Publications by authors named "Syed Ali Khurram"

23 Publications

  • Page 1 of 1

Burkitt lymphoma of the head and neck: An international collaborative study.

J Oral Pathol Med 2021 Jun 5. Epub 2021 Jun 5.

Oral Diagnosis Department, Semiology and Oral Pathology, Piracicaba Dental School, University of Campinas, Piracicaba, Brazil.

Background: Burkitt lymphoma (BL) is an aggressive B-cell lymphoma with three variants (endemic, sporadic, and immunodeficiency-associated), presenting with specific epidemiological and clinical features. Burkitt lymphoma affects the head and neck region (BLHN) in approximately 10% of cases. The aim of this study was to undertake a comparative analysis of the clinicopathologic and immunohistochemical (IHC) features of BLHN diagnosed in patients from Africa, Guatemala, and Brazil.

Methods: Cases diagnosed as BLHN were collected from the files of six oral pathology laboratory services (Brazil, South Africa, and Guatemala), and one Brazilian pediatric oncology hospital from 1986 to 2020. Clinicopathological and IHC data, and Epstein-Barr virus (EBV) status by in situ hybridization data for each case were reviewed and described.

Results: Of the 52 cases, BLHN was predominant in pediatric patients [43 (82.69%)] and males [43 (82.69%)], with a mean age of 11.26 ± 9.68 years (range, 1-39 years). Neck and cervical lymph nodes [14 (26.92%)], and involvement of both maxilla and mandible [8 (15.38%)], were the most common anatomical sites. Clinically, tumor/swelling [40 (31.25%)], cervical lymphadenopathy [14 (10.94%)], pain [12 (9.38%)], and bone destruction [12 (9.38%)] were frequent findings. All cases showed typical morphological characteristics of BL. IHC profiles included positivity for CD20 [52 (100%)], CD10 [38 (79.17%)], Bcl6 [29 (87.88%)], and c-Myc protein [18 (81.82%)]. EBV was positive in 18 cases (62.07%). The Ki-67 index ranged from 90-100%.

Conclusion: The clinicopathological and EBV profile of BLHN in South African, Guatemalan and Brazilian patients is similar.
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http://dx.doi.org/10.1111/jop.13209DOI Listing
June 2021

Impact of tumor site on the prognosis of salivary gland neoplasms: A systematic review and meta-analysis.

Crit Rev Oncol Hematol 2021 Jun 12;162:103352. Epub 2021 May 12.

Brazilian Bioscience National Laboratory, Brazil Center of Research in Energy and Materials, Campinas, Brazil.

In numerous types of cancer, the primary tumor site can show a correlation with disease behavior and survival outcomes. In salivary gland tumors (SGTs) this association remains controversial. This study assessed the association between primary sites of SGTs and prognosis. Studies from five databases were assessed and a meta-analysis was performed using studies that presented 95 % confidence interval (95 % CI), hazard ratio (HR) and survival analysis. Gathered information from 46,361 patients showed that site had a prognostic impact on SGTs. Tumors involving minor salivary glands showed worse overall survival (HR = 1.60; 95 % CI = 1.17-2.19; p = 0.003), disease-specific survival (HR=1.63; 95 % CI = 1.12-2.37; p = 0.01), and cause-specific survival (HR=2.10; 95 % CI = 1.72-2.55; p = 0.00001). Tumors from major salivary glands showed better recurrence-free survival (HR=2.31; 95 % CI = 1.77-3.02; p = 0.00001), and locoregional control of disease (HR=2.66; 95 % CI = 1.20-5.91; p = 0.02). Our results showed that the primary site of SGTs has an impact on patient prognosis.
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http://dx.doi.org/10.1016/j.critrevonc.2021.103352DOI Listing
June 2021

Microsecretory Adenocarcinoma of Salivary Glands: An Expanded Series of 24 Cases.

Head Neck Pathol 2021 May 12. Epub 2021 May 12.

Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA.

