Prospective Cohort Study Identifies Medical Predictors of Treatment-Related Oral Toxicities in Oral and Oropharyngeal Cancer Patients.

The dental treatment of patients with oral cavity and oropharyngeal squamous cell carcinoma (OOPSCC) may be challenging for dentists. This study aimed to characterize systemic changes in patients with OOPSCC undergoing dental treatment prior to cancer therapy, with a specific focus on laboratory assessments. The primary objectives included identifying potential adverse events, such as infections or bleeding, resulting from dental procedures. Additionally, the study aimed to correlate baseline patient characteristics with treatment-related toxicities. This was a prospective cohort study that included 110 OOPSCC patients referred to the Dental Oncology Service at São Paulo State Cancer Institute, Brazil, between November/2019 and December/2020. Comorbidities, sociodemographic data, medication in use, cancer treatment-related toxicities, and altered laboratory tests results were correlated. The most common comorbidities and altered laboratory results were hypertension, dyslipidemia, diabetes, as well as elevated levels of C-reactive protein, hemoglobin, and hematocrit. Toxicities exhibited a progressive pattern over time, encompassing oral mucositis (OM), xerostomia, dysphagia, dysgeusia, trismus, and radiodermatitis. No correlation between comorbidities and cancer treatment-related toxicities, a positive correlation between medications in use and OM, and a negative correlation between medications and dysgeusia were found. OM was associated with altered thyroxine (T4) and free thyroxine (FT4), calcium, urea, creatinine, alkaline phosphatase, and syphilis. Family income and housing were OM predictors. Altered T4/FT4/urea/calcium/alkaline phosphatase/creatinine/syphilis may be useful clinical predictors of OM. Despite the elevated prevalence of comorbidities and abnormal laboratory findings, dental treatment prior to cancer treatment yielded no adverse events.

The impact of radiation caries on morbidity and mortality outcomes of head and neck squamous cell carcinoma patients.

AIMS: Radiation caries (RC) is a highly prevalent and chronic complication of head and neck radiotherapy (HNRT) and presents a challenge for clinicians and patients. The present study aimed to assess the impact of RC on the morbidity and mortality outcomes of head and neck squamous cell carcinoma (HNSCC) patients. METHODS AND RESULTS: Patients were divided into three groups: (1) RC (n = 20), (2) control (n = 20), and (3) edentulous (n = 20). Information regarding the number of appointments, dental procedures, osteoradionecrosis (ORN), prescriptions, and hospital admissions were collected. Mortality outcomes were assessed through disease-free survival (DFS) and overall survival (OS) rates. RC patients required more dental appointments (p < .001), restorations (p < .001), extractions (p = .001), and antibiotic and analgesic prescriptions (p < .001). Kaplan-Meier subgroup analyses showed a significantly increased risk of ORN in RC compared to edentulous patients (p = .015). RC patients presented lower DFS rates (43.2 months) than the control and edentulous groups (55.4 and 56.1 months, respectively). CONCLUSIONS: RC impacts morbidity outcomes among cancer survivors due to increased demand for medication prescriptions, multiple specialized dental appointments, invasive surgical treatments, increased risk of ORN, and increased need for hospital admissions.

Dosimetric parameters and radiotherapy simulation methods used in preclinical studies of radiation damage to the dentition: a systematic review.

OBJECTIVE: This systematic review investigated the dosimetric parameters used in preclinical studies. STUDY DESIGN: Searches were performed in 3 databases (PubMed, Scopus, and Embase) and gray literature to identify studies for review. In vitro and ex vivo studies that examined the effect of radiation on human permanent teeth were included. The modified Consolidated Standards Of Reporting Trials checklist of items for reporting preclinical in vitro studies was used to assess the risk of bias. RESULTS: In total, 32 studies met the inclusion criteria. The average radiation dose of in vitro studies was 53 (±22) Gy and in ex vivo studies was 69 (±1) Gy. Twenty-two studies used 5 different fractionation schemes. Twenty-two of the included studies did not report the radiotherapy modality of those reporting. Twenty studies used linear accelerators, and 7 used Cobalt-60 with the source-surface-distance of radiation ranging from 1.5 to 100 cm. Distilled water was the storage solution for the dental structure used most commonly. Biases were observed, including small sample sizes, lack of randomization, and blinding processes. CONCLUSION: The dosimetric parameters used in the preclinical studies, including radiation dose, radiotherapy modality, fractionation regime, and the storage solutions used did not support the hypothesis of direct effects of radiation on the dental structure.

