A spindle cell neoplasm with MYH9::EGFR fusion and co-expression of S100 and CD34, further expanding the family of kinase fusion positive spindle cell neoplasms.

Soft tissue neoplasms displaying CD34 and S100 positivity with immunohistochemistry are rare with a wide morphological range and frequent neurotrophic tyrosine receptor kinase (NTRK) alterations. Recent reports describe fusions in other kinases besides NTRK in these tumors. In the present article, we report a case of a young male suffering from a soft tissue neoplasm in the lumbar region. At microscopic examination, it was a CD34 and S100-positive soft tissue tumor showing a multilobulated growth pattern composed of cells with pale cytoplasm and abundant normal smooth muscle stroma. The genetic profile showed two alterations affecting EGFR gene represented by a novel MYH9::EGFR fusion transcript and a p.K714N mutation.

Human papilomaviru-related oropharyngeal squamous cell carcinoma and radiomics: A new era?

BACKGROUND: The increase of the incidence of human papillomavirus dependent oropharyngeal squamous cell carcinoma is alarming, although we have greatly progressed in the classification and staging of this disease. We now know that human papillomavirus related oropharyngeal squamous cell carcinoma is a sub-type of head and neck squamous cell carcinoma with favourable prognosis and good response to therapy that needs a proper system of classification and staging. Thus, in routine practice it is essential to test patients for the presence of human papillomavirus. The most popular technique to assess human papillomavirus status is immunohistochemistry on biopsy samples with p16, which is an excellent surrogate for high-risk human papillomavirus infection. Another highly sensitive and specific tissue-based technique for the detection of human papillomavirus is RNAscope In situ hybridization that has a prohibitive cost, limiting its use in routine practice. Radiomics is an artificial intelligence based non-invasive method of computational analysis of computed tomography, magnetic resonance imaging, positron emission tomography, and ultrasound images. METHODS: In this review, we summarise the last findings of radiomics applied to human papillomavirus associated oropharyngeal squamous cell carcinoma. RESULTS: A growing body of evidence suggest that radiomics is able to characterise and detect early relapse after treatment, and enable development of tailored therapy of human papillomavirus positive oropharyngeal squamous cell carcinoma.

Positive Linear Relationship between Nucleophosmin Protein Expression and the Viral Load in HPV-Associated Oropharyngeal Squamous Cell Carcinoma: A Possible Tool for Stratification of Patients.

Most oropharyngeal squamous cell carcinomas (OPSCCs) are human papillomavirus (HPV)-associated, high-risk (HR) cancers that show a better response to chemoradiotherapy and are associated with improved survival. Nucleophosmin (NPM, also called NPM1/B23) is a nucleolar phosphoprotein that plays different roles within the cell, such as ribosomal synthesis, cell cycle regulation, DNA damage repair and centrosome duplication. NPM is also known as an activator of inflammatory pathways. An increase in NPM expression has been observed in vitro in E6/E7 overexpressing cells and is involved in HPV assembly. In this retrospective study, we investigated the relationship between the immunohistochemical (IHC) expression of NPM and HR-HPV viral load, assayed by RNAScope in situ hybridization (ISH), in ten patients with histologically confirmed p16-positive OPSCC. Our findings show that there is a positive correlation between NPM expression and HR-HPV mRNA (Rs = 0.70, p = 0.03), and a linear regression (r2 = 0.55; p = 0.01). These data support the hypothesis that NPM IHC, together with HPV RNAScope, could be used as a predictor of transcriptionally active HPV presence and tumor progression, which is useful for therapy decisions. This study includes a small cohort of patients and, cannot report conclusive findings. Further studies with large series of patients are needed to support our hypothesis.

HPV42-associated Seborrhoeic Keratosis-like Lesion of the Cervix: First Reported Case With High-grade Morphology.

Seborrheic keratosis-like lesion (SKLL) is an extremely rare, morphologically distinct lesion occurring in the cervix and vagina that differs histologically from usual squamous intraepithelial lesions in these sites, by bearing close resemblance to cutaneous seborrheic keratosis and lacking koilocytosis. Like many vulvar seborrheic keratoses, which are associated with low-risk human papillomavirus (HPV), an association between SKLL and low-risk HPV is suggested based on the identification of HPV42, regarded as a low-risk genotype, in 4 of 8 reported cases. We report a further HPV42-associated SKLL of the cervix which differs from the previously reported cases by the presence of high-grade morphology and block-type p16 immunoreactivity. This novel finding challenges the classification of HPV42 as a low-risk genotype and expands the reported morphologic spectrum of SKLL, suggesting that they may not always be clinically indolent.

