Two-tier Grading System Research Articles

Quality Assessment of Periapical Radiographs Taken by Dental Assistants Using the Recent Faculty of General Dental Practice (FGDP) Guidelines.

Periapical radiographs play a pivotal role in dentistry, offering invaluable insights essential for various dental procedures. This study aims to systematically assess the quality of intraoral periapical (IOPA) radiographs evaluating adherence to the recent guidelines established by the Faculty of General Dental Practice (FGDP). A cross-sectional study was conducted at the University College of Dentistry (UCD), employing a non-probability consecutive sampling technique to acquire a calculated sample of 300 IOPA radiographs from the operative, oral surgery, and oral radiology departments. Two senior faculty members evaluated the radiographs according to the recent two-tier grading system outlined in the FGDP guidelines. The study revealed that 197 (65.67%) of the assessed radiographs were diagnostically acceptable, while 103 (34.33%) were deemed diagnostically unacceptable. Contrast problems emerged as the most prevalent issue, accounting for 85 (28.3%) of the cases. Other common problems included incorrect film positioning in 66 (22%), incorrect vertical cone angulation in 37 (12.3%), incorrect horizontal cone angulation in 11 (3.7%), and incorrect processing in 15 (5%) of the IOPA radiographs. This study revealed that approximately two-thirds of the IOPA radiographs were deemed diagnostically acceptable. However, contrast issues emerged as the predominant concern affecting image quality. These findings highlight the critical importance of continuous quality improvement initiatives in radiographic practices to enhance diagnostic precision and ensure optimal patient care.

Transcriptomic Differences in Medullary Thyroid Carcinoma According to Grade

Medullary thyroid carcinoma (MTC) is a rare cancer derived from neuroendocrine C-cells of the thyroid. In contrast to other neuroendocrine tumors, a histological grading system was lacking until recently. A novel two-tier grading system based on the presence of high proliferation or necrosis is associated with prognosis. Transcriptomic analysis was conducted on 21 MTCs, including 9 high-grade tumors, with known mutational status, using the NanoString Tumor Signaling 360 Panel. This analysis, covering 760 genes, revealed upregulation of the genes EGLN3, EXO1, UBE2T, UBE2C, FOXM1, CENPA, DLL3, CCNA2, SOX2, KIF23, and CDCA5 in high-grade MTCs. Major pathways differentially expressed between high-grade and low-grade MTCs were DNA damage repair, p53 signaling, cell cycle, apoptosis, and Myc signaling. Validation through qRT-PCR in 30 MTCs demonstrated upregulation of ASCL1, DLL3, and SOX2 in high-grade MTCs, a gene signature akin to small-cell lung carcinoma, molecular subgroup A. Subsequently, DLL3 expression was validated by immunohistochemistry. MTCs with DLL3 overexpression (defined as ≥ 50% of positive tumor cells) were associated with significantly lower disease-free survival (p = 0.041) and overall survival (p = 0.01). Moreover, MTCs with desmoplasia had a significantly increased expression of DLL3. Our data supports the idea that DLL3 should be further explored as a predictor of aggressive disease and poor outcomes in MTC.

Cutaneous Canine Mast Cell Tumor: The Use of Proliferative Markers (Ki-67 and Ki-67 × AgNOR) in Cytological Samples for Diagnosis and Prognosis.

A cytological grading system for canine mast cell tumors (MCTs) has been developed, but its integration into clinical routine has been hindered due to its diagnostic limitations. The aim of this study was to assess the prognostic value of Ki-67 and argyrophilic nucleolar organizing region (AgNOR) markers in cytological MCT samples and to determine cut-off values for these markers in correlation with histopathological grading. Cytological samples were collected prior to surgical excision, and histopathological samples were obtained postsurgery from 45 dogs diagnosed with cutaneous mast cell tumors (MCTs). The cytological specimens were classified using a two-tier grading system, and their Ki-67 (average immunopositive nuclei per 100 cells) and AgNOR (average AgNOR counts per 100 nuclei) signaling was assessed. Through receiver operating characteristic (ROC) analysis, cut-off values for Ki-67 and Ki-67 × AgNOR were determined to better align with histopathological grading (classified as low or high grade according to Kiupel's scoring system). Without the inclusion of proliferative markers, there was a 73% agreement between cytological and histopathological grading. The prediction of histopathological grade was slightly more accurate when assessing Ki-67 and Ki-67 × AgNOR signaling in cytological specimens (75% and 80%, respectively) compared to the initial cytological grading. The cytological assessment of canine MCTs proves beneficial for the initial evaluation, and the incorporation of the evaluation of Ki-67 and AgNOR markers may assist in identifying diagnostically highly malignant MCTs.