Microsecretory adenocarcinoma (MSA) is a recently described salivary gland tumor with a characteristic histologic and immunophenotypic profile and recurrent MEF2C-SS18 fusions. Because only six cases of MSA have been published, its complete clinicopathologic spectrum is unclear, and its biologic behavior has not been documented. Here, we present an updated and expanded experience of 24 MSA cases. All cases of MSA were obtained from the authors' files. Immunohistochemistry for S100, SOX10, p63, p40, SMA, calponin, and mammaglobin was performed. Molecular analysis was performed by targeted RNA sequencing, SS18 break apart fluorescence in situ hybridization, and/or reverse transcriptase polymerase chain reaction for MEF2C-SS18 fusion. Clinical follow-up was obtained from medical records. A total of 24 MSA cases were collected, from 13 women and 11 men, ranging from 17 to 83 years (mean 49.5 years). The vast majority (23 of 24) arose in the oral cavity, with the palate (n = 14) and buccal mucosa (n = 6) as the most frequent subsites. Tumors showed consistent histologic features including: (1) microcystic tubules, (2) flattened intercalated duct-like cells, (3) monotonous oval hyperchromatic nuclei, (4) abundant basophilic luminal secretions, (5) fibromyxoid stroma, and (6) circumscribed borders with subtle infiltration. The tumors were very consistently positive for S100 (24 of 24), p63 (24 of 24), and SOX10 (14 of 14) and negative for p40 (0 of 21), calponin (0 of 12) and mammaglobin (0 of 16), while SMA (4 of 20) was variable. MEF2C-SS18 fusion was demonstrated in 21 of 24 cases; in the remaining 3 cases with insufficient RNA, SS18 break apart FISH was positive. Treatment information was available in 17 cases, all of which were managed with surgery only. In 14 cases with follow-up (1-216 months, mean 30), no cases recurred or metastasized. MSA is a distinct salivary gland neoplasm with remarkably consistent clinical, histologic, immunophenotypic, and genetic features that generally behaves in an indolent manner following surgery alone. These observations solidify MSA as a unique, low-grade salivary gland carcinoma that warrants inclusion in the next version of the WHO classification of head and neck tumors.
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http://dx.doi.org/10.1007/s12105-021-01331-7DOI Listing
May 2021

Convolutional Neural Network-Based Clinical Predictors of Oral Dysplasia: Class Activation Map Analysis of Deep Learning Results.

Cancers (Basel) 2021 Mar 14;13(6). Epub 2021 Mar 14.

Center for Biomedical Informatics, Wake Forest School of Medicine, Winston-Salem, NC 27101, USA.

Oral cancer/oral squamous cell carcinoma is among the top ten most common cancers globally, with over 500,000 new cases and 350,000 associated deaths every year worldwide. There is a critical need for objective, novel technologies that facilitate early, accurate diagnosis. For this purpose, we have developed a method to classify images as "suspicious" and "normal" by performing transfer learning on Inception-ResNet-V2 and generated automated heat maps to highlight the region of the images most likely to be involved in decision making. We have tested the developed method's feasibility on two independent datasets of clinical photographic images of 30 and 24 patients from the UK and Brazil, respectively. Both 10-fold cross-validation and leave-one-patient-out validation methods were performed to test the system, achieving accuracies of 73.6% (±19%) and 90.9% (±12%), F1-scores of 97.9% and 87.2%, and precision values of 95.4% and 99.3% at recall values of 100.0% and 81.1% on these two respective cohorts. This study presents several novel findings and approaches, namely the development and validation of our methods on two datasets collected in different countries showing that using patches instead of the whole lesion image leads to better performance and analyzing which regions of the images are predictive of the classes using class activation map analysis.
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http://dx.doi.org/10.3390/cancers13061291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001078PMC
March 2021

Observer agreement in the diagnosis of oral lichen planus using the proposed criteria of the American Academy of Oral and Maxillofacial Pathology.

J Oral Pathol Med 2021 May 8;50(5):520-527. Epub 2021 Apr 8.

UWA Dental School, The University of Western Australia, Nedlands, WA, Australia.

Background: Oral lichen planus (OLP) is a common chronic inflammatory condition with an undefined malignant transformation potential. There have been many attempts at providing a specific definition of OLP without conclusive outcomes. A new set of diagnostic criteria was proposed in 2016 by the American Academy of Oral and Maxillofacial Pathology (AAOMP) in an endeavour to resolve this issue, and this has not yet been evaluated. This study aimed to assess the utility of AAOMP proposed criteria for the diagnosis of OLP.

Methods: Five pathologists blindly assessed a cohort of 215 digital whole slide images (WSI) obtained from haematoxylin and eosin-stained microscopic slides. Forty-six WSI were included twice to assess the intra-observer agreement. Included cases were diagnosed clinically as either OLP or oral lichenoid reaction. Each pathologist was asked to utilize the AAOMP histopathological criteria while assessing slides. The variations in diagnoses were assessed by unweighted kappa statistics.

Results: The level of intra-observer agreement was very good (0.801 to 0.899). The level of inter-observer agreement among the observers varied from good (0.658) to very good (0.842) when the responses were categorized as evident/compatible OLP versus no OLP and was good (0.62 to 0.725) when the responses were categorized as evident OLP, versus compatible OLP, versus no OLP. The clinico-pathological correlation was 87.6%.

