Comparative analysis of the value of amide proton transfer-weighted imaging and diffusion kurtosis imaging in evaluating the histological grade of cervical squamous carcinoma.

BACKGROUND: Uterine cervical cancer (UCC) was the fourth leading cause of cancer death among women worldwide. The conventional MRI hardly revealing the microstructure information. This study aimed to compare the value of amide proton transfer-weighted imaging (APTWI) and diffusion kurtosis imaging (DKI) in evaluating the histological grade of cervical squamous carcinoma (CSC) in addition to routine diffusion-weighted imaging (DWI). METHODS: Forty-six patients with CSC underwent pelvic DKI and APTWI. The magnetization transfer ratio asymmetry (MTRasym), apparent diffusion coefficient (ADC), mean diffusivity (MD) and mean kurtosis (MK) were calculated and compared based on the histological grade. Correlation coefficients between each parameter and histological grade were calculated. RESULTS: The MTRasym and MK values of grade 1 (G1) were significantly lower than those of grade 2 (G2), and those parameters of G2 were significantly lower than those of grade 3 (G3). The MD and ADC values of G1 were significantly higher than those of G2, and those of G2 were significantly higher than those of G3. MTRasym and MK were both positively correlated with histological grade (r = 0.789 and 0.743, P <  0.001), while MD and ADC were both negatively correlated with histological grade (r = - 0.732 and - 0.644, P <  0.001). For the diagnosis of G1 and G2 CSCs, AUC (APTWI+DKI + DWI) > AUC (DKI + DWI) > AUC (APTWI+DKI) > AUC (APTWI+DWI) > AUC (MTRasym) > AUC (MK) > AUC (MD) > AUC (ADC), where the differences between AUC (APTWI+DKI + DWI), AUC (DKI + DWI) and AUC (ADC) were significant. For the diagnosis of G2 and G3 CSCs, AUC (APTWI+DKI + DWI) > AUC (APTWI+DWI) > AUC (APTWI+DKI) > AUC (DKI + DWI) > AUC (MTRasym) > AUC (MK) > AUC (MD > AUC (ADC), where the differences between AUC (APTWI+DKI + DWI), AUC (APTWI+DWI) and AUC (ADC) were significant. CONCLUSION: Compared with DWI and DKI, APTWI is more effective in identifying the histological grades of CSC. APTWI is recommended as a supplementary scan to routine DWI in CSCs.

Impact of prostate biopsy secondary pathology review on radiotherapy management.

BACKGROUND: The Gleason scoring system is the most widely used method to assess prostate adenocarcinoma pathology however interobserver variability is significant. Gleason score, PSA level, and clinical stage comprise the NCCN risk stratification that guides treatment decision making. Given the importance of an accurate Gleason score and wide interobserver variability, referral centers routinely review outside pathology at the time of consultation. We sought to address the impact a secondary pathology review had on radiation therapy treatment recommendations in men with prostate cancer at our institution. METHODS: We retrospectively collected patient data on 342 patients seen at our institution from January 2012 to December 2018. Clinicopathologic data were used to subdivide patients into risk groups and available treatment options per NCCN criteria. Cases reviewed by our genitourinary pathologist (GUP) were compared with reports from outside pathologists. Inter-rater reliability between pathologists was assessed with weighted Cohen's kappa statistic and agreement of treatment options was determined by McNemar's exact tests. RESULTS: GUP scored more cores positive in 16.47% of cases on secondary review. Primary Gleason score was changed in 12.28% of patients and secondary score in 26.02% of cases. Total Gleason score was different in 29.24% of cases, 19.01% were downgraded and 10.23% upgraded. The weighted kappa statistic was 0.759 (95% confidence interval [CI]: 0.711, 0.807). 18.77% of patients were assigned to a different NCCN risk group following secondary review. The weighted kappa statistic comparing NCCN risk stratification was 0.802 (95% CI: 0.754, 0.850). Secondary review influenced radiation therapy recommendations pertaining to brachytherapy boost and androgen deprivation therapy in men with high risk disease (χ2 = 5.33, p = 0.0386; χ2 = 8.05, p = 0.0072, respectively). Kappa statistic was found to be highest when GUP assessed high-risk disease versus all other categories (κ = 0.823, 95% CI: 0.750, 0.895). CONCLUSIONS: We found nearly one in five men (18.7%) was assigned a different NCCN risk group and thus offered potentially different treatment options after a secondary pathology review at our institution. Given the inherent nature of prostate cancer and lung disease-specific survival associated with modern therapies, our study demonstrates the importance of a secondary pathology review and its potential impact on radiation therapy recommendations.