Liquid-Based Cervical Cytology: Monitoring the Laboratory Quality Indicators.

Many developments in cervical cancer screening have happened in the past century, helping women in earlier detection of cervical cancer and its precursors. Cytology still holds the fort as being a specific test, though it suffers in sensitivity. As a part of the quality control program, the aim of the study is to determine the total number of abnormal liquid-based cervical cytology (LBC) at our center and correlate the abnormal LBC with histology and human papillomavirus (HPV) DNA test results. Retrospective analysis of 4286 LBC screening cases was carried out over a period of 5 years. For cytology-histology correlation, cervical biopsy and cytology test results were analyzed. The two-tier grading system for biopsy interpretation was used. HPV DNA test results wherever available were correlated. Of the 4286 LBC cases, 157 samples (3.7%) were unsatisfactory for evaluation, 3915 samples (91.3%) were negative for intra-epithelial lesion or malignancy, and 214 samples (5%) showed epithelial cell abnormality. ASC-US was reported in 60 cases (1.4%), ASC-H in 35 cases (0.8%), LSIL in 47 cases (1.1%), HSIL in 41 cases (1.0%), squamous cell carcinoma in a single case (0.02%), and atypical glandular cells in 30 cases (0.7%). The ASC/SIL ratio was 1.07:1. The CHC major discrepancy was calculated as 16.2%. The concordance of HSIL on cytology and biopsy as a measure of PPV is 94.4%. Of the epithelial cell abnormalities, 24 cases were positive for high-risk HPV (hrHPV). Molecular test results of 2737 samples showed HPV detected in 50 cases, of which 24 cases were positive for hrHPV. The study helped us to analyze the quality parameters of our cytopathology laboratory which are within the acceptable limits.

Interobserver agreement of pathologic classification and grading of tumoral intraductal pre-invasive neoplasms of the bile duct

Current WHO terminology and recent publications have classified tumoral (grossly visible) intraductal pre-invasive neoplasms of bile duct (TIDN) into three categories: intraductal papillary neoplasm of bile duct (IPNB), intraductal papillary oncocytic neoplasm (IOPN), and intraductal tubulopapillary neoplasm (ITPN). A total of 227 cases of TIDN and related lesions ≥3 mm in height were examined by 10 biliary pathologists referring to these 3 categories and two pathologic gradings: two-tiered system (low- and high-grade dysplasia) and modified types 1 and 2 subclassification. Among them, IPNB was the most frequent (183 cases), followed by IOPN (28 cases), while ITPN was rare (2 cases), and interobserver agreement in this classification was “substantial” (κ-value, 0.657). The interobserver agreement of two-tiered grading system of TIDN was “slight” (κ-value, 0.201), while that of modified types 1 and 2 subclassification was “moderate” (κ-value, 0.515), and 42 % were of type 1, and 58 % were of type 2. Type 1 TIDN showed occasional stromal invasion (6.7 %), whereas type 2 TIDN was frequently associated with stromal invasion (49.6 %) (p < 0.01). In conclusion, the classification of TIDN into three categories and modified types 1 and 2 subclassification are a practically applicable classification and grading system for TIDN.

Updates on grading mesothelioma.

Mesothelioma is a rare disease with an historically poor prognosis. Over the past decade, a grading system has been developed that is a powerful prognostic tool in epithelioid mesothelioma. Grading of epithelioid mesothelioma is now required or strongly recommended by expert consensus, the College of American Pathologists, the World Health Organization, and the International Mesothelioma Interest Group. The original nuclear grading system for epithelioid mesothelioma, developed in the United States, split epithelioid mesotheliomas into three prognostic groups with marked differences in survival. Now, this three-tiered nuclear grading system has been combined with the presence or absence of necrosis to form the currently recommended two-tiered grading system of low- and high-grade epithelioid mesothelioma. This review will focus on the development of this grading system in mesothelioma, the grading system's shortcomings, and the application of the grading system to cytology specimens and other extra-pleural sites. Lastly, this review will briefly discuss alternative grading systems and future considerations.

Exploration of Digital Image Analysis for Ki67 Quantification in the Grading of Medullary Thyroid Carcinoma: A Pilot Study with 85 Cases.

