evaluated using Harrell's Concordance Index (C-index), proportion of variation explained (PVE), Akaike information criterion, and Bayesian information criterion. Results N1S3 and ITEM demonstrated good distribution into risk categories in contrast to the AJCC system, which classified the majority (90.6%) of patients as N2-3 and Stage IV due to the high rate of extranodal extension. The N2c and N3a categories appeared redundant. There was considerable discordance between systems in risk allocation on an individual patient basis. N1S3 was the best performed (DSS: C-index 0.62, PVE 10.9%; OS: C-index 0.59, PVE 4.5%), albeit with relatively poor predictive value. Conclusions The AJCC N category and tumor node metastasis stage have poor patient distribution and predictive performance in HNcSCC. The AJCC stage, N1S3, and ITEM score all provide limited prognostic information based on objective measures highlighting the need to develop a staging system specific to HNcSCC.

The vermilion lip is a unique anatomical junction between cutaneous and mucosal surfaces. Squamous cell carcinoma (SCC) of the vermilion lip (vlSCC) was previously classified as oral SCC (oSCC) under the American Joint Committee on Cancer (AJCC) 7th edition (AJCC7), but has been recategorized as a cutaneous SCC of the head and neck (HNcSCC) in the AJCC 8th edition (AJCC8). We investigated the locoregional control (LRC), disease-free survival (DFS), and overall survival (OS) for the various pathological T categories and disease stages of vlSCC as per AJCC8. We performed a retrospective cohort study of 297 patients diagnosed with vlSCC between January 2004 and February 2019. For this study, vlSCC cases were staged according to both AJCC7 and AJCC8. Kaplan–Meier survival curves and Cox regression models were used to analyze differences in LRC, DFS, and OS between each pT category and disease stage, and log-rank tests were performed for subgroup analysis. Restaging of vlSCC using the AJCC8 resulted in 19% of patients being upstaged to pT3, and 16% being upstaged to stage III. No patients were downstaged in pT stage or overall stage. Our study shows that when the AJCC8 HNcSCC staging system is applied to vlSCC, there are important aberrations leading to unwarranted upstaging of pT1 and redundancy of pT2. Understanding of these limitations are important in considering treatment escalation.

BACKGROUND In head and neck cancers, tumor margin assessment has important prognostic and therapeutic implications. Frozen section control of margins is commonly employed intraoperatively. However, this is not without limitations. The aim of this study is to determine whether intraoperative slicing of the whole specimen is feasible and what impact this may have on tumor margin assessment and the requirement for postoperative radiotherapy. METHODS From September 2016 to August 2018, we recruited 22 patients as a pilot study looking at both the practicalities and the clinical relevance of whole margin tumor analysis intraoperatively. Our project is a prospective single arm study with historical controls. RESULTS Forty-one percent of our patients required further intraoperative resection for close or involved margins. Seven of these patients who otherwise would have required adjuvant radiotherapy due to their margin status did not, after our intervention. CONCLUSIONS We found that although requiring resources, this process was feasible without unduly increasing operative times and with potential patient benefit including reduced incidence of adjuvant radiotherapy.

Oral squamous cell carcinoma (OSCC) in the young (50 years), without known carcinogenic risk factors, is on the rise globally. Whole genome duplication (WGD) has been shown to occur at higher rates in cancers without an identifiable carcinogenic agent. We aimed to evaluate the prevalence of WGD in a cohort of OSCC patients under the age of 50 years.Whole genome sequencing (WGS) was performed on 28 OSCC patients from the Sydney Head and Neck Cancer Institute (SHNCI) biobank. An additional nine cases were obtained from The Cancer Genome Atlas (TCGA).WGD was seen in 27 of 37 (73%) cases. Non-synonymous, somatic TP53 mutations occurred in 25 of 27 (93%) cases of WGD and were predicted to precede WGD in 21 (77%). WGD was significantly associated with larger tumor size (p = 0.01) and was frequent in patients with recurrences (87%, p = 0.36). Overall survival was significantly worse in those with WGD (p = 0.05).Our data, based on one of the largest WGS datasets of young patients with OSCC, demonstrates a high frequency of WGD and its association with adverse pathologic characteristics and clinical outcomes. TP53 mutations also preceded WGD, as has been described in other tumors without a clear mutagenic driver.