Preservation of immunoexpression of type I collagen, BSP and BMP4 in the dentin-pulp complex of head and neck cancer patients after radiotherapy.

This study tested the hypothesis that head and neck radiotherapy (HNRT) impacts the immunoexpression of type I collagen, bone sialoprotein (BSP) and bone morphogenetic protein 4 (BMP4), thereby leading to micromorphological changes in the dentin-pulp complex (DPC), and promoting the onset and progression of radiation caries (RC). Twenty-two demineralized sections of carious teeth (a group of 11 irradiated teeth and a control group of 11 non-irradiated teeth) extracted from 19 head and neck cancer patients were analyzed by conventional optical microscopy and immunohistochemistry to investigate the micromorphology (cellular layer hierarchy, blood vessels, odontoblasts, fibroblasts, extracellular matrix, calcification, necrosis, reactionary dentin formation, and chronic inflammation), and the patterns of staining/immunolocalization of type I collagen, BSP and BMP4 in the dental pulp of irradiated and control samples. No significant differences attributable to the direct impact of radiotherapy were detected in DPC micromorphology between the groups. In addition, the patterns of immunohistochemical staining and immunolocalization of the proteins studied did not differ between the irradiated and the control samples for type I collagen, BSP or BMP4. This study rejected the hypothesis that HNRT directly damages dentition by changing the organic components and the microstructure of the DPC, ultimately leading to RC.

Extraoral photobiomodulation for prevention of oral and oropharyngeal mucositis in head and neck cancer patients: interim analysis of a randomized, double-blind, clinical trial.

PURPOSE: To assess the safety and efficacy of prophylactic extraoral photobiomodulation (PBM) for the prevention of oral and oropharyngeal mucositis (OM) on clinical outcomes and survival in patients with oral cavity and oropharyngeal squamous cell carcinoma (OOPSCC). METHODS: OOPSCC patients who received radiotherapy (RT) were prospectively randomized to two groups: prophylactic extraoral PBM and placebo. OM grade (NCI), pain (VAS), analgesia, and anti-inflammatory prescriptions were assessed weekly. Quality of life questionnaires (QoL) were performed at the first and last day of RT. Following RT, participants were evaluated quarterly for oncological outcomes follow-up. RESULTS: Fifty-five patients met the inclusion criteria. The first occurrence of OM was observed at week 1, for the placebo group (p = 0.014). Later, OM onset and severity was observed for the PBM group, with first occurrence at week 2 (p = 0.009). No difference in severe OM incidence was observed (p > 0.05). Lower mean pain score was noted at week 7 for the PBM group (2.1) compared to placebo group (4.5) (p = 0.009). Less analgesics (week 3; p = 0.009/week 7; p = 0.02) and anti-inflammatory prescription (week 5; p = 0.0346) were observed for the PBM group. Better QoL scores were observed for the PBM group at last day of RT (p = 0.0034). No difference in overall survival among groups was observed in 1 year of follow-up (p = 0.889). CONCLUSION: Prophylactic extraoral PBM can delay OM onset, reduce pain, and reduce analgesic and anti-inflammatory prescription requirements. Extraoral PBM was associated with better QoL. There was no evidence of PBM impact on oncological outcomes. TRIAL REGISTRATION: TRN:RBR-4w4swx (date of registration: 01/20/2020).

Preservation of immunoexpression of type I collagen, BSP and BMP4 in the dentin-pulp complex of head and neck cancer patients after radiotherapy