Although uncommon, medullary thyroid carcinoma (MTC) accounts for a significant proportion of thyroid cancer deaths. Recent studies have validated the two-tier International Medullary Thyroid Carcinoma Grading System (IMTCGS) to predict clinical outcomes. A 5% Ki67 proliferative index (Ki67PI) cut-off separates low-grade from high-grade MTC. In this study, we compared digital image analysis (DIA) to manual counting (MC) for determining the Ki67PI in a MTC cohort, and explored the challenges encountered. Available slides from 85 MTCs were reviewed by two pathologists. The Ki67PI was documented by immunohistochemistry for each case, scanned with the Aperio® slide scanner at 40× magnification, and quantified using the QuPath® DIA platform. The same hotspots were screenshot, printed in color, and blindly counted. For each case, over 500 MTC cells were counted. Each MTC was graded using IMTCGS criteria. In our MTC cohort (n = 85), 84.7 and 15.3% were low- and high-grade with the IMTCGS. In the entire cohort, QuPath® DIA performed well (R2 = 0.9891) but appeared to undercall compared to MC. QuPath® performed better in high-grade cases (R2 = 0.99) compared to low-grade cases (R2 = 0.7071). Overall, Ki67PI determined with either MC or DIA did not affect IMTCGS grade. Encountered DIA challenges include optimizing cell detection, overlapping nuclei, and tissue artifacts. Encountered MC challenges include background staining, morphologic overlap with normal elements, and counting time. Our study highlights the utility of DIA in quantifying Ki67PI for MTC and can serve as an adjunct for grading in conjunction with the other criteria of mitotic activity and necrosis.

Grading system for medullary thyroid carcinoma; an institutional experience

ObjectiveMedullary thyroid carcinoma (MTC) is a rare type of thyroid malignancy. Recently, a two-tier grading system (GS) for MTC has been suggested. We conducted this study to evaluate the generalizability, as well as application of recently proposed GS to our cohort of Medullary thyroid carcinoma (MTC) cases. MethodsWe assigned grades to MTC cases and divided them into two groups by using morphologic criteria only as suggested by recent studies: low-grade (LG, <5 mitosis per 2 mm2, and no necrosis) and high-grade (HG, ≥5 mitosis per 2mm2 or necrosis). ResultsA total of 59 MTC cases were evaluated and of those 52 (88 %) were LG and 7 (12 %) were HG. Vascular invasion (VI) (p = 0.017), distant metastasis (DM) (p < 0.0001), nuclear pleomorphism (NP) (p = 0.017) and prominent nucleoli (p = 0.03) were prominently noted in the HG group. After controlling for demographics using multivariate cox regression, tumor grade and necrosis remained significantly associated with the overall survival (HR = 22.7, p < 0.01 and HR = 11.1, p = 0.008, respectively). Upon comparing the cases with and without nodal disease, we found that nodal disease is more strongly associated with NP (p = 0.029), tumor fibrosis (p = 0.0001), VI (p = 0.001) and DM (p = 0.005). ConclusionsWe applied the two-tier GS for MTC to our cohort of cases and found statistically significant differences in the overall survival among the two groups. Adding the grading to the pathology report communicates additional information regarding risk stratification in MTC.

Conventional Adenomatous Polyps: Study of Histomorphological Features Using a Novel Scoring System

Introduction: Conventional adenomatous polyps are dysplastic proliferations that arise from the surface of the mucosa and grow in a top-down fashion. Dysplasia is graded as low-grade and high-grade using a two-tiered grading system. Aim: To grade the dysplasia in conventional adenomatous polyps by applying a novel scoring system. Materials and Methods: This cross-sectional study was conducted in the Department of Pathology, ESIC Medical College and Post Graduate Institute of Medical Science and Research (PGIMSR), Rajajinagar, Bengaluru, Karnataka, India. A total of 46 cases reported as conventional adenomatous polyps were reviewed from January 2020 to June 2022. A cytological grading system was applied, evaluating eight parameters consisting of architectural and cytological features. Each parameter was scored, resulting in a total score ranging from 8 to 24. The final diagnosis was determined based on the histological pattern and the total cytological score. The results were tabulated in an excel sheet and analysed using mean, standard deviation, percentage, and frequency tables. The relationship between the independent variables was evaluated using the Chi-square test. A p-value of less than 0.05 was considered significant. Results: Out of the 46 cases, most presented in the 4th decade of life 12 (32.61%) cases. The mean age of presentation was 54.56±11.91 years (mean±SD) with a male to female ratio of 1.4:1. The most common site was the sigmoid colon 17 (36.96%) cases. There were 26 cases of low-grade dysplasia with a mean score of 9.1 and 20 cases of high-grade dysplasia with a mean score of 15.2. The most common type was tubular adenoma with low-grade dysplasia 24 (52.17%) cases and a mean cytological score of 9. The high-grade dysplasia in tubular adenomas 7 (15.22%) cases, tubulovillous adenomas 11 (23.19%) cases, and villous adenomas 2 (4.35%) cases had mean scores of 13.3, 15.2, and 18, respectively. Conclusion: Dysplasia in adenomatous polyps is an independent risk factor for malignancy. The cytological scoring system helps in accurately diagnosing the grade of dysplasia and simplifies the process. The present study emphasizes the need for objective criteria, paving the way for implementing relevant surveillance and clinical protocols.