Purpose:The tumor immune microenvironment impacts the biological behavior of the tumor, but its effect on clinical outcomes in head and neck cutaneous squamous cell carcinomas (HNcSCC) is largely unknown.Experimental Design:We compared the immune milieu of high-risk HNcSCC that never progressed to metastasis with those that metastasized using multiparameter imaging mass cytometry. The cohort included both immunosuppressed patients (IS) and patients with an absence of clinical immune-suppression (ACIS). Spatial analyses were used to identify cellular interactions that were associated with tumor behavior.Results:Nonprogressing primary HNcSCC were characterized by higher CD8+ and CD4+ T-cell responses, including numerically increased regulatory T cells. In contrast, primary lesions from HNcSCC patients who progressed were largely devoid of T cells with lower numbers of innate immune cells and increased expression of checkpoint receptors and in the metastatic lesions were characterized by an accumulation of B cells. Spatial analysis reveals multiple cellular interactions associated with nonprogressing primary tumors that were distinct in primary tumors of disease-progressing patients. Cellular regional analysis of the tumor microenvironment also shows squamous cell–enriched tumor regions associated with primary nonprogressing tumors.Conclusions:Effective responses from both CD8+ and CD4+ T cells in the tumor microenvironment are essential for immune control of primary HNcSCC. Our findings indicate that the early events that shape the immune responses in primary tumors dictate progression and disease outcomes in HNcSCC.

AimsTo investigate trends in representation of women among authors and editorial boards of surgical pathology journals over the last two decades.Secondary aims: to identify barriers and potential solutions.MethodsThe names and gender of first, middle, last authors and editorial board members were obtained from original articles from seven pathology journals from various geopolitical regions in 2002, 2011 and 2021. The proportion of women first, middle, last authors and editorial board members were compared over time.Results1097 publications and 8012 individual authors were extracted. In 2002, 2011 and 2021, respectively, the percentage of women first authors were 28.3% (257 of 907), 31.9% (566 of 1773) and 41.1% (1421 of 3457); women middle authorship rates were 30.0% (159 of 530), 32.8% (375 of 1145) and 40.9% (1067 of 2609) and women last authors were 18.0% (34 of 188), 26.0% (82 of 315) and 36.0% (152 of 422). Women representation on editorial boards has increased (11.3%, 15.8%, 26.5%), but of the chief editors, there was only one woman in 2021, while all were men in 2002 and 2011.ConclusionsTo our knowledge, this study is the first to document under-representation of women among authors and editorial boards of surgical pathology journals. While women representation has increased over time, predominance of men remains relative to workforce proportions. Our findings are comparable to those from other medical fields and prompt the need to investigate the underlying causes for this imbalance and implement strategies to promote diversity, equity and inclusion in academic surgical pathology.

To describe the incidence of primary cutaneous squamous cell carcinoma in coastal NSW Australia.The design is a case-controlled study of reported cSCC from 2016 to 2019 within a defined region of coastal southern NSW. Participants include all reported pathological diagnoses of cSCC in patients greater than 20 years of age. The main outcome measures the incidence and relative risk of cSCC.The age-adjusted incidence rate of primary cSCC was 856/10The rates of cSCC are far higher than previously reported and demand a reappraisal of our national management of this disease.

Metastatic cutaneous squamous cell carcinoma (cSCC) is a highly morbid disease requiring radical surgery and adjuvant therapy that is associated with reduced overall survival. Yet compared to other advanced malignancies, relatively little is known of the genomic landscape of metastatic cSCC. We have previously reported the mutational signatures and mutational patterns of CCCTC-binding factor (CTCF) regions in metastatic cSCC. However, many other genomic components (indel signatures, non-coding drivers, and structural variants) of metastatic cSCC have not been reported. To this end, we performed whole genome sequencing on lymph node metastases and blood DNA from 25 cSCC patients with regional metastases of the head and neck. We designed a multifaceted computational analysis at the whole genome level to provide a more comprehensive perspective of the genomic landscape of metastatic cSCC.In the noncoding genome, 3’UTR regions ofEVC(48% of specimens),PPP1R1A(48% of specimens) andABCA4(20% of specimens) along with the tumor-suppressing lncRNA LINC01003 (64% of specimens) were significantly functionally altered (Q-value < 0.05) and represent potential noncoding biomarkers of cSCC. Recurrent copy number loss in the tumor suppressor genePTPRDwas observed. Gene amplification was much less frequent and few genes were recurrently amplified. Single nucleotide variants driver analyses from 3 tools confirmedTP53andCDKN2Aas recurrently mutated genes but also identifiedC9as potential novel driver in this disease. Further, indel signature analysis highlighted the dominance of ID signature 13 (ID13) followed by ID8 and ID9. ID 9 has previously been shown to have no association with skin melanoma, unlike ID 13 and 8, suggesting a novel pattern of indel variation in metastatic cSCC. The enrichment analysis of various genetically altered candidates shows enrichment of ‘TGF-beta regulation of extracellular matrix’ and ‘Cell cycle G1 to S check points’. These enriched terms are associated with genetic instability, cell proliferation, and migration providing mechanisms of genomic drivers of metastatic cSCC.