Abstract This study tested the hypothesis that head and neck radiotherapy (HNRT) impacts the immunoexpression of type I collagen, bone sialoprotein (BSP) and bone morphogenetic protein 4 (BMP4), thereby leading to micromorphological changes in the dentin-pulp complex (DPC), and promoting the onset and progression of radiation caries (RC). Twenty-two demineralized sections of carious teeth (a group of 11 irradiated teeth and a control group of 11 non-irradiated teeth) extracted from 19 head and neck cancer patients were analyzed by conventional optical microscopy and immunohistochemistry to investigate the micromorphology (cellular layer hierarchy, blood vessels, odontoblasts, fibroblasts, extracellular matrix, calcification, necrosis, reactionary dentin formation, and chronic inflammation), and the patterns of staining/immunolocalization of type I collagen, BSP and BMP4 in the dental pulp of irradiated and control samples. No significant differences attributable to the direct impact of radiotherapy were detected in DPC micromorphology between the groups. In addition, the patterns of immunohistochemical staining and immunolocalization of the proteins studied did not differ between the irradiated and the control samples for type I collagen, BSP or BMP4. This study rejected the hypothesis that HNRT directly damages dentition by changing the organic components and the microstructure of the DPC, ultimately leading to RC.

Awareness of the risk of radiation-related caries in patients with head and neck cancer: A survey of physicians, dentists, and patients.

OBJECTIVES: Radiation-related caries (RRC) is one of the most aggressive complications of radiotherapy (RT) in survivors of head and neck cancer (HNC). Lack of RRC awareness may contribute to the occurrence of this oral cavity complication. RRC may be considered a "forgotten oral complication" by patients with HNC, oncologists, and dentists. The present study aimed to assess the level of awareness of RRC among physicians, dentists, and patients. STUDY DESIGN: Physicians (group 1, G1), dentists (group 2, G2), and patients with HNC undergoing RT (group 3, G3) answered questionnaires concerning their awareness of RRC. Physicians (G1) were divided into group 1A (oncological experience) and group 1B (general physicians/other specialties). Dentists (G2) were divided into group 2A (oncological experience) and group 2B (general dentists/other specialties). Personalized questionnaires were designed for each group. RESULTS: Recruitment was as follows: physicians (n = 124): 1A (n = 64), 1B (n = 60); dentists: (n = 280), 2A (n = 160), 2B (n = 120). In addition, 58 patients answered the questionnaire. In terms of RRC awareness, 46.77% of physicians, 81.78% of dentists, and 24.13% of patients had some knowledge of the problem. CONCLUSION: Patient awareness of RRC was poor. The heterogeneity of answers among physicians and dentists suggests an opportunity to improve patient education and prevention of this serious oral complication of RT.

Cost-effectiveness of photobiomodulation therapy for the prevention and management of cancer treatment toxicities: a systematic review.

PURPOSE: To identify and summarize the evidence on the cost-effectiveness of photobiomodulation (PBM) therapy for the prevention and treatment of cancer treatment-related toxicities. METHODS: This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (PRISMA) and Meta-analysis Of Observational Studies in Epidemiology (MOOSE). Scopus, MEDLINE/PubMed, and Embase were searched electronically. RESULTS: A total of 1490 studies were identified, and after a two-step review, 4 articles met the inclusion criteria. The included studies analyzed the cost-effectiveness of PBM therapy used in the context of lymphedema for breast cancer and oral mucositis (OM) induced by chemotherapy and radiotherapy. Better outcomes were associated with PBM therapy. The incremental cost-effectiveness ratio ranged from 3050.75 USD to 5592.10 USD per grade 3-4 OM case prevented. PBM therapy cost 21.47 USD per percentage point reduction in lymphedema in comparison with 80.51 USD for manual lymph drainage and physical therapy. CONCLUSION: There is limited evidence that PBM therapy is cost-effective in the prevention and treatment of specific cancer treatment-related toxicities, namely, OM and breast cancer-related lymphedema. Studies may have underreported the benefits due to a lack of a comprehensive cost evaluation. This suggests a wider acceptance of PBM therapy at cancer treatment centers, which has thus far been limited by the number of robust clinical studies that demonstrate cost-effectiveness for the prevention and treatment of toxicities.

Salivary alpha-1-antitrypsin and macrophage migration inhibitory factor may be potential prognostic biomarkers for oncologic treatment-induced severe oral mucositis.