Secretory carcinoma of the salivary gland: a multi-institutional clinicopathologic study of 90 cases with emphasis on grading and prognostic factors.

A detailed clinicopathologic review was conducted on 90 SCs from the major and minor salivary glands. The median age at presentation was 50 years (range: 7-93). Sixty-nine (77%) tumours originated from major salivary glands, whereas the remaining 21 involved minor salivary glands.Six cases (7%) had cervical nodal metastasis. Only lymphovascular invasion (LVI) was associated with a risk of nodal metastasis (P < 0.05). The 5-year disease-specific survival and disease-free survival (DFS) were 98% and 87%, respectively. On univariate survival analysis, adverse prognostic factors associated with decreased DFS included minor salivary gland origin, atypical mitosis, high mitotic index, high-grade transformation (HGT), necrosis, nuclear pleomorphism, infiltrative tumour border, fibrosis at the invasive front, LVI, positive margin, and advanced pT stage (P < 0.05). When adjusted for pT stage and margin status, mitotic index, LVI, nuclear pleomorphism, and HGT remained as independent prognostic factors. We therefore propose a two-tiered grading system for SC. The low-grade SC is defined as those with <5 mitoses /10 high-power fields and no tumour necrosis, and high-grade SC as those with ≥5 mitoses /10 high-power fields and/or necrosis. This proposed grading system can be useful to risk stratify patients with SC for appropriate clinical management.

Defining prognostic parameters of well-differentiated gastric neuroendocrine tumors based on metastatic potential: a two-center experience.

Gastric neuroendocrine tumors [gNETs] are heterogeneous tumors and we are still unable to predict the behavior of these tumors. We aim to define the prognostic parameters of well-differentiated gNETs based on metastatic potential and to evaluate the current classification systems. We retrospectively retrieved 44 well differentiated gNET cases who underwent radical surgery between 2000-2015 at two tertiary-care centers. Among the 44 well-differentiated gNET patients, 17 (38%) patients had metastatic disease to lymph nodes and/or distant sites, while 27 (62%) were confined to the stomach. Higher risk of metastasis was observed with increasing tumor size, grade, depth of invasion and with type-3 and solitary tumors. 30 (68%) patients had type-1 gNET and 14 (32%) had type-3 gNET. Majority of the type-1 cases (76,6%) were Grade 1 [G1] and type-3 cases (78,5%) were Grade 3 [G3]. Type-1 subgroup had no G3 tumor, and type-3 had no G1. Grade 2 [G2] tumors were more controversial, with metastatic and non-metastatic cases. G2 cases with a >10% Ki67 expression or type-3, had a worse prognosis. Although most of the type-1 gNETs had an indolent course, 6 of 30 (20%) patients had metastatic disease. Metastasizing type-1 gNETs were >10 mm in diameter or extended to/beyond the submucosa. Regarding our results, tumor type, grade, size, focality and depth of invasion are the prognostic parameters for gNETs, based on metastatic potential. Besides these parameters, a two-tiered grading system with a 10% Ki-67 proliferation index cut-off value could be considered for right treatment choice.

Tumor cell budding as a prognostic and potentially therapeutically targetable biomarker in head and neck cancer.