Conclusion: A reliable level of agreement can be achieved by pathologists for the diagnosis of OLP using the AAOMP criteria for differentiation between lichenoid and other conditions. There are still limitations in discriminating OLP from oral lichenoid lesions microscopically.
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http://dx.doi.org/10.1111/jop.13170DOI Listing
May 2021

Fully digital pathology laboratory routine and remote reporting of oral and maxillofacial diagnosis during the COVID-19 pandemic: a validation study.

Virchows Arch 2021 Mar 13. Epub 2021 Mar 13.

Oral Diagnosis Department, Semiology and Oral Pathology Areas, Piracicaba Dental School, University of Campinas (UNICAMP), Av. Limeira, 901, Bairro Areião, Piracicaba, SP, 13414-903, Brazil.

The role of digital pathology in remote reporting has seen an increase during the COVID-19 pandemic. Recently, recommendations had been made regarding the urgent need of reorganizing head and neck cancer diagnostic services to provide a safe work environment for the staff. A total of 162 glass slides from 109 patients over a period of 5 weeks were included in this validation and were assessed by all pathologists in both analyses (digital and conventional) to allow intraobserver comparison. The intraobserver agreement between the digital method (DM) and conventional method (CM) was considered almost perfect (κ ranged from 0.85 to 0.98, with 95% CI, ranging from 0.81 to 1). The most significant and frequent disagreements within trainees encompassed epithelial dysplasia grading and differentiation among severe dysplasia (carcinoma in situ) and oral squamous cell carcinoma. The most frequent pitfall from DM was lag in screen mirroring. The lack of details of inflammatory cells and the need for a higher magnification to assess dysplasia were pointed in one case each. The COVID-19 crisis has accelerated and consolidated the use of online meeting tools, which would be a valuable resource even in the post-pandemic scenario. Adaptation in laboratory workflow, the advent of digital pathology and remote reporting can mitigate the impact of similar future disruptions to the oral and maxillofacial pathology laboratory workflow avoiding delays in diagnosis and report, to facilitate timely management of head and neck cancer patients. Graphical abstract.
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http://dx.doi.org/10.1007/s00428-021-03075-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955219PMC
March 2021

Self-Path: Self-supervision for Classification of Pathology Images with Limited Annotations.

IEEE Trans Med Imaging 2021 Feb 1;PP. Epub 2021 Feb 1.

While high-resolution pathology images lend themselves well to 'data hungry' deep learning algorithms, obtaining exhaustive annotations on these images for learning is a major challenge. In this paper, we propose a self-supervised convolutional neural network (CNN) frame-work to leverage unlabeled data for learning generalizable and domain invariant representations in pathology images. Our proposed framework, termed as Self-Path, employs multi-task learning where the main task is tissue classification and pretext tasks are a variety of self-supervised tasks with labels inherent to the input images.We introduce novel pathology-specific self-supervision tasks that leverage contextual, multi-resolution and semantic features in pathology images for semi-supervised learning and domain adaptation. We investigate the effectiveness of Self-Path on 3 different pathology datasets. Our results show that Self-Path with the pathology-specific pretext tasks achieves state-of-the-art performance for semi-supervised learning when small amounts of labeled data are available. Further, we show that Self-Path improves domain adaptation for histopathology image classification when there is no labeled data available for the target domain. This approach can potentially be employed for other applications in computational pathology, where annotation budget is often limited or large amount of unlabeled image data is available.
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http://dx.doi.org/10.1109/TMI.2021.3056023DOI Listing
February 2021

NUT Carcinoma Arising from the Parotid Gland: A Case Report and Review of the Literature.

Head Neck Pathol 2020 Dec 22. Epub 2020 Dec 22.

Unit of Oral and Maxillofacial Pathology, School of Clinical Dentistry, 19 Claremont Crescent, Sheffield, S10 2TA, UK.

NUT carcinoma is an aggressive carcinoma with an overall poor survival outcome. The mediastinum and head and neck area, especially the sinonasal region, are among the common sites of disease. Histopathological diagnosis of NUT carcinoma is often very challenging due to its overlapping features with other poorly differentiated carcinomas. We report a case of NUT carcinoma arising from the parotid gland of a young female patient. Primary NUT carcinoma of salivary gland is very rare, with only 15 such cases reported in the literature to date. Our case highlights the diagnostic challenges associated with such lesions.
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http://dx.doi.org/10.1007/s12105-020-01254-9DOI Listing
December 2020

Clinicopathological analysis and survival outcomes of primary salivary gland tumors in pediatric patients: A systematic review.

J Oral Pathol Med 2021 May 8;50(5):435-443. Epub 2021 Jan 8.

Department of Oral Diagnosis, Piracicaba Dental School, State University of Campinas, Piracicaba, Brazil.