AIMS: Evaluate the abundance of the selected targets, alpha-1-antitrypsin (A1AT) and macrophage migration inhibitory factor (MIF), and correlate these findings with the risk of developing severe oral mucositis (OM). MATERIALS AND METHODS: Head and neck squamous cell carcinoma (HNSCC) patients submitted to radiotherapy (RT) or chemoradiotherapy (CRT) were assessed. OM grade and pain were evaluated daily during treatment. Two protein targets, A1AT and MIF, were evaluated, using selected reaction monitoring-mass spectrometry (SRM-MS), in whole saliva, collected prior to oncologic treatment. The results obtained from the targeted proteomic analysis were correlated with OM clinical outcomes. RESULTS: A total of 27 patients were included, of whom 21 (77.8%) had locally advanced disease (clinical stage III or IV). Most patients (70.4%) received CRT. OM grades 2 (40.8%) and 3 (33.3%) were the most prevalent during RT with a mean highest reported OM-related pain of 3.22 through the visual analogue scale (VAS). The abundance of A1AT and MIF correlated significantly with severe (grades 3 or 4, p < 0.02) compared with moderate-low (grades 1 or 2, p < 0.04) OM grade. CONCLUSIONS: There is a correlation between the abundance of salivary A1AT and MIF and oncologic treatment-induced OM. The correlation of MIF expression with severe OM appears to be compatible with its physiological pro-inflammatory role. These results open up great possibilities for the use of salivary MIF and A1AT levels as prognostic markers for effective therapeutic interventions, such as photobiomodulation therapy, patient-controlled analgesia, or personalized medicaments.

Patterns of oral mucositis in advanced oral squamous cell carcinoma patients managed with prophylactic photobiomodulation therapy-insights for future protocol development.

To characterize oral sites affected by radiation-induced oral mucositis (OM) and related clinical outcomes in oral cancer patients subjected to prophylactic photobiomodulation therapy (PBMT). This study included advanced oral squamous cell carcinoma (OSCC) patients treated with prophylactic PBMT for OM. The site distribution of OM, OM grading (CTCAE NCI, Version 4.0, 2010), OM-related pain (VAS), analgesic protocol (WHO Analgesic Ladder), and use of enteral nutrition were evaluated weekly during treatment. Data analysis was performed using descriptive statistics expressed as median values and percentages. A total of 145 OSCC patients were included. OM most frequently affected the lateral border of the tongue (44.1%), buccal mucosa (37.2%), and labial mucosa (33.8%). Keratinized oral mucosa sites, including the tongue dorsum (6.21%), retromolar trigone (8.3%), and hard palate (2.76%), were less frequently affected. Peak OM scores were observed at weeks 5, 6, and 7, with severe OM (NCI grades 3 and 4) rates of 11%, 20%, and 25%, respectively. The cumulative occurrence of severe OM was 23%, which developed as early as week 3 and as late as week 7. The highest mean value of OM-related pain (2.7) was observed at the sixth week, and 13.8% of the patients required feeding support. This study showed, compared with studies that did not provide PBMT, reduced severity of mucositis, reduced pain and analgesic use, and reduced tube feeding in patients treated with PBMT. OM involving keratinized and non-keratinized surfaces should be included in the prophylactic PBMT to reduce severe OM in future studies.

Morphological patterns of circumpulpal dentin affected by radiation-related caries.

BACKGROUND: The aim of this work was to evaluate the microscopic characteristics through polarized light microscopy, scanning electron microscopy and the mineral content of circumpulpal dentin of irradiated (IT) and non-irradiated teeth (NIT), with deep caries that reached the root canal. MATERIAL AND METHODS: A total of 25 IT were analyzed macroscopically, and radiographed. 5 NIT were used as controls. Two 100-µm-thick sections, per specimen, were evaluated in a polarized light microscopy and a scanning electron microscope. Demographics and clinical data were collected. RESULTS: The results did not demonstrate distinct morphology of the IT compared with NIT. Mineral content values by weight percentage of Ca and P were also similar, corresponding to 66.65% and 33.21% in the IT and 66.60% and 33.29% in the NIT. The Ca/P ratio did not show statistical differences between groups being respectively 2.74 and 2.72, in the IT and NIT (p> 0.05). CONCLUSIONS: Radiotherapy does not change morphology and mineral content of circumpulpal dentin in IT. Key words:Root canal, radiation-related caries, polarization microscopy, scanning electron microscopy, radiotherapy, oral neoplasms, dentin.

Radiation-related caries: current diagnostic, prognostic, and management paradigms.