6053 Background: Several studies have demonstrated a negative prognostic impact of tumor cell budding (TCB) in HPV- head and neck squamous cell carcinoma (HNSCC), but analyses of its prognostic impact in HPV+ HNSCC and of the underlying molecular alterations are lacking. Methods: The study cohort included 331 HPV- and HPV+ HNSCC from TCGA with digitalized H&amp;E-stained slides available. Corresponding mutation, methylation, and gene expression data were obtained from the pan-cancer atlas web page. Tumor buds were defined as clusters of up to four tumor cells separated from the tumor mass. The numbers of tumor buds were evaluated in ten digital high-power fields by a senior pathologist. A two-tier cellular dissociation grading system was introduced by separating tumors with six or more tumor buds (TCB-high) from tumors with fewer tumor buds (TCB-low). The impact of TCB on overall survival (OS) was analyzed using Cox proportional hazard models. Results with p &lt; 0.05 were considered significant. Association of TCB with mutations was analyzed using the Wilcoxon test. Association of TCB with gene expression and methylation was analyzed using Spearman correlations. Lists of altered genes were compiled correcting the p-values with the Benjamin-Hochberg method and controlling the FDR at 5%. Results: In a univariate analysis, OS was significantly shorter in TCB-high tumors compared to TCB-low tumors in HPV- HNSCC (HR = 1.4, 95% CI 1.0-2.3) and HPV+ HNSCC (HR = 5.0, 95% CI 1.9-13.7). Shorter OS in TCB-high HNSCC was confirmed in a multivariate analysis including age, sex, HPV status, tumor site, tumors stage, and tumor margin status (HR = 1.7, 95% CI 1.2-2.4). Significant association of TCB with mutations was detected for two genes: NSD1 mutations correlated negatively with TCB in HPV- HNSCC, while TP53 mutations correlated positively with TCB in HPV+ HNSCC. Methylation of 126 (1%) genes was associated with TCB in HPV- HNSCC, while methylation of 511 (3%) genes was associated with TCB in HPV+ HNSCC. Expression of 422 (2%) genes was associated with TCB in HPV- HNSCC, while expression of 786 (4%) genes was associated with TCB in HPV+ HNSCC. Among these genes, those annotated to the epithelial mesenchymal transition were highly significantly enriched in both HPV- HNSCC (5.5-fold enrichment) and HPV+ HNSCC (2.7-fold enrichment). Conclusions: Evaluation of TCB based on digital HE slides was conducted in a large clinically and molecularly characterized HNSCC cohort. The prognostic impact of TCB could be validated in HPV- HNSCC, while a prognostic impact of TCB could be demonstrated for the first time in HPV+ HNSCC. TCB correlated with mutations of only two genes and theses correlations were imperfect. A plethora of genes correlated with TCB on the level of methylation and gene expression level. These genes should be further analyzed and prioritized for the evaluation of therapeutic targeting.

MRI tumour regression grade in locally recurrent rectal cancer.

BackgroundThis study aimed to investigate the agreement between magnetic resonance tumour regression grade (mrTRG) and pathological regression grade (pTRG) in patients with locally recurrent rectal cancer (LRRC). Also, the reproducibility of mrTRG was investigated.MethodsAll patients with LRRC who underwent a resection between 2010 and 2018 after treatment with induction chemotherapy and neoadjuvant chemo(re)irradiation in whom a restaging MRI was available were retrospectively selected. All MRI scans were reassessed by two independent radiologists using the mrTRG, and the pTRG was reassessed by an independent pathologist. The interobserver agreement between the radiologists as well as between the radiologists and the pathologist was assessed with the weighted kappa test. A subanalysis was performed to evaluate the influence of the interval between imaging and surgery.ResultsOut of 313 patients with LRRC treated during the study interval, 124 patients were selected. Interobserver agreement between the radiologists was fair (k = 0.28) using a two-tier grading system (mrTRG 1–2 versus mrTRG 3–5). For the lead radiologist, agreement with pTRG was moderate (k = 0.52; 95 per cent c.i. 0.36 to 0.68) when comparing good (mrTRG 1–2 and Mandard 1–2) and intermediate/poor responders (mrTRG 3–5 and Mandard 3–5), and the agreement was fair between the other abdominal radiologist and pTRG (k = 0.39; 95 per cent c.i. 0.22 to 0.56). A shorter interval (less than 7 weeks) between MRI and surgery resulted in an improved agreement (k = 0.69), compared with an interval more than 7 weeks (k = 0.340). For the lead radiologist, the positive predictive value for predicting good responders was 95 per cent (95 per cent c.i. 71 per cent to 99 per cent), whereas this was 56 per cent (95 per cent c.i. 44 per cent to 66 per cent) for the other radiologist.ConclusionThis study showed that, in LRRC, the reproducibility of mrTRG among radiologists is limited and the agreement of mrTRG with pTRG is low. However, a shorter interval between MRI and surgery seems to improve this agreement and, if assessed by a dedicated radiologist, mrTRG could predict good responders.

International Medullary Thyroid Carcinoma Grading System: A Validated Grading System for Medullary Thyroid Carcinoma.