Background: Salivary gland tumors are a diverse group of uncommon neoplasms that are rare in pediatric patients. The aim of this study was to evaluate the clinicopathological profile and survival outcomes of pediatric patients affected by salivary gland tumors.

Materials And Methods: An extensive search was carried out using the MEDLINE/PubMed, EMBASE, Scopus databases, and grey literature. The risk of bias was available in all papers included.

Results: A total of 2,830 articles were initially retrieved with 54 remaining for data extraction, resulting in 2,937 cases. This comprised forty-five case series' and nine cohort studies. These tumors were slightly more prevalent in females (57.4%). The patients' age ranged from 0.3 to 19 years old, with a mean age of 13.3 years. Parotid was the most affected site (81.9%), and 99.2% of cases clinically exhibited a swelling. Presence of pain/tenderness was reported in 13.5% of the cases, with an average duration of 12.6 months for the appearance of symptoms. Most of the reported cases were malignant tumors (75.4%), with mucoepidermoid carcinoma the most common tumor of all tumors (44.8%), followed by pleomorphic adenoma (24.1%). Surgery alone was the leading treatment choice in 74.9% cases, and the 5-year overall survival rate of patients was 93.1%. Patients with symptoms (P = .001), local recurrence (P < .001), metastasis (P < .001), and those not undergoing surgery or surgery combined with radiotherapy (P < .001) showed lower survival rates.

Conclusion: The pediatric patients present a high frequency of malignant salivary neoplasms and a high overall survival rate.
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http://dx.doi.org/10.1111/jop.13151DOI Listing
May 2021

Central odontogenic fibroma: an international multicentric study of 62 cases.

Oral Surg Oral Med Oral Pathol Oral Radiol 2021 May 27;131(5):549-557. Epub 2020 Aug 27.

Department of Oral Pathology and Oral Biology, School of Dentistry, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa.

Objective: The aim of this study was to report the clinicopathologic features of 62 cases of central odontogenic fibroma (COdF).

Study Design: Clinical and radiographic data were collected from the records of 13 oral pathology laboratories. All cases were microscopically reviewed, considering the current World Health Organization classification of tumors and were classified according to histopathologic features.

Results: There were 43 females and 19 males (average age 33.9 years; range 8-63 years). Clinically, COdF lesions appeared as asymptomatic swellings, occurring similarly in the maxilla (n = 33) and the mandible (n = 29); 9 cases exhibited palatal depression. Imaging revealed well-defined, interradicular unilocular (n = 27), and multilocular (n = 12) radiolucencies, with displacement of contiguous teeth (55%) and root resorption (46.4%). Microscopically, classic features of epithelial-rich (n = 33), amyloid (n = 10), associated giant cell lesion (n = 7), ossifying (n = 6), epithelial-poor (n = 3), and granular cell (n = 3) variants were seen. Langerhans cells were highlighted by CD1a staining in 17 cases. Most patients underwent conservative surgical treatments, with 1 patient experiencing recurrence.

Conclusions: To the best of our knowledge, this study represents the largest clinicopathologic study of COdF. Most cases appeared as locally aggressive lesions located in tooth-bearing areas in middle-aged women. Inactive-appearing odontogenic epithelium is usually observed within a fibrous/fibromyxoid stroma, occasionally exhibiting amyloid deposits, multinucleated giant cells, or granular cells.
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http://dx.doi.org/10.1016/j.oooo.2020.08.022DOI Listing
May 2021

Automated feature detection in dental periapical radiographs by using deep learning.

Oral Surg Oral Med Oral Pathol Oral Radiol 2021 Jun 27;131(6):711-720. Epub 2020 Aug 27.

Senior Clinical Lecturer, Consultant Oral Pathologist, University of Sheffield, Sheffield, UK.

Objective: The aim of this study was to investigate automated feature detection, segmentation, and quantification of common findings in periapical radiographs (PRs) by using deep learning (DL)-based computer vision techniques.

Study Design: Caries, alveolar bone recession, and interradicular radiolucencies were labeled on 206 digital PRs by 3 specialists (2 oral pathologists and 1 endodontist). The PRs were divided into "Training and Validation" and "Test" data sets consisting of 176 and 30 PRs, respectively. Multiple transformations of image data were used as input to deep neural networks during training. Outcomes of existing and purpose-built DL architectures were compared to identify the most suitable architecture for automated analysis.

Results: The U-Net architecture and its variant significantly outperformed Xnet and SegNet in all metrics. The overall best performing architecture on the validation data set was "U-Net+Densenet121" (mean intersection over union [mIoU] = 0.501; Dice coefficient = 0.569). Performance of all architectures degraded on the "Test" data set; "U-Net" delivered the best performance (mIoU = 0.402; Dice coefficient = 0.453). Interradicular radiolucencies were the most difficult to segment.