OBJECTIVE AND STUDY DESIGN: This narrative review summarizes the current state of art of radiation-related caries (RC), an aggressive disease that affects approximately 30% of post-head and neck radiotherapy (HNRT) patients. RESULTS: RC mainly affects the tooth cervical areas and incisal/cuspal tips and develops 6 to 12 months after HNRT. Early RC signs include black/brownish tooth discoloration and enamel cracks, which progress to enamel delamination, exposing underlying dentin to a highly cariogenic oral environment and rapid tooth destruction/dental crown amputation. As RC advances and renders the tooth nonrestorable, it may lead to osteoradionecrosis spontaneously or upon extraction if the tooth is in a highly irradiated field of the oral cavity. This requires aggressive treatment, which would have a negative impact on a cancer survivor's quality of life and contribute to the incremental cost of cancer care. Chlorhexidine mouth rinses and topical fluoride applications are effective agents used in RC prevention; however, there are no well-established treatment protocols. Once RC progresses, dental restorations should be performed with adhesive materials in association with systematic fluoride application as illustrated in the clinical case presented in this review. Post-HNRT patients should be closely followed up for optimal RC prevention, early diagnosis, and prompt treatment. CONCLUSIONS: Future clinical studies are necessary to establish a contemporary, clinically validated protocol for RC management.

Impact of Clustering Oral Symptoms in the Pathogenesis of Radiation Caries: A Systematic Review.

Radiation-related caries (RRC) is a disease with a high potential for destruction of the dentition, which impairs quality of life in head-and-neck (HN) cancer (HNC) patients who undergo radiotherapy. In light of the recently described "clustering of oral symptoms theory," the present systematic review (PROSPERO CRD42019132709) aims to assess HN and gastrointestinal (GI) symptom clusters among HNC patients and discusses how these indirect effects of cancer therapy play a pivotal role in the pathophysiology of RRC. The search was performed at PubMed, Scopus, and Embase and resulted in 11 studies that met the inclusion criteria. Data extraction was performed with respect to the presence of HN/GI symptom clusters among HNC patients. The methodological data of the studies included were assessed using the MAStARI and GRADE instruments. The most prevalent reported HN symptoms were dysphagia, xerostomia, and pain. Taste alterations and fatigue were also commonly reported by the patients. Loss of appetite and weight loss were regularly reported in the studies, as well as nausea and vomiting. The results of the present study suggest that HNC treatment generates clusters of oral symptoms, leading to dietary changes, impaired oral hygiene, enamel fragility, and a highly cariogenic oral environment, which may impact the risk for RRC. A better understanding of oral symptom clustering could be of considerable clinical significance for the oral health and quality of life of HNC patients. Therefore, contemporary protocols of RRC prevention must take this broader treatment scenario of symptom clusters such as oral side effects into account.

Young head and neck cancer patients are at increased risk of developing oral mucositis and trismus.

OBJECTIVES: To evaluate cancer treatment-related toxicities in young head and neck cancer (HNC) patients. MATERIAL AND METHODS: A total of 44 patients were included in the present retrospective cohort study, which was designed to access oral toxicities of cancer treatment in young (< 45 years of age, Group I, n = 22) and old (> 58 years of age, Group II, n = 22) HNC patients with similar tumor stage and treatment protocols. Oral mucositis (OM), xerostomia, dysphagia, dysgeusia, trismus, and radiodermatitis were assessed during days 7th, 21st, and 35th of head and neck radiotherapy (HNRT) according to previously validated scales (World Health Organization criteria and the National Cancer Institute and Common Terminology Criteria for Adverse Events version 4.0). RESULTS: Patients from both groups showed high incidence and severity of oral toxicities by the end of the HNRT with OM (81.9% (Group I); 63.6% (Group II)) and xerostomia (72.6% (Group I); 77.2% (Group II)) being the most prevalent toxicities. No differences regarding xerostomia, dysphagia, dysgeusia, and radiodermatitis incidences or severity could be observed between groups. However, higher incidences and severity of OM at 21st and 35th fractions (odds ratio = 2.22 and 5.71, respectively) and trismus at 21st and 35th fractions (odds ratio = 6.17 and 14.5, respectively) were observed throughout the treatment in young patients when compared to older patients (p < 0.01 and p < 0.05, respectively). CONCLUSION: Young HNC patients are more affected by cancer treatment-related OM and trismus despite the similarities in clinical staging and treatment protocols with elderly patients.