Vascularised periosteum can used for reconstructing bony defects due to its intrinsic osteogenic properties. This osteogenic potential can be harnessed as a vascularised flap to induce bone growth of complex constructs in-vivo. The authors aimed to use a novel pedicled periosteal flap from the scapula to induce bone growth in a critical sized construct.Eight sheep were used as live animal models. A novel periosteal flap was raised from the infraspinous fossa of each animal and wrapped around non-vascularised autologous bone graft. The constructs were allowed to incubate between 1 and 84 days before harvest. Analysis of the flap was done via histopathology using haematoxylin and eosin staining.All flaps were viable at the conclusion of surgery. Seven flaps showed variable thickening with matrix deposition. One flap was devitalised at time of harvest.The novel periosteal scapular flap described is a promising technique to induce bone growth in complex constructs.

Perinueral invasion (PNI) is recognized as an independent adverse prognostic factor associated with shorter disease free and disease specific survival in a range of malignancies. However, not all histologically detected PNI demonstrate aggressive biologic behaviour. Herein, we systematically review the literature to identify neurotrophic biomarkers that may potentially be used to predict the biologic potential of PNI.A systematic review was conducted based on PRISMA guidelines utilising the search terms 'PNI', 'DNA' and 'RNA' analysis in select malignancies following registry of the search strategy on PROSPERO. The biologic role of the molecular markers identified through the literature review was examined using publicly available databases, such as Gene Cards and Kyoto Encyclopedia of Genes and Genomes (KEGG) with a focused literature review of the identified pathways.The systematic search identified 256 studies, of which 78 studies were suitable for data extraction. A variety of methodologies including immunohistochemistry, immunoblotting, nucleic acid sequencing, Luciferase assays and CRISPR techniques have been undertaken to evaluate the biologic potential of PNI. The studies evaluated 136 unique molecules. Of these, only 15 molecules were investigated through multiple studies with concordant results or had robust functional analyses. Three pathways were identified as playing a role in PNI, namely; the epithelial-mesenchymal transition pathway, neurotrophic pathway and Notch pathway.Our understanding of the complex and reciprocal interaction between tumour and nerve cells that drives PNI is still evolving. The knowledge gaps can largely be attributed to publication bias, lack of availability of high-quality patient derived tissues and limitations of currently available technology. This review summarises the current knowledge regarding development and progression of PNI that can be harnessed for prognostication and treatment. This review also summarises the lacunae in our understanding of the pathogenesis of PNI thus identifying avenues for future studies.

BackgroundThe incidence of tongue cancer in young adults is on the rise. This trend is more pronounced in females. Although the aetiology is still unclear, there is mounting evidence that genetic syndromes can play a key role in development of oral cancers in this patient group. We report the first case of oral squamous cell carcinoma (oSCC) in a young adult with an MYH9-related disorder (MYH9-RD).Case presentationA 19-year-old female with a germlineMYH9variant (missense variant in exon 2: c.287C > T, (p.Ser96Leu)) was referred to the head and neck surgery department for investigation of a painful, thick right tongue ulcer. She was diagnosed with Epstein syndrome, an MYH9-RD, at 12 years of age. Her main phenotypic features were profound thrombocytopenia and marked renal impairment. The tongue biopsy confirmed SCC. Preoperative positron emission tomography (PET) revealed avidity in the right tongue and ipsilateral level 2A neck lymph node. With substantial preoperative multidisciplinary input, she underwent cancer ablation and microvascular free flap reconstruction. Her pathology showed a 35 mm diameter, 14 mm thick moderately differentiated SCC with perineural and lymphovascular invasion. Two out of 38 right neck nodes were positive for metastasis with extranodal extension. None of the 34 left neck nodes was involved.She had an uneventful recovery and was discharged home on day 6 postoperative day. On day 15 postoperative day, she had catastrophic bleeding in the neck with a respiratory arrest after a forceful cough. She required an emergency tracheostomy and returned to the theatre for haemostasis. Following a short inpatient stay, she was again discharged home and underwent adjuvant therapy consisting of external beam radiotherapy of 60Gy in 30 fractions. On clinical examination and PET at 6 months after surgery, she had no evidence of disease recurrence.ConclusionsMYH9-RD can present with advanced locoregional oral cavity malignancy at an early age. The combination of profound thrombocytopenia and marked renal impairment can impact heavily on routine major head and neck cancer surgery and adjuvant treatment. This rare and challenging condition underlines the importance of early detection of cancer and multidisciplinary team input.