Medullary thyroid carcinoma (MTC) is an aggressive neuroendocrine tumor (NET) arising from the calcitonin-producing C cells. Unlike other NETs, there is no widely accepted pathologic grading scheme. In 2020, two groups separately developed slightly different schemes (the Memorial Sloan Kettering Cancer Center and Sydney grade) on the basis of proliferative activity (mitotic index and/or Ki67 proliferative index) and tumor necrosis. Building on this work, we sought to unify and validate an internationally accepted grading scheme for MTC. Tumor tissue from 327 patients with MTC from five centers across the United States, Europe, and Australia were reviewed for mitotic activity, Ki67 proliferative index, and necrosis using uniform criteria and blinded to other clinicopathologic features. After reviewing different cutoffs, a two-tiered consensus grading system was developed. High-grade MTCs were defined as tumors with at least one of the following features: mitotic index ≥ 5 per 2 mm2, Ki67 proliferative index ≥ 5%, or tumor necrosis. Eighty-one (24.8%) MTCs were high-grade using this scheme. In multivariate analysis, these patients demonstrated decreased overall (hazard ratio [HR] = 11.490; 95% CI, 3.118 to 32.333; P < .001), disease-specific (HR = 8.491; 95% CI, 1.461 to 49.327; P = .017), distant metastasis-free (HR = 2.489; 95% CI, 1.178 to 5.261; P = .017), and locoregional recurrence-free (HR = 2.114; 95% CI, 1.065 to 4.193; P = .032) survivals. This prognostic power was maintained in subgroup analyses of cohorts from each of the five centers. This simple two-tiered international grading system is a powerful predictor of adverse outcomes in MTC. As it is based solely on morphologic assessment in conjunction with Ki67 immunohistochemistry, it brings the grading of MTCs in line with other NETs and can be readily applied in routine practice. We therefore recommend grading of MTCs on the basis of mitotic count, Ki67 proliferative index, and tumor necrosis.

Clinicopathological Features and Survival Outcomes of Primary Pulmonary Invasive Mucinous Adenocarcinoma.

Simple SummaryPulmonary invasive mucinous adenocarcinoma (IMA) is a recognized variant of lung adenocarcinoma (ADC) that has unique histological patterns. Comprehensively clinical studies and pathological analyses on IMAs have been limited because IMA is rarely diagnosed compared with other subtypes. We compared the clinical characteristics, pathological features, and survival outcomes of 77 IMA patients with 520 non-IMA-type ADC patients. Currently, IMAs lack a simple pathological prognostic grading system to predict survival. We therefore proposed a simple two-tier grading system, which was modified from the low- and high-grade PanIN grading system, to evaluate its prognostic value. We found that IMAs have more distinct clinicopathological characteristics compared to non-IMA-type ADCs. For patients with stage I–IIIA IMA, a new two-tier grading system might be useful in predicting recurrence-free survival. We demonstrated that stage I and II IMAs have better overall survival compared with non-IMA-type ADCs.Pulmonary invasive mucinous adenocarcinoma (IMA) has unique histological patterns. This study aimed to comprehensively evaluate the clinicopathological features, prognosis, and survival outcomes of IMAs. We retrospectively identified 77 patients with pulmonary IMA and reviewed their clinical and pathological features. Another 520 patients with non-IMA-type ADC were retrieved for comparison with patients with IMA. A new two-tier grading system (high-grade and low-grade IMAs) modified from the pancreatic intraepithelial neoplasia classification system was used for survival analyses. Compared to patients with non-IMA-type ADC, patients with IMA tended to have never smoked (p = 0.01) and had early-stage IMA at initial diagnosis (p < 0.001). For stage I–II diseases, the five-year overall survival (OS) rates were 76% in IMAs and 50% in non-IMA-type ADCs, and a longer OS was observed in patients with IMA (p = 0.002). KRAS mutations were the most commonly detected driver mutations, which occurred in 12 of the 28 (43%) patients. High-grade IMAs were associated with a shorter recurrence-free survival (RFS) for stage I–IIIA diseases (p = 0.010) than low-grade IMAs but not for OS. In conclusion, patients with stage I and II IMA had better OS than those with non-IMA-type ADC. A new two-tier grading system might be useful for predicting RFS in stage I–IIIA IMAs.

Two-tier Grading System for NPDR Severities of Diabetic Retinopathy in Retinal Fundus Images