An update on extracapsular dissection for the management of parotid gland pleomorphic adenoma.

Superficial parotidectomy has been the gold standard for surgical removal of benign mobile parotid gland tumours. The comparatively newer technique of extracapsular dissection, which involves careful dissection of the tumour itself without the need for formal gland excision, has gained popularity in recent years. Tumours can be removed via smaller incision, and the technique reduces the risk of Frey's syndrome (gustatory sweating) and hollowing at the site of surgery. The risk of facial nerve damage can also be lower with extracapsular dissection. If done carefully, the incidence of tumour recurrence, particularly for pleomorphic adenomas, is comparable with formal parotidectomy. We provide a brief update overview of the current evidence for extracapsular dissection in the treatment of benign parotid tumours and include several meta-analyses which provide evidence for the safety of the technique. We have also included our audited results of over 100 recent extracapsular dissections, with 0% incidence of permanent facial nerve weakness, reported Frey's syndrome and recurrence rates over the last 5 years.

Diagnostic accuracy of ultrasonography-guided core needle biopsy of parotid gland neoplasms: A large, single-institution experience in United Kingdom.

Salivary gland tumours present a pleomorphic and complex morphology and, apart from the most common neoplasms with well-established histopathological criteria, may create diagnostic difficulty for histopathologists. The majority of salivary gland tumours occur in the parotid gland and the use of ultrasound guided parotid biopsy (US-PB) has increased. US-PB in contrast with fine needle aspiration (FNA), which is an easy and relatively painless technique, is performed under local anaesthesia, usually by radiologists. US-PB offers some advantages over the FNA such as tumour grading and the possibility of performing immunohistochemistry. We report our experience of the diagnostic value of US-PB in a large, referral centre in the United Kingdom.

Hybrid odontogenic lesions: A systematic review of 203 cases reported in the literature.

BACKGROUND: Hybrid odontogenic lesions combine histopathological characteristics of two or more odontogenic cysts and/or tumours. The aim of this study was to evaluate the available data on hybrid odontogenic lesions (HOL) and to analyse their epidemiological/clinical features and biological behaviour. METHODS: An electronic search was done in January 2021 using multiple databases. Eligibility criteria encompassed publications with sufficient clinical and histological information to confirm the tumours' diagnoses. RESULTS: A total of 147 articles were included in this study, comprising 203 cases. Calcifying odontogenic cyst associated with odontoma (COC/OD) (37/18.2%) was the most common HOL. Females were more affected with a mean age of 24.9 years. Lesions presented as asymptomatic swellings, with a mean evolution time of 8.2 months (0.3-96), and mean tumour size of 4.8 cm (0.3-7). Radiographic aspects frequently showed radiolucent (139/68.4%) and unilocular (52/25.6%) images with well-defined limits (48/23.6%). The lesions mostly affected mandibular pre-molars (69/34%) and mandibular molars (69/34%) regions. Enucleation (89/43.8%) and surgical excision (59/29%) were the most common treatment modalities. The mean follow-up time was 33.8 months (0.5-216 months) and recurrences were observed in four cases (1.9%), all of which were central odontogenic fibroma associated with central giant cell granuloma (COF/CGCG). CONCLUSION: COC/OD is the most common HOL and recurrence is a rare event, being usually associated with the diagnosis of COF/CGCG.

An update on the ophthalmic features in hereditary haemorrhagic telangiectasia (Rendu-Osler-Weber syndrome).