Conclusions: DL has potential for automated analysis of PRs but warrants further research. Among existing off-the-shelf architectures, U-Net and its variants delivered the best performance. Further performance gains can be obtained via purpose-built architectures and a larger multicentric cohort.
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http://dx.doi.org/10.1016/j.oooo.2020.08.024DOI Listing
June 2021

The use of digital microscopy as a teaching method for human pathology: a systematic review.

Virchows Arch 2020 Oct 24;477(4):475-486. Epub 2020 Aug 24.

Oral Diagnosis Department, Semiology and Oral Pathology Areas, Piracicaba Dental School, University of Campinas (UNICAMP), Av. Limeira, 901, Bairro Areão, Piracicaba, São Paulo, 13414-903, Brazil.

Since digital microscopy (DM) has become a useful alternative to conventional light microscopy (CLM), several approaches have been used to evaluate students' performance and perception. This systematic review aimed to integrate data regarding the use of DM for education in human pathology, determining whether this technology can be an adequate learning tool, and an appropriate method to evaluate students' performance. Following a specific search strategy and eligibility criteria, three electronic databases were searched and several articles were screened. Eight studies involving medical and dental students were included. The test of performance comprised diagnostic and microscopic description, clinical features, differential, and final diagnoses of the specimens. The students' achievements were equivalent, similar or higher using DM in comparison with CLM in four studies. All publications employed question surveys to assess the students' perceptions, especially regarding the easiness of equipment use, quality of images, and preference for one method. Seven studies (87.5%) indicated the students' support of DM as an appropriate method for learning. The quality assessment categorized most studies as having a low bias risk (75%). This study presents the efficacy of DM for human pathology education, although the high heterogeneity of the included articles did not permit outlining a specific method of performance evaluation.
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http://dx.doi.org/10.1007/s00428-020-02908-3DOI Listing
October 2020

CEOT Variants or Entities: Time for a Rethink? A Case Series with Review of the Literature.

Head Neck Pathol 2021 Mar 8;15(1):186-201. Epub 2020 Jul 8.

Unit of Oral and Maxillofacial Medicine, Pathology and Surgery, School of Clinical Dentistry, University of Sheffield, 19 Claremont Crescent, Sheffield, S10 2TA, UK.

The first detailed description of calcifying epithelial odontogenic tumor (CEOT) are ascribed to Jens Pindborg, but this tumor was described some years previously. Subsequently, CEOT was included in the 1971 WHO classification of odontogenic tumors and a since then number of variants have been described, which have added confusion to the diagnostic criteria. We aimed to survey the literature on the variants of CEOT, in parallel with a review of our single institution experience of CEOTs. Cases identified were collated, including available clinical, radiological and histological information and then reviewed, taking into account changes in the understanding and classifications of odontogenic tumors since initial diagnosis. We identified 26 cases from 1975 to 2017 for which histological material was available. Of these, only 13 (50%) showed the "classic" histological appearance, whilst two cases were identified as recognized variants. In 11 cases, other diagnoses or a differential diagnosis were preferred, with no agreed diagnosis in four of these. The proliferation fraction (Ki67) in the 10 cases tested was 2.1% ± 0.18. These findings illustrate the diagnostic challenges in this group of tumors and highlight the gaps in knowledge. Techniques, such as EWSR1 gene cytogenetic analysis, may be helpful in cases with clear cells. However, in other areas of controversy, including the non-calcifying and Langerhans cell rich variants, further investigation, perhaps utilizing sequencing technologies may be needed to refine the classification. Owing to the relative rarity of these lesions it would be beneficial if future work could be pursued as an international collaboration.
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http://dx.doi.org/10.1007/s12105-020-01200-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010033PMC
March 2021

Oral cancer stem cells drive tumourigenesis through activation of stromal fibroblasts.

Oral Dis 2020 Jun 27. Epub 2020 Jun 27.

School of Clinical Dentistry, University of Sheffield, Sheffield, UK.

Background: Cancer stem cells are responsible for tumour progression and chemoresistance. Fibroblasts surrounding a tumour also promote progression and fibroblast "activation" is an independent prognostic marker in oral cancer. Cancer stem cells may therefore promote tumourigenesis through communication with stromal fibroblasts.

Methods: Cancer stem cells were isolated from oral cancer cell lines by adherence to fibronectin or cisplatin resistance. Fibroblasts were exposed to conditioned medium from these cells, and the activation markers, alpha smooth muscle actin and interleukin-6, were assessed using qPCR and immunofluorescence. Stem cell markers and smooth muscle actin were examined in oral cancer tissue using immunohistochemistry.