Clinical experience and treatment approaches in sinonasal osteomas from a Tertiary Care Hospital in Turkey.

OBJECTIVE: Osteomas are slow-growing benign osseous tumors that particularly located in the paranasal sinuses (PS). Here, we aimed to define the clinical symptoms and features, diagnostic conditions caused by osteomas located in four different PSs, to evaluate the surgical indications and methods, to compare the factors that can affect the surgical decision, radiological findings, and prognosis. METHODS: The data of patients with paranasal sinus lesions and diagnosed as osteoma according to the radiological imaging, who applied to our clinic between 2010 and 2020, were retrospectively collected and re-evaluated in the light of clinical, radiological, and pathological data. Patients who underwent surgical treatments and were definitively diagnosed as osteoma by pathology were enrolled in this study. RESULTS: We presented the data of 117 patients retrospectively. Most of these cases (n = 77, 65.8%) had an osteoma located in the frontal sinus, while 32 cases (27.4%) had osteoma in the ethmoid, two cases (1.7%) had in sphenoid and six cases (5.1%) had in maxillary sinus. We found that the presence of symptoms, diameter of osteoma, surgical indications including state of sinus drainage, and chronic/recurrent sinusitis influence the choices of physicians in management of frontal sinus osteomas. Moreover, we found a significant correlation between the grading systems defined to classify the frontal sinus osteoma to be operated (r = 0.878, 95% CI: 0.724-0.949, P<0.0001). CONCLUSION: There are several grading systems useful for the choice of surgical approaches, however, the clinical symptoms and surgical indications should not be neglected in the follow-up of patients with frontal sinus osteoma. If there are concerns about the grade of osteoma and the endoscopic approach is considered not to be sufficient for resection, the surgical procedure may be initiated endoscopically, and, if necessary, it can be combined with an external approach.

Concordance of biopsy and pathologic ISUP grading in salvage radical prostatectomy patients for recurrent prostate cancer.

PURPOSE: To investigate the concordance of biopsy and pathologic International Society of Urological Pathology (ISUP) grading in salvage radical prostatectomy (SRP) patients for recurrent prostate cancer. METHODS: Within a high-volume center database, we identified patients who underwent SRP for recurrent prostate cancer (PCa) between 2004 and 2020. Upgrading, downgrading, concordance, and any discordance between posttreatment biopsy ISUP and ISUP at SRP were tested. Logistic regression models were used to predict ISUP upgrading and ISUP discordance. Models were adjusted for prostatic specific antigen before SRP, age at surgery, initial prostatic specific antigen (PSA), type of primary treatment, time from primary PCa diagnosis to SRP, number of positive cores at biopsy, and original Gleason score. RESULTS: Overall, 184 patients with available biopsy and pathologic ISUP grading were identified. Of those, 17.4% (n = 32), 40.8% (n = 75), 19.6% (n = 36), and 22.2% (n = 41) harbored biopsy ISUP 1, ISUP 2, ISUP 3, and ISUP 4-5 grading, respectively. Pathologic ISUP 1, ISUP 2, ISUP 3, and ISUP 4-5 grading was recorded in 6.0% (n = 11), 40.8% (n = 75), 32.1% (n = 59), and 21.2% (n = 39), respectively. Median PSA before SRP was 5.5 ng/ml (interquartile range [IQR]: 3.1-8.1 ng/ml), median age at SRP was 65.1 years (IQR:60.7-69.4 years) and median time from original PCa diagnosis to SRP was 47 months (IQR: 27.3-85.2 months). Concordance of biopsy and pathologic ISUP was identified in 45.1% (n = 83). Conversely, any ISUP discordance, upgrading and downgrading of at least one ISUP group was identified in 54.9% (n = 101), 35.3% (n = 65), and 19.6% (n = 36). In logistic models, none of the preoperative characteristics was associated with upgrading or ISUP discordance (all p > 0.1). CONCLUSION: Discordance between biopsy and pathologic ISUP grading is common at SRP. However, in 45% of SRP cases biopsy ISUP is capable to predict pathologic ISUP. Further studies are necessary to identify characteristics for ISUP upgrading at SRP.

Percentage grade 4 tumour predicts outcome for prostate adenocarcinoma in needle biopsies from patients with advanced disease: 10-year data from the TROG 03.04 RADAR trial.