Hereditary haemorrhagic telangiectasia (HHT) or Osler-Rendu-Weber syndrome is a rare autosomal dominant disease, characterised by systemic angiodysplasia. Dysfunction of the signalling pathway of ß transforming growth factor is the main cause of HHT principally owing to mutations of the genes encoding for endoglin (ENG) and activin A receptor type II-like 1 (ACVRL1). Clinical manifestations can range from mucocutaneous telangiectasia to organ arterio-venous malformations and recurrent epistaxis. The early clinical manifestations may sometimes be subtle, and diagnosis may be delayed. The main ophthalmic manifestations historically reported in HHT are haemorrhagic epiphora, and conjunctival telangiectasia present in 45-65% of cases, however, imaging with wide-field fluorescein angiography has recently shown peripheral retinal telangiectasia in 83% of patients. Optimal management of HHT requires both understanding of the clinical presentations and detection of early signs of disease. Advances in imaging methods in ophthalmology such as wide-field fluorescein angiography, spectral domain optical coherence tomography, and near infrared reflectance promise further insight into the ophthalmic signs of HHT towards improved diagnosis and early management of possible severe complications.

Genetic Polymorphisms of Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) and clinical outcomes post-allogeneic hematopoietic stem cell transplantation: A systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: Although HLA matching is considered as a key genetic predictor of allo-HSCT outcomes, genetic polymorphisms in non-HLA genes, especially in genes encoding immunoregulatory proteins, have also been proposed as additional risk factors linked to the occurrence of transplant complications. This study aimed to carry out a systematic review and meta-analysis from all eligible cohort studies to determine the effect of CTLA-4 gene polymorphisms, including rs231775, rs3087243, rs4553808, rs5742909, and rs733618, on clinical outcomes in patients receiving an allo-HSCT. METHODS: A systematic literature search in PubMed, Web of Science, and Scopus was performed to identify the relevant studies, and related information was extracted. The effect size (ES) and corresponding 95% confidence intervals (CIs) were calculated to estimate the association. RESULTS: 16 studies were eligible and included in the meta-analysis. The pooled results showed that only the dominant models of rs3087243 were significantly associated with chronic GVHD (cGVHD), while other SNPs were not significantly associated with overall survival, disease-free survival, relapse, and GVHD. CONCLUSIONS: Our study represents, for the first time, a comprehensive meta-analysis on the role of CTLA-4 polymorphisms on outcomes after allo-HSCT. The results indicate that the CT60 CTLA-4 polymorphism could be a significant risk factor for cGVHD.

Prognostic significance of CD30 expression in diffuse large B-cell lymphoma: A systematic review with meta-analysis.

BACKGROUND: CD30 is variably expressed in diffuse large B-cell lymphoma (DLBCL), but its prognostic potential for the affected patients remains debatable and unclear. Therefore, we aimed to determine the frequency of CD30 expression in DLBCL and its potential for prognostic determination. METHODS: An electronic systematic review was performed using multiple databases, followed by a quantitative meta-analysis to assess the frequency of CD30 expression with positivity cut-off values of >0% and >20%, and to determine its association with clinicopathological features and patients' survival. RESULTS: Using a cut-off value >0%, we observed that 3.5%-59.1% of the cases were considered positive for CD30. There was a significant association of the protein expression with a lower number of extra-nodal sites affected by the neoplasm, with Ann Arbor advanced stage, the absence of B-symptoms, the lack of MYC and BCL2 translocations, and a lower ECOG performance. Using a cut-off value >20%, we observed that 2.5%-36.7% of the cases were considered positive for CD30, being significantly associated with a lower number of extra-nodal sites affected by the neoplasm, Ann Arbor stages III/IV, non-GCB tumours, the lack of MYC and BCL2 translocations, and a lower ECOG value. CD30 expression was significantly associated with a better survival rate, regardless of what cut-off parameter was used. CONCLUSION: Despite variations in the cut-off values used to determine CD30 positivity in DLBCL, the expression of this protein seems to be associated with a higher survival rate and better prognosis.

Recent advances in the histopathological assessment of salivary disease.