Background: Diabetic Retinopathy is the leading cause of vision impairment and its early stage diagnosis relies on regular monitoring and timely treatment for anomalies exhibiting subtle distinction among different severity grades. The existing Diabetic Retinopathy (DR) detection approaches are subjective, laborious and time consuming which can only be carried out by skilled professionals. All the patents related to DR detection and diagnoses applicable for our research problem were revised by the authors. The major limitation in classification of severities lies in poor discrimination between actual lesions, background noise and other anatomical structures. Methods: A robust and computationally efficient Two-Tier DR (2TDR) grading system is proposed in this paper to categorize various DR severities (mild, moderate and severe) present in retinal fundus images. In the proposed 2TDR grading system, input fundus image is subjected to background segmentation and the foreground fundus image is used for anomaly identification followed by GLCM feature extraction forming an image feature set. The novelty of our model lies in the exhaustive statistical analysis of extracted feature set to obtain optimal reduced image feature set employed further for classification. Results: Classification outcomes are obtained for both extracted as well as reduced feature set to validate the significance of statistical analysis in severity classification and grading. For single tier classification stage, the proposed system achieves an overall accuracy of 100% by k- Nearest Neighbour (kNN) and Artificial Neural Network (ANN) classifier. In second tier classification stage, an overall accuracy of 95.3% with kNN and 98.0% with ANN is achieved for all stages utilizing optimal reduced feature set. Conclusion:: 2TDR system demonstrates overall improvement in classification performance by 2% and 6% for kNN and ANN respectively after feature set reduction, and also outperforms the accuracy obtained by other state of the art methods when applied to the MESSIDOR dataset. This application oriented work aids in accurate DR classification for effective diagnosis and timely treatment of severe retinal ailment.

ES17.04 Updates in Mesothelioma

The histologic subtype of malignant mesothelioma of the pleura has an impact on prognosis and treatment decisions and therefore has to be documented in diagnostic pathology reports. Epithelioid morphology is associated with a better prognosis when compared to sarcomatoid and biphasic subtypes. Surgical treatment may also have a prognostic impact in epithelioid subtype, while the same benefit is not seen in biphasic and sarcomatoid mesotheliomas. The 2020/21 WHO classification divides mesothelial proliferations into benign and preinvasive (adenomatoid tumor, well-differentiated papillary mesothelial tumor, mesothelioma in situ) and mesothelioma (localized pleural mesothelioma, diffuse pleural mesothelioma). The main change is the introduction of mesothelioma in situ (MIS) in the classification. Until recently the consensus was that MIS cannot be separated from reactive surface mesothelial proliferations on morphology alone. However, the concept of MIS was recently reintroduced for surface, usually flat or simple papillary, mesothelial proliferations with loss of BAP1 nuclear staining by immunohistochemistry or CDKN2A homozygous deletion, in the absence of radiologic or clinical gross evidence of the disease.1-3 Clinically, MIS is suspected in patients with unexplained recurrent effusions in the setting of heavy asbestos exposure, after irradiation and in patients with familial predisposition. The diagnosis requires sufficient tissue usually large biopsy samples. Small biopsy and cytology samples are not appropriate. Patients with MIS have a high incidence of eventual development of invasive mesothelioma. The updated classification of epithelioid mesotheliomas includes architectural patterns (tubular, papillary, tubulopapillary, trabecular, solid, adenomatoid and microcystic), stromal (myxoid) and cytologic (pleomorphic ,rhabdoid, deciduoid, small cell, clear cell, signet ring) features. Their identification is important for correct diagnosis, and some have prognostic values. Two cytologic features, transitional and pleomorphic, were previously classified as epithelioid patterns. They have shown a similar survival to biphasic and sarcomatoid mesothelioma and should be reclassified.5-8 Transitional features have appearance between epithelioid and sarcomatoid morphology, and have genomic characteristics similar to sarcomatoid subtype, and therefore were reclassified as cytologic feature of sarcomatoid mesothelioma. 6. Epithelioid mesotheliomas with transitional features should be reclassified as biphasic mesothelioma. Transitional features within biphasic mesothelioma carry negative prognostic significance, with a median survival of 6 months for cases with transitional features compared to 12 months for those without transitional features .6 Pleomorphic features, as described in epithelioid mesothelioma, can also be seen in sarcomatoid mesotheliomas. In contrast to transitional features, emerging genomic data suggest that a mesothelioma with pleomorphic features genomically can cluster with either sarcomatoid or epithelioid subtypes. Therefore, mesotheliomas with pleomorphic features should be classified based on the most predominant morphology as either sarcomatoid or epithelioid. A two-tier grading system for epithelioid mesothelioma allows the identification of more aggressive mesotheliomas and can be applied to biopsy and resection specimens 9, 10 It is primarily based on the combination of nuclear features, mitotic rate and the presence or absence of necrosis (Figure 1). Molecular testing in mesothelioma compared to other cancers is very limited. Recently, there have been several sequencing efforts to provide insights into the genomic characteristics and improved prognostic classification of mesothelioma. 10

Reappraisal of pathological features of intraductal papillary neoplasm of bile duct with respect to the type 1 and 2 subclassifications