The impact of radiation caries in the quality of life of head and neck cancer patients.

PURPOSE: The objective of this multicentre study was to verify the relationship between the scores of quality of life (QoL) and the decayed, missing and filled teeth (DMFT) and radiation caries (RC) in patients treated with radiation therapy (RT) for head and neck cancer, and through this to determine if RC is capable of causing a significant decrease in the QoL. METHODS: One hundred patients were divided into 2 groups: patients with at least 1 year of RT completion who developed RC (study group, n = 50); and patients with at least 1 year of RT completion who did not develop RC (control group, n = 50). All patients answered the Brazilian-Portuguese version of the University of Washington quality of life (UW-QoL) questionnaire, which was divided into physical and social-emotional functioning domains and evaluated the DMFT index score. RESULTS: The mean score of QoL was 927.2 in the control group and 878.1 in the study group (P = 0.24). The mean score of DMFT was 30.5 in the study group and 20.7 in the control group (P = 0.001). The items recreation and saliva, which belong to the physical function domain, showed a statistically significant difference between the study and control groups (P = 0.031 and P = 0.047, respectively). Saliva was the item with the higher number of patient complaints in both groups. CONCLUSION: RC had a negative impact on the QoL of HNC patients.

Tumor safety and side effects of photobiomodulation therapy used for prevention and management of cancer treatment toxicities. A systematic review.

Photobiomodulation therapy (PBMT), also known as low-level laser therapy (LLLT), has been increasingly used for the treatment of toxicities related to cancer treatment. One of the challenges for the universal acceptance of PBMT use in cancer patients is whether or not there is a potential for the light to stimulate the growth of residual malignant cells that evaded oncologic treatment, increasing the risk for tumor recurrences and development of a second primary tumor. Current science suggests promising effects of PBMT in the prevention and treatment of breast cancer-related lymphedema and oral mucositis, among other cancer treatment toxicities. Nevertheless, this seems to be the first systematic review to analyze the safety of the use of PBMT for the management of cancer-related toxicities. Scopus, MEDLINE/PubMed, and Embase were searched electronically. A total of 27 articles met the search criteria. Selected studies included the use of PBMT for prevention and treatment of oral mucositis, lymphedema, radiodermatitis, and peripheral neuropathy. Most studies showed that no side effects were observed with the use of PBMT. The results of this systematic review, based on current literature, suggest that the use of PBMT in the prevention and management of cancer treatment toxicities does not lead to the development of tumor safety issues.

Dentin-pulp complex reactions in conventional and radiation-related caries: A comparative study.

BACKGROUND: Radiation-related caries (RRC) is one of the most significant oral toxicities of head and neck radiotherapy (HNRT); however, the potential of radiation to directly cause harmful dentin and pulpal effects and impair response to caries progression is controversial. MATERIAL AND METHODS: Therefore, the aim of this study was to characterize the reactions of the dentin-pulp complex in teeth affected by RRC. Patients and methods: Twenty-two carious teeth extracted from 22 head and neck cancer (HNC) patients were divided into control (conventional caries; n=11) and irradiated (RRC; n=11) groups and paired matched by dental homology, clinical patterns of caries progression following the Post-Radiation Dental Index (PRDI) and microscopic depth of carious invasion. Histopathological characteristics based on morphological hierarchy, cell populations of dental pulp, blood vessels, neural elements, extracellular matrix components, inflammation, patterns of carious invasion and reactionary dentin presence were evaluated by optical light microscopy and histomorphometry. RESULTS: Mean PRDI scores were 3.2 for the control group and 3.8 for the irradiated group. Dentin demineralization patterns were also similar between the groups and the mean depths of demineralization were 1,158.58µm and 1,056.89µm for the control and irradiated groups, respectively. CONCLUSIONS: Pulp histopathological changes and dentin reaction patterns were similar between groups and varied according to the PRDI scores and carious lesions depth. Dentin and pulp reactions are highly preserved in RRC teeth. Key words:Cancer, radiotherapy, radiation-related caries, teeth, pulp.

The performance of digital microscopy for primary diagnosis in human pathology: a systematic review.