BACKGROUND: Salivary gland disease includes a wide range of unique and rare conditions that are treated by ear, nose and throat (ENT), oral and maxillofacial surgeons (OMFS) and oral medicine specialists. Histopathological diagnosis is pivotal to making a diagnosis and treatment planning. There is a vast range of conditions and controversies in the histopathological assessment of salivary gland diseases. Most colleagues in oral pathology and oral medicine work closely with the OMFS but might have missed some of the recent articles published by the speciality. METHODS: We reviewed articles thought to be relevant to oral medicine and pathology specialists published over an 8-year period between 2012 and 2019 in the leading British Journal of Oral and Maxillofacial Surgery (BJOMS). RESULTS: A total of 44 published articles relating to the histopathology of salivary glands disease were selected. Papers were published on population studies, benign and malignant tumours, sialadenitis, metastasis to the parotid gland and cytology. The publication type and numbers published were as follows: review (n = 9), meta-analysis/randomised controlled study (n = 1), retrospective study (n = 10) and case report/technical notes (n = 23). CONCLUSIONS: The greatest proportion of publications published in BJOMS were case reports. This emphasises the paucity of consensus and the need for development in this field. Salivary gland disease remains an area with many controversies and would benefit from further research.

A proposal for classification of oropharyngeal squamous cell carcinoma: Morphology and status of HPV by immunohistochemistry and molecular biology.

The current three-tier grading system (well, moderate and poorly differentiated) used to morphologically classify head and neck squamous cell carcinoma (HNSCC) is inadequate for categorisation of oropharyngeal squamous cell carcinoma (OPSCC) owing to the lack of prognostic value. The aim of this study was to assess the validity of a classification system for OPSCC based on morphology and human papilloma virus (HPV) infection status. Haematoxylin and eosin slides of 121 patients (100 M, 21 F, age range 40-89 years) with OPSCC were reviewed and categorised as histological types I, II and III. The presence of HPV was assessed by immunohistochemistry with p16 and RNAscope In situ hybridization (ISH). The follow-up period was 36 months. Ninety-six patients were p16+ and clinical stage I. Patient survival with types I, II and III was 93%, 50% and 96%, respectively. Twenty-five patients were p16-: 10 clinical stage I and 15 stage III. Amongst this group, no type I morphology was identified. At follow-up, 65% of type II and 75% of type III patients were alive. All p16+ cases were also positive for E6/E7 mRNA high-risk HPV by ISH, while 23 p16- cases were negative and two were positive. Cox regression identified three predictors of mortality: older age (HR = 1.14, 95% CI = 1.06-1.23, P = .001); female gender (HR = 0.22.95% CI 0.05-0.88, P = .033); and type II morphology (HR = 13.1, 95% CI = 1.09-157.0, P = .043). OPSCC morphological classification in three sub-types, along with HPV infection status, seems to reflect the outcome of patients with OPSCC.

KRAS mutations in brown tumor of the jaws in hyperparathyroidism.

BACKGROUND: Brown tumors are giant cell-rich lesions that result from abnormal bone metabolism in hyperparathyroidism, one of the most common endocrine disorders worldwide. Brown tumors occasionally affect the jaws and, despite well-known clinical and microscopic features, their molecular pathogenesis remains unclear. We investigated the presence of pathogenic activating mutations in TRPV4, FGFR1, and KRAS in a cohort of brown tumors since these have recently been reported in giant-cell lesions of the jaws and non-ossifying fibromas of the bones (FGFR1 and KRAS), which are histologic mimics of brown tumors. METHODS: We target sequenced 13 brown tumors of the jaws associated with primary or secondary hyperparathyroidism. As mutations in these genes are known to activate the MAPK/ERK signaling pathway, we also assessed the immunostaining of the phosphorylated form of ERK1/2 (pERK1/2) in these lesions. RESULTS: KRAS pathogenic mutations were detected in seven cases (p.G12V n = 4, p.G12D n = 1, p.G13D n = 1, p.A146T n = 1). KRAS variants of unknown significance (VUS), p.A134T and p.E37K, were also detected. All samples showed wild-type sequences for FGFR1 and TRPV4 genes. The activation of the MAPK/ERK signaling pathway was demonstrated by pERK1/2 immunohistochemical positivity of the brown tumors´ mononuclear cells. CONCLUSION: Mutations in KRAS and activation of the MAPK/ERK signaling pathway were detected in brown tumors of hyperparathyroidism of the jaws, expanding the spectrum of giant cell lesions whose molecular pathogenesis involve RAS signaling.

Neuroprotective effects of metformin on traumatic brain injury in rats is associated with the AMP-activated protein kinase signaling pathway.