Soft tissue metastases (STMs) are reported to predict worse prognosis than extra-nodal extension (ENE) in metastatic head and neck cutaneous squamous cell carcinoma. This study aimed to update the authors’ previous analysis of STM in a larger series. The study analyzed 535 cases of consecutive cSCC metastatic to the parotid and/or neck treated by primary surgical resection between 1987 and 2007. A Cox proportional hazard model was used to determine the effect of STM, with adjustment for other relevant prognostic factors. Overall survival (OS) and disease-specific survival (DSS) were the primary end points. Of the 535 patients, 275 (51.4%) had STM. After adjustment for the effects of age, tumor location, number of metastatic deposits, and adjuvant radiotherapy, both STM (hazard ratio [HR], 1.55; 95% confidence interval [CI], 1.08–2.22; p = 0.018) and ENE (HR, 1.56; 95% CI 1.10–2.22; p = 0.013) were shown to be independent predictors of reduced OS, with similar size of effect. In metastatic cSCC of the head and neck, STM is an independent predictor of reduced survival and has an impact on survival similar to that of ENE.

High-risk human papillomavirus (HPV) positive squamous cell carcinoma (SCC) of the head and neck is reported most commonly in the oropharynx but can also uncommonly be found in other sites such as the anterior oral cavity and sinonasal tract. While HPV positive oropharyngeal squamous cell carcinoma (HPV-OPSCC) has been shown to have a more favourable prognosis than conventional smoking- and alcohol-related anterior oral cavity squamous cell carcinoma (OSCC), HPV positive SCC arising elsewhere in the head and neck region does not carry the same favourable prognosis. HPV-OPSCC often tends to present with large cystic metastases in the cervical lymph nodes, with a clinically and radiologically occult primary. Correct diagnosis of the initial biopsy/cytology specimen is critical for directing further investigations and management. In recognition of its distinct biological behaviour, the 8th edition of the American Joint Commission on Cancer (AJCC 8) has proposed a separate clinical and pathological staging system for HPV-OPSCC compared to that for a conventional primary OSCC or neck metastasis of similar size. The new AJCC staging does not apply to other HPV positive SCC of the head and neck. This review examines the current biology of HPV positive SCC, focusing on HPV-OPSCC. The value and pitfalls of current detection methods of HPV are discussed with an emphasis on the role of the pathologist in the diagnosis and management of HPV positive SCC of the head and neck.

Objectives The aim of this study was to investigate the association between oral cavity squamous cell carcinoma (OSCC) and PD-L1 expression, and smoking, and p53 expression. Study Design Histologic review of archival slides of patients with OSCC, obtained from the Sydney Head and Neck Cancer Institute database from 1995 to 2015, was undertaken with tissue microarray construction and immunohistochemistry to identify PD-L1 and p53 expression. Results Of the 255 patients identified, PD-L1 expression was observed in 70 (27.5%) and more commonly in females (odds ratio [OR] = 2.19; P = .005). PD-L1 expression of 1% or greater was associated with p53 expression (P = .019) and associated with absence of smoking (P = .06). PD-L1 expression, at 1%, was not significantly associated with overall survival (P = .482), disease-specific survival (P = .864), and disease-free survival (P = .731). Conclusions Our data demonstrate that PD-L1 expression of 1% or greater is more frequent in OSCC in females, nonsmokers, and in patients with p53-positive OSCC. These findings have important implications for immune therapy for OSCC.