Validation studies of whole slide imaging (WSI) systems produce evidence regarding digital microscopy (DM). This systematic review aimed to provide information about the performance of WSI devices by evaluating intraobserver agreement reported in previously published studies as the best evidence to elucidate whether DM is reliable for primary diagnostic purposes. In addition, this review delineates the reasons for the occurrence of discordant diagnoses. Scopus, MEDLINE/PubMed, and Embase were searched electronically. A total of 13 articles were included. The total sample of 2145 had a majority of 695 (32.4%) cases from dermatopathology, followed by 200 (9.3%) cases from gastrointestinal pathology. Intraobserver agreements showed an excellent concordance, with values ranging from 87% to 98.3% (κ coefficient range 0.8-0.98). Ten studies (77%) reported a total of 128 disagreements. The remaining three studies (23%) did not report the exact number and nature of disagreements. Borderline/challenging cases were the most frequently reported reason for disagreements (53.8%). Six authors reported limitations of the equipment and/or limited image resolution as reasons for the discordant diagnoses. Within these articles, the reported pitfalls were as follows: difficulties in the identification of eosinophilic granular bodies in brain biopsies; eosinophils and nucleated red blood cells; and mitotic figures, nuclear details, and chromatin patterns in neuropathology specimens. The lack of image clarity was reported to be associated with difficulties in the identification of microorganisms (e.g., Candida albicans, Helicobacter pylori, and Giardia lamblia). However, authors stated that the intraobserver variances do not derive from technical limitations of WSI. A lack of clinical information was reported by four authors as a source for disagreements. Two studies (15.4%) reported poor quality of the biopsies, specifically small size of the biopsy material or inadequate routine laboratory processes as reasons for disagreements. One author (7.7%) indicated the lack of immunohistochemistry and special stains as a source for discordance. Furthermore, nine studies (69.2%) did not consider the performance of the digital method-limitations of the equipment, insufficient magnification/limited image resolution-as reasons for disagreements. To summarize the pitfalls of digital pathology practice and better address the root cause of the diagnostic discordance, we suggest a Categorization for Digital Pathology Discrepancies to be used in further validations studies. Among 99 discordances, only 37 (37.3%) had preferred diagnosis rendered by means of WSI. The risk of bias and applicability concerns were judged with the QUADAS-2. Two studies (15.4%) presented an unclear risk of bias in the sample selection domain and 2 (15.4%) presented a high risk of bias in the index test domain. Regarding applicability, all studies included were classified as a low concern in all domains. The included studies were optimally designed to validate WSI for general clinical use, providing evidence with confidence. In general, this systematic review showed a high concordance between diagnoses achieved by using WSI and conventional light microscope (CLM), summarizes difficulties related to specific findings of certain areas of pathology-including dermatopathology, pediatric pathology, neuropathology, and gastrointestinal pathology-and demonstrated that WSI can be used to render primary diagnoses in several subspecialties of human pathology.

Cracked tooth syndrome in irradiated patients with head and neck cancer.

OBJECTIVES: The aim of this study was to assess the presence of enamel craze lines (ECLs), part of the spectrum of the so-called cracked tooth syndrome, on the surface of teeth irradiated in vivo. STUDY DESIGN: Forty teeth extracted from patients with head and neck cancer were paired, matched, and equally divided into 4 groups: noncarious irradiated (G1); noncarious control (G2); radiation-related caries (RRC) (G3), and carious control (G4). Samples were examined for ECL detection with a fiberoptic transillumination device and photographed, and ECL mean size, number, and patterns of topographic distribution in tooth crown were determined. Groups were compared accordingly: G1 versus G2; G3 versus G4. RESULTS: We analyzed 538 ECLs, of which 30.1% were found in noncarious irradiated teeth, 19.3% in noncarious controls, 27.6% in RRC, and 23% in carious controls. Non-carious irradiated teeth presented higher quantities of ECL than non-carious control (P < 0.05). Higher incidences of ECLs were identified in specific enamel topographies of anterior G1 and G3 samples (P <.05). There was no correlation between ECL size/numbers and radiation isodose delivery to teeth. CONCLUSIONS: Increased incidence of ECLs may indicate weakened enamel structure in irradiated teeth, and this may play a role in the onset and progression of RRC.