Metformin is an activator of AMP-activated protein kinase (AMPK). Thus, it has the potential to restore energy in damaged neurons and attenuate secondary brain damage due to traumatic brain injury (TBI). This study aims to investigate the potential neuroprotective effects of metformin through the energy balance reestablishment in acute severe brain injury after TBI and explore the underlying mechanisms. Male Wistar rats were divided into eight groups. The veterinary coma scale (VCS) was used to assess short-term neurological deficits. Blood-Brain barrier (BBB) disruption was evaluated by Evans Blue method 6 h post-injury. Vestibulomotor function was evaluated by beam-walk and beam-balance methods. Brain water content and brain tissue phosphorylated and total AMPK were assessed by the wet/dry method and enzyme-linked immunosorbent assay (ELISA), respectively. In order to eliminate the effect of AMPK, compound C was used as an AMPK inhibitor. The presented study showed that TBI has led to significant brain edema, BBB disruption, neurological deficit, vestibulomotor dysfunction and decrease AMPK phosphorylation in the rat brain. Metformin (100 and 200 mg/kg doses) attenuated brain edema, improved BBB and vestibulomotor dysfunction compared to TBI or Vehicle groups (P < 0.001). Furthermore, the p-AMPK/AMPK ratio was increased by metformin administration compare to TBI or Vehicle groups (p < 0.0001). Inhibition of AMPK by compound C abolished Metformin neuroprotective effects (P < 0.05 compared to Met 200 group). This study suggests that metformin inhibits TBI-mediated secondary injury via phosphorylation of AMPK and improves neurobehavioral function following TBI, which provides a potential therapeutic opportunity in the treatment of TBI.

Radioguided sentinel node biopsy to avoid unnecessary neck dissection in T1-T2N0 oral cavity squamous cell carcinoma: personal experience with same day protocol.

PURPOSE: Data from literature show a mean incidence of occult metastases of 33% in early OCSCC. The gold standard for most authors is a selective neck dissection and a routine pathological examination. 60-70% of unnecessary neck dissections with associated morbidity, can be avoided by using SNB. The aim of this study is to present the results of one of the major Italian centres for the SNB procedure, reserving neck dissection only for proven positive lymphatic metastases. METHODS: From July 2004 to March 2015, 48 patients with transorally resectable cT1-T2N0 oral SCC were submitted to a lymphoscintigraphic examination one-three hours before surgery and a radio-guided SNB (same day protocol). Patients with a negative SNB were checked every 3 months by ultrasound examination. The minimum follow-up was 5 years. RESULTS: Sentinel nodes were found in all cases, with 71% localized in the ipsilateral neck only in levels I-II. Metastases were found in 15 out of 48 cases (31.2%), on levels I, II and III. Further metastatic nodes were found in 6 cases in the neck dissection specimen. In the cohort of 33 patients with SNB negative at 5 years, no-one had a recurrence on the ipsilateral neck. CONCLUSION: This study confirms the accuracy of SNB in predicting the presence of occult metastases, sparing the need for unnecessary neck dissection in 70% of cases. The same day protocol is designed to detect sentinel nodes, which are almost always on neck level I-II, thereby limiting the number of nodes examined and the extension of the surgical approach.

Human factors awareness and recognition during multidisciplinary team meetings.

Multidisciplinary team (MDT) meetings are widely used throughout medicine and dentistry, bringing together expertise and different opinions across many disciplines to benefit patient care. Depending on the cancer site and specialties involved, some MDTs can last for several hours, especially if there are many complex patients to discuss. However, concentration and attention can vary and distraction is almost inevitable with separate conversations between MDT members and the ever-increasing use of smartphones. The role of human factors (HF) in contributing to error is well known in high-risk activities including medicine and surgery. Surprisingly, while there is increasing awareness of their importance by medical and dental professionals to enhance patient safety, to our knowledge nothing to date has been published about the possible effect and role of HF at MDTs. Here we provide a brief HF overview and focus on the factors at an MDT that could lead to distraction, providing suggestions (including some from aviation) for possible ways to enhance and improve discussion during these often-long meetings. It is hoped that this paper will generate some thought and discussion around the current "normal" MDT practice in head and neck and other specialties and challenge colleagues to embrace HF and safety principles in a just and learning culture.

Machine learning and its potential applications to the genomic study of head and neck cancer-A systematic review.