Results: Adherent and chemoresistant cells expressed increased levels of stem cell markers CD24, CD44 and CD29 compared with unsorted cells. Adherent cells exhibited lower growth rate, higher colony forming efficiency and increased cisplatin resistance than unsorted cells. Smooth muscle actin and Interleukin-6 expression were increased in fibroblasts exposed to conditioned medium. In oral cancer tissue, there was a positive correlation between expression of αSMA and stem cell markers.

Conclusions: Adherence to fibronectin and chemoresistance isolates stem-like cells that can activate fibroblasts, which together with a correlation between markers of both in vivo, provides a mechanism by which such cells drive tumourigenesis.
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http://dx.doi.org/10.1111/odi.13513DOI Listing
June 2020

The chemokine lymphotactin and its recombinant variants in oral cancer cell regulation.

Oral Dis 2020 Nov 30;26(8):1668-1676. Epub 2020 Jun 30.

Unit of Oral and Maxillofacial Pathology, School of Clinical Dentistry, University of Sheffield, Sheffield, UK.

Background: The expression of XCR1 receptor and its metamorphic ligand lymphotactin (hLtn) has been shown in cancers but their precise role in tumorigenesis is poorly understood including the significance of the physiologically existing hLtn monomeric (CC3) and dimeric (W55D) confirmations where the latter thought to function as the receptor antagonist. The aim of this study was to explore the functional role of bioengineered hLtn variants and the role of fibroblasts in XCR1/hLtn expression regulation in oral cancer cells (OCCL).

Material And Methods: qRT-PCR and flow cytometry were performed to evaluate mRNA and protein expression of XCR1 and hLtn. Recombinant hLtn variants (wild-type, CC3 and W55D mutant) were designed, expressed, purified and evaluated using proliferation, adhesion and chemotaxis assays. XCR1 and hLtn expression regulation by fibroblasts was determined using indirect co-culture. XCR1 and hLtn expression in primary and metastatic OSCC tissue was assessed using immunohistochemistry.

Results: hLtn caused a significant decrease in OCCL XCR1 surface protein expression. hLtn CC3 mutant was highly functional facilitating proliferation and migration. Conditioned media from primary cancer-associated and senescent fibroblasts significantly upregulated XCR1 and hLtn mRNA expression in OCCL. Immunohistochemistry revealed higher XCR1 and hLtn expression in metastatic tumour deposits and surrounding stroma compared to primary OSCC tissue.

Conclusions: The development of hLtn biological mutants, regulation of XCR1 expression by its ligand hLtn and crosstalk with fibroblasts are novel findings suggesting an important role for the XCR1/hLtn axis within the OSCC tumour microenvironment. These discoveries build upon previous studies and suggest that the hLtn/XCR1 axis has a significant role in stromal crosstalk and OSCC progression.
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http://dx.doi.org/10.1111/odi.13500DOI Listing
November 2020

Cancer Image Quantification With And Without, Expensive Whole Slide Imaging Scanners.

Annu Int Conf IEEE Eng Med Biol Soc 2019 Jul;2019:4462-4465

Automated analysis of digitized pathology images in tele-health applications can have a transformative impact on under-served communities in the developing world. However, the vast majority of existing image analysis algorithms are trained on slide images acquired via expensive Whole-Slide-Imaging (WSI) scanners. High scanner cost is a key bottleneck preventing large-scale adoption of digital pathology in developing countries. In this work, we investigate the viability of automated analysis of slide images captured from the eyepiece of a microscope via a smart phone. The mitosis detection application is considered as a use case.Results indicate performance degradation when using (lower-quality) smartphone images; as expected. However, the performance gap is not too wide (F1-score smartphone=0.65, F1-score WSI=0.70) demonstrating that smartphones could potentially be employed as image acquisition devices for digital pathology at locations where expensive scanners are not available.
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http://dx.doi.org/10.1109/EMBC.2019.8857765DOI Listing
July 2019

Human papillomavirus (HPV) can establish productive infection in dysplastic oral mucosa, but HPV status is poorly predicted by histological features and p16 expression.

Histopathology 2020 Mar 24;76(4):592-602. Epub 2020 Jan 24.

Unit of Oral and Maxillofacial Medicine and Pathology, University of Sheffield, Sheffield, UK.

Aims: Previous studies have reported the presence of high-risk human papillomavirus (HR-HPV) in a subset of dysplastic oral epithelial lesions. Many cases show a histological spectrum of atypia similar to that seen in non-human papillomavirus (HPV) severe epithelial dysplasia, but some studies have suggested that HPV status can be inferred on the basis of histological features. We aimed to assess the utility of such histological features and p16 as surrogate markers of HPV infection in a retrospective cohort of 33 cases of severe epithelial dysplasia, with matched clinicopathological data and histological features.