The pathological spectrum of intraductal papillary neoplasm of bile duct (IPNB) remains to be clarified. A total of 186 IPNBs were pathologically examined using the type 1 and 2 subclassifications proposed by Japanese and Korean biliary pathologists incorporating a two-tiered grading system (low-grade and high-grade dysplasia), with reference to four subtypes (intestinal [i], gastric [g], pancreatobiliary [pb], and concocytic [o] subtype). IPNBs were classifiable into type 1 composed of low-grade dysplasia and 'high-grade dysplasia with regular structures' (69 IPNBs), and type 2 of 'high grade dysplasia with irregular structures and complicated lesions' (117 IPNBs). Type 1 was more common in the intrahepatic bile duct (78%), whereas type 2 was frequently located in the extrahepatic bile duct (58%). Mucin hypersecretion was more common in type 1 (61%) than in type 2 (37%). IPNBs were classifiable into the four subtypes: 86 iPNBs, 40 gIPNBs, 31 pbIPNBs, and 29 oIPNBs. The four subtypes were histologically evaluable with reference to the type 1 and 2 subclassifications. iIPNB and pbIPNBs were frequently classified as type 2, whereas types 1 and 2 were observed at similar rates in gIPNB and oIPNB. Stromal invasion was almost absent in type 1, irrespective of subtype, but was found in 66 of 117 type 2 IPNBs (P<.01), and postoperative outcome was favorable in IPNBs without invasion compared with IPNBs with invasion (P<.05). The type 1 and 2 subclassifications with reference to the four subtypes may provide useful information for understanding IPNB.

A novel histopathological grading system for ganglioglioma.

Gangliogliomas are central nervous system tumors located in the temporal lobe of young patients, frequently associated with epilepsy. In this paper, we propose a grading system based solely on histopathological criteria. We reevaluated all cases of ganglioglioma, atypical ganglioglioma, and anaplastic ganglioglioma diagnosed between 2011 and 2020 in the Pathology Department of the Emergency Clinical Hospital Bagdasar-Arseni, based on the type of glial mitoses, the number of neuronal and glial mitoses, presence of necrosis, microvascular proliferation, eosinophilic granular bodies, hypercellularity, presence and disposition of inflammatory infiltrate and atypical pleomorphism. Based on the proposed grading system, a score of 0–4 corresponded to a benign ganglioglioma, 5–9 to an atypical ganglioglioma, and 10–18 to an anaplastic ganglioglioma. The survival rates were 90% for benign ganglioglioma, 71.43% for atypical ganglioglioma, and 62.54% for anaplastic ganglioglioma. One case of benign ganglioglioma underwent a malignant transformation into anaplastic ganglioglioma, and recurrences were noticed in 28.57% of atypical ganglioglioma cases and 30.7% of all anaplastic gangliogliomas. The presence of rare glial mitoses and hypercellularity was correlated with mortality in cases of atypical ganglioglioma. We believe this histopathological scoring system could be used as a three-tier system to identify atypical ganglioglioma cases that are bound to have an aggressive course of evolution and require close follow-up. The other option would be to convert it to a two-tier grading system that can separate low-grade gangliogliomas from high-grade ones. The latter category can encompass both atypical and anaplastic ganglioglioma due to the high mortality of both entities.

Prognostic Indicators and Clinical Outcome in Dogs with Subcutaneous Mast Cell Tumors Treated with Surgery Alone: 43 Cases.

The purpose of this study was to determine if clinical findings, histologic grade, or other histologic features were associated with clinical outcome in dogs with subcutaneous mast cell tumors (MCTs). Medical records of 43 client-owned dogs were retrospectively reviewed, and follow-up information was gathered via phone or follow-up examination. Progression-free survival (PFS), disease-free interval (DFI), and overall survival were calculated. Forty-two and twenty-two dogs, respectively, had grade 2 (Patnaik grading system) or low-grade tumors (two-tier grading system). Median PFS was 1474 days. Median DFI was not reached at >1968 days. Overall median survival time was not reached at >1968 days. In univariate analysis, argyrophilic nucleolar organizer regions (AgNORs), proliferating cell nuclear antigen, and mitotic index were negatively prognostic for PFS whereas Ki-67, proliferating cell nuclear antigen, and microvessel density were negatively prognostic for DFI. In multivariate analysis, AgNORs remained negatively prognostic for PFS. Results suggest that proliferation indices, especially AgNORs, may be useful in predicting the rare poor outcomes in dogs with subcutaneous MCTs. The vast majority of subcutaneous MCTs appear to be low or intermediate grade with excellent outcomes from good local tumor control.