BACKGROUND: Machine learning (ML) is powerful tool that can identify and classify patterns from large quantities of cancer genomic data that may lead to the discovery of new biomarkers, new drug targets, and a better understanding of important cancer genes. The aim of this systematic review was to evaluate the existing literature and assess the application of machine learning of genomic data in head and neck cancer (HNC). MATERIALS AND METHODS: The addressed focused question was "Does machine learning of genomic data play a role in prognostic prediction of HNC?" PubMed, EMBASE, Scopus, Web of Science, and gray literature from January 1990 up to and including May 2018 were searched. Two independent reviewers performed the study selection according to eligibility criteria. RESULTS: A total of seven studies that met the eligibility criteria were included. The majority of studies were cohort studies, one a case-control study and one a randomized controlled trial. Two studies each evaluated oral cancer and laryngeal cancer, while other one study each evaluated nasopharyngeal cancer and oropharyngeal cancer. The majority of studies employed support vector machine (SVM) as a ML technique. Among the included studies, the accuracy rates for ML techniques ranged from 56.7% to 99.4%. CONCLUSION: Our findings showed that ML techniques for the analysis of genomic data can play a role in the prognostic prediction of HNC.

Clinicopathological analysis of oral diffuse large B-cell lymphoma, NOS: A systematic review.

BACKGROUND: Diffuse large B-cell lymphoma, NOS (DLBCL NOS) is the commonest extranodal non-Hodgkin lymphoma diagnosed in the oral and maxillofacial region. However, few studies are currently available and its prognostic determinants remain undefined. PURPOSE: To analyse the available data on oral DLBCL NOS and to describe its clinicopathological features, identifying potential prognostic factors. METHODS: An electronic systematic search was performed using multiple databases with a specific search strategy in April 2018. All reports describing DLBCL NOS involving the oral cavity and jaw bones with sufficient clinicopathological information were assessed. RESULTS: Sixty-three publications were included in the study, comprising 122 cases. Oral DLBCL NOS was found predominantly in elderly males (61.5%), and most often presented as an asymptomatic swelling of the gingiva. Patients commonly were HIV-negative (36.1%), with few reports describing EBV-positive cases (four cases/3.3%). Only eight cases presented B symptoms and most cases were classified as stage I or II (48.4%). CHOP therapy was the main treatment option (24.5%) and the overall 5-year survival rate achieved 83%. Males and advanced Ann Arbor stage patients presented significantly lower survival rates in the univariate analysis, but no significance was found in the multivariate model. CONCLUSION: Oral DLBCL NOS is an aggressive malignancy, but with a high survival rate.

Pigment dispersion syndrome and pigmentary glaucoma: a review and update.

INTRODUCTION: Pigment dispersion syndrome (PDS) is a condition where anomalous iridozonular contact leads to pigment dispersion throughout the anterior segment and the released pigment is abnormally deposited on various ocular structures. CLINICAL PRESENTATION: The clinical presentation of PDS is defined by the presence of pigmented cells on the corneal endothelium, an increase of pigmentation of the trabecular meshwork, and mid-periphery transillumination defects of the iris. This syndrome, more common in myopes, is usually bilateral and can be associated with ocular hypertension or glaucoma. Secondary open-angle pigmentary glaucoma (PG) can develop due to reduction of the outflow of aqueous humour and consequent increase in intraocular pressure leading to glaucomatous optic neuropathy. Diagnosis of PG is commonly between 40 and 50 years of age, occurring more frequently in men. The advent of ultrasound biomicroscopy and anterior segment optical coherence tomography has contributed to enhancing our knowledge on the condition. Typical alterations of the anterior segment are the posterior insertion of the iris and iris concavity. Treatment of PG should be initiated early to hinder disease progression, glaucomatous damage, and vision loss. Management is based on medical therapy, laser iridotomy, selective laser trabeculoplasty, and filtration procedures. CONCLUSIONS: The differential diagnosis of PDS with other disorders can be challenging and awareness of the condition together with meticulous ophthalmologic examination allows early diagnosis followed by appropriate management strategies. The present review is a comprehensive report on the clinical characteristics, pathogenesis, current management, and status quo of PDS and PG.

Correction to: Pigment dispersion syndrome and pigmentary glaucoma: a review and update.

In the original publication, introduction section under Abstract was published incorrectly. The correct version is given below.