Methods And Results: Tissue sections were assessed for the expression of p16, minichromosome maintenance 2, HPV E4 and HPV L1 by the use of immunohistochemistry. HPV16/18 E6 and E7 expression was assessed by the use of RNA in-situ hybridisation (RNAScope). In the cohort, 18.2% of cases (6/33) were HR-HPV-positive, with no age/gender differences between the HPV-positive and HPV-negative groups. HPV E4 and HPV L1 were expressed in surface keratinocytes in four of six (66%) HPV-positive cases, indicative of productive HPV infection. Lack of p16 expression was predictive of HPV-negative status, but sensitivity and specificity varied according to the cut-off. Histologically, the presence of karyorrhectic nuclei and abnormal mitotic figures was higher in HPV-positive lesions (P < 0.05), but the predictive specificity and sensitivity were suboptimal (sensitivity, 0.75; specificity, 0.52).

Conclusions: This study demonstrates, for the first time, that a minority of severely dysplastic oral lesions harbour productive, biologically relevant HPV infection. Consideration should be given to the specific assessment of HPV status in severe epithelial dysplasia cases, as both p16 status and the presence of karyorrhectic cells are poor predictive markers of HPV status.
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http://dx.doi.org/10.1111/his.14019DOI Listing
March 2020

A Novel Digital Score for Abundance of Tumour Infiltrating Lymphocytes Predicts Disease Free Survival in Oral Squamous Cell Carcinoma.

Sci Rep 2019 09 16;9(1):13341. Epub 2019 Sep 16.

Department of Computer Science, University of Warwick, Coventry, CV47AL, UK.

Oral squamous cell carcinoma (OSCC) is the most common type of head and neck (H&N) cancers with an increasing worldwide incidence and a worsening prognosis. The abundance of tumour infiltrating lymphocytes (TILs) has been shown to be a key prognostic indicator in a range of cancers with emerging evidence of its role in OSCC progression and treatment response. However, the current methods of TIL analysis are subjective and open to variability in interpretation. An automated method for quantification of TIL abundance has the potential to facilitate better stratification and prognostication of oral cancer patients. We propose a novel method for objective quantification of TIL abundance in OSCC histology images. The proposed TIL abundance (TILAb) score is calculated by first segmenting the whole slide images (WSIs) into underlying tissue types (tumour, lymphocytes, etc.) and then quantifying the co-localization of lymphocytes and tumour areas in a novel fashion. We investigate the prognostic significance of TILAb score on digitized WSIs of Hematoxylin and Eosin (H&E) stained slides of OSCC patients. Our deep learning based tissue segmentation achieves high accuracy of 96.31%, which paves the way for reliable downstream analysis. We show that the TILAb score is a strong prognostic indicator (p = 0.0006) of disease free survival (DFS) on our OSCC test cohort. The automated TILAb score has a significantly higher prognostic value than the manual TIL score (p = 0.0024). In summary, the proposed TILAb score is a digital biomarker which is based on more accurate classification of tumour and lymphocytic regions, is motivated by the biological definition of TILs as tumour infiltrating lymphocytes, with the added advantages of objective and reproducible quantification.
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http://dx.doi.org/10.1038/s41598-019-49710-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746698PMC
September 2019

Methods for Segmentation and Classification of Digital Microscopy Tissue Images.

Front Bioeng Biotechnol 2019 2;7:53. Epub 2019 Apr 2.

Cancer Imaging Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.

High-resolution microscopy images of tissue specimens provide detailed information about the morphology of normal and diseased tissue. Image analysis of tissue morphology can help cancer researchers develop a better understanding of cancer biology. Segmentation of nuclei and classification of tissue images are two common tasks in tissue image analysis. Development of accurate and efficient algorithms for these tasks is a challenging problem because of the complexity of tissue morphology and tumor heterogeneity. In this paper we present two computer algorithms; one designed for segmentation of nuclei and the other for classification of whole slide tissue images. The segmentation algorithm implements a multiscale deep residual aggregation network to accurately segment nuclear material and then separate clumped nuclei into individual nuclei. The classification algorithm initially carries out patch-level classification via a deep learning method, then patch-level statistical and morphological features are used as input to a random forest regression model for whole slide image classification. The segmentation and classification algorithms were evaluated in the MICCAI 2017 Digital Pathology challenge. The segmentation algorithm achieved an accuracy score of 0.78. The classification algorithm achieved an accuracy score of 0.81. These scores were the highest in the challenge.
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http://dx.doi.org/10.3389/fbioe.2019.00053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454006PMC
April 2019

Oral potentially malignant disorders: risk of progression to malignancy.