An unexplained increase in the incidence of oral cavity squamous cell carcinoma (oSCC) has been observed despite decreasing smoking rates, particularly in younger patients. Links to defects in the DNA mismatch repair (MMR) system are well established in early onset colorectal, urothelial and gynaecological malignancies. MMR deficient patients treated with immune checkpoint inhibitors have demonstrated improved response rates. Studies exploring MMR status in head and neck squamous cell carcinoma (HNSCC) demonstrate conflicting results. This study explores the incidence of MMR protein loss and its association with clinicopathological features and outcome in oSCC. Immunohistochemical staining using tissue microarrays to assess the expression of MMR proteins (hMLH1, hMSH2, hMSH6, and hPMS2) was performed on 285 consecutive oSCC cases between 2000 and 2016. Data on smoking, alcohol and metachronous malignancies were retrospectively collected. Proportional hazards regression models were used to compare survival in MMR intact and deficient patients. MMR deficiency was seen in 21 patients (7.4%). MMR deficient tumours were associated with bone invasion (52% vs 32%, p=0.05), higher pT stage (pT4 in 57% vs 35%, p

Objectives Prognostic significance of perineural invasion (PNI) in oral squamous cell carcinoma (OSCC) characterized as unifocal and multifocal was compared to depth of invasion (DOI) and extranodal extension (ENE). Materials and methods Univariable and multivariable analyses of 861 consecutive patients with OSCC undergoing treatment between 1995 and 2018 were performed, with local failure (LF) and disease-specific mortality (DSS) as the primary endpoints. Results After adjusting for other adverse histopathological factors and adjuvant therapy, multifocal PNI was associated with a greater risk of LF (P = .01) and DSS (P = 0.02) compared to DOI. The effect of multifocal PNI was comparable to the effect of nodal metastases without ENE (P = 0.02). LF and DSS were not improved by the administration of adjuvant radiotherapy within unifocal or multifocal PNI groups. Conclusion Multifocal PNI is associated with a greater risk of death in OSCC than DOI. Its effect is comparable to that of nodal metastases (without ENE).

ObjectiveCutaneous squamous cell carcinoma (cSCC) is the second most common malignancy, most frequently affecting the head and neck. Treatment often requires surgery and can have significant functional morbidity. Research into disease pathogenesis and second line medical management of cSCC is limited. We assess genetic mutations in high-risk, primary head and neck cutaneous squamous cell carcinomas (HNcSCC) that may hinder or be beneficial for use of targeted therapy in disease management.MethodsGenetic alterations and variant allele frequencies (VAFs) were analysed using a clinically relevant 48 gene panel in 10 primary high-risk non-metastatic treatment-naïve HNcSCC to evaluate applicability of targeted therapeutics. Variants present at all VAFs were evaluated for pathogenicity. Somatic mutation patterns of individual tumours were analysed.ResultsHigh-risk HNcSCC showed a high proportion (82%) of C to T transitions in keeping with ultraviolet-mediated damage. There was significant intratumour genetic heterogeneity in this cohort (MATH scores 20–89) with the two patients TP53 was altered at VAF >22% in all cases, and mutations with highest VAF were observed in tumour suppressor genes in 80%. 70% of cases demonstrated at least one mutation associated with treatment resistance (KIT S821F, KIT T670I, RAS mutations at codons 12 and 13).ConclusionWe demonstrate high proportion tumour suppressor loss of function mutations, high intratumour genetic heterogeneity, and presence of well recognised resistance mutations in treatment naïve primary HNcSCC. These factors pose challenges for successful utilisation of targeted therapies.

Evidence suggests recent improvements in outcome in early breast cancer (EBC).To analyse recurrence in women with EBC from our region from 1997 to 2015.We analysed recurrence in 3,765 women with EBC. Median follow up was 83·0 months. 62·5% had a symptomatic presentation. 81·8% were hormone receptor positive and 38·5% were node positive. Lymphovascular invasion (LVI) was present in 24·3%. Of the 2,686 women entered from 2002 onwards tested for HER2 status, 72·7% had a luminal tumour, 15·2% had a HER2+ tumour and 12·1% had a triple negative (TN) tumour.Recurrence occurred in 459 (12·2%), predominantly in distant sites (71·7%). In women entered from 2002 onwards, the five and 10 year recurrence rates were significantly lower in the luminal group than the HER2+ and the TN groups. Few recurrences occurred in HER2+ and TN cancers after 36 months. On multivariate analysis the following were associated with a significantly increased risk of recurrence: nodal involvement (p 0·0001), tumour grade (p 0·0001), symptomatic presentation (p 0·0001), presence of LVI (p = 0·001), non-luminal tumour type (p 0·0001) and tumour size50 mm (p = 0·02).The recurrence rate in this series was much lower than in previous older series. Lymph node involvement, tumour grade, symptomatic presentation, presence of LVI, non-luminal tumour type and tumour size (50 mm) were associated with an increased risk of recurrence. We strongly recommend that clinicians include the presence of LVI and symptomatic presentation as well as the other established tumour factors, when assessing the risk of recurrence in women with EBC.