Oral Surg Oral Med Oral Pathol Oral Radiol 2018 06 29;125(6):612-627. Epub 2017 Dec 29.

UWA Dental School, The University of Western Australia, Nedlands, Australia.

Oral potentially malignant disorders (OPMDs) have a statistically increased risk of progressing to cancer, but the risk varies according to a range of patient- or lesion-related factors. It is difficult to predict the risk of progression in any individual patient, and the clinician must make a judgment based on assessment of each case. The most commonly encountered OPMD is leukoplakia, but others, including lichen planus, oral submucous fibrosis, and erythroplakia, may also be seen. Factors associated with an increased risk of malignant transformation include sex; site and type of lesion; habits, such as smoking and alcohol consumption; and the presence of epithelial dysplasia on histologic examination. In this review, we attempt to identify important risk factors and present a simple algorithm that can be used as a guide for risk assessment at each stage of the clinical evaluation of a patient.
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http://dx.doi.org/10.1016/j.oooo.2017.12.011DOI Listing
June 2018

Adenoid dysplasia of the oral mucosa.

Oral Surg Oral Med Oral Pathol Oral Radiol 2014 Nov 15;118(5):586-92. Epub 2014 Aug 15.

Department of Oral Pathology and Oral Biology, School of Dentistry, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa. Electronic address:

Objective: To describe an unusual variant of oral epithelial dysplasia and to provide an appraisal of its immunohistochemical profile.

Study Design: An unusual form of epithelial dysplasia, which we have termed adenoid dysplasia, was evaluated for staining of cytokeratins AE1/AE3, vimentin, E-cadherin, and β-catenin. The immunohistochemical results were compared with those observed in moderate epithelial dysplasia, moderately differentiated squamous cell carcinoma, and acantholytic squamous cell carcinoma.

Results: The immunoprofile of adenoid dysplasia was similar to that of acantholytic squamous cell carcinoma. Cytokeratin positivity within the acantholytic dysplastic cells confirmed their epithelial nature, and upregulation of vimentin was suggestive of epithelial-mesenchymal transition. The most distinctive finding was a loss of E-cadherin expression within the discohesive cells, accompanied by increased cytosolic expression of β-catenin.

Conclusions: This report presents the histomorphologic features of a unique form of oral epithelial dysplasia, termed adenoid dysplasia.
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http://dx.doi.org/10.1016/j.oooo.2014.08.009DOI Listing
November 2014

IgG4-related sclerosing disease clinically mimicking oral squamous cell carcinoma.

Oral Surg Oral Med Oral Pathol Oral Radiol 2013 Feb 15;115(2):e48-51. Epub 2012 Aug 15.

Unit of Oral and Maxillofacial Pathology, School of Clinical Dentistry, University of Sheffield, Sheffield, United Kingdom.

IgG4-related sclerosing disease is a distinct clinicopathologic entity known to involve the maxillofacial region, particularly the salivary, lacrimal, and pituitary glands. We report a case with lesions involving the tongue and palatine tonsil with associated skin lesions. A 45-year-old female patient presented with a history of soreness, dysphagia, and an asymptomatic rash involving the upper trunk. The initial clinical diagnosis of her oral lesions was squamous cell carcinoma. The diagnosis of an IgG4-related lesion was confirmed by histologic examination of the oral and skin lesions as well as confirmation of raised serum IgG4 levels. Tapering systemic corticosteroid therapy resulted in complete resolution of the lesions. This is the first report of IgG4-related sclerosing disease presenting as concurrent oral and skin lesions, with the oral lesion clinically resembling oral squamous cell carcinoma. Such lesions present a diagnostic challenge, but the outcome is very favorable.
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http://dx.doi.org/10.1016/j.oooo.2012.04.011DOI Listing
February 2013

Crystal storing histiocytosis of the tongue as the initial presentation of multiple myeloma.

Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2011 Apr;111(4):494-6

Oral and Maxillofacial Pathology, School of Clinical Dentistry, University of Sheffield, Sheffield, United Kingdom.

Crystal-storing histiocytosis (CSH) is a rare consequence of abnormal accumulation of immunoglobulins which may arise in a number of different clinical scenarios. In this report, we describe the case of a male patient who presented with an apparently innocuous lesion on the dorsum of tongue which showed the typical features of CSH. Subsequent investigations revealed an associated plasmacytoma, and the patient developed further systemic lesions. The rarity of such lesions presents diagnostic difficulties, yet accurate diagnosis underpins the timely implementation of appropriate therapy.
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http://dx.doi.org/10.1016/j.tripleo.2010.12.019DOI Listing
April 2011