Previous reports have shown that quantification of high tumour grade is of prognostic significance for patients with prostate cancer. In particular, percent Gleason pattern 4 (GP4) has been shown to predict outcome in several studies, although conflicting results have also been reported. A major issue with these studies is that they rely on surrogate markers of outcome rather than patient survival. We have investigated the prognostic predictive value of quantifying GP4 in a series of prostatic biopsies containing Gleason score 3+4=7 and 4+3=7 tumours. It was found that the length of GP4 tumour determined from the measurement of all biopsy cores from a single patient, percent GP4 present and absolute GP4 were all significantly associated with distant progression of tumour, all-cause mortality and cancer-specific mortality over a 10-year follow-up period. Assessment of the relative prognostic significance showed that these parameters outperformed division of cases according to Gleason score (3+4=7 versus 4+3=7). International Society of Urological Pathology (ISUP) Grade Groups currently divide these tumours, according to Gleason grading guidelines, into grade 2 (3+4=7) and grade 3 (4+3=7). Our results indicate that this simple classification results in the loss of important prognostic information. In view of this we would recommend that ISUP Grade Groups 2 and 3 be amalgamated as grade 2 tumour with the percentage of GP4 carcinoma being appended to the final grade, e.g., 3+4=7 carcinoma with 40% pattern 4 tumour would be classified as ISUP Grade Group 2 (40%).

Development and Validation of an Artificial Intelligence-Powered Platform for Prostate Cancer Grading and Quantification.

Importance: The Gleason grading system has been the most reliable tool for the prognosis of prostate cancer since its development. However, its clinical application remains limited by interobserver variability in grading and quantification, which has negative consequences for risk assessment and clinical management of prostate cancer. Objective: To examine the impact of an artificial intelligence (AI)-assisted approach to prostate cancer grading and quantification. Design, Setting, and Participants: This diagnostic study was conducted at the University of Wisconsin-Madison from August 2, 2017, to December 30, 2019. The study chronologically selected 589 men with biopsy-confirmed prostate cancer who received care in the University of Wisconsin Health System between January 1, 2005, and February 28, 2017. A total of 1000 biopsy slides (1 or 2 slides per patient) were selected and scanned to create digital whole-slide images, which were used to develop and validate a deep convolutional neural network-based AI-powered platform. The whole-slide images were divided into a training set (n = 838) and validation set (n = 162). Three experienced academic urological pathologists (W.H., K.A.I., and R.H., hereinafter referred to as pathologists 1, 2, and 3, respectively) were involved in the validation. Data were collected between December 29, 2018, and December 20, 2019, and analyzed from January 4, 2020, to March 1, 2021. Main Outcomes and Measures: Accuracy of prostate cancer detection by the AI-powered platform and comparison of prostate cancer grading and quantification performed by the 3 pathologists using manual vs AI-assisted methods. Results: Among 589 men with biopsy slides, the mean (SD) age was 63.8 (8.2) years, the mean (SD) prebiopsy prostate-specific antigen level was 10.2 (16.2) ng/mL, and the mean (SD) total cancer volume was 15.4% (20.1%). The AI system was able to distinguish prostate cancer from benign prostatic epithelium and stroma with high accuracy at the patch-pixel level, with an area under the receiver operating characteristic curve of 0.92 (95% CI, 0.88-0.95). The AI system achieved almost perfect agreement with the training pathologist (pathologist 1) in detecting prostate cancer at the patch-pixel level (weighted κ = 0.97; asymptotic 95% CI, 0.96-0.98) and in grading prostate cancer at the slide level (weighted κ = 0.98; asymptotic 95% CI, 0.96-1.00). Use of the AI-assisted method was associated with significant improvements in the concordance of prostate cancer grading and quantification between the 3 pathologists (eg, pathologists 1 and 2: 90.1% agreement using AI-assisted method vs 84.0% agreement using manual method; P < .001) and significantly higher weighted κ values for all pathologists (eg, pathologists 2 and 3: weighted κ = 0.92 [asymptotic 95% CI, 0.90-0.94] for AI-assisted method vs 0.76 [asymptotic 95% CI, 0.71-0.80] for manual method; P < .001) compared with the manual method. Conclusions and Relevance: In this diagnostic study, an AI-powered platform was able to detect, grade, and quantify prostate cancer with high accuracy and efficiency and was associated with significant reductions in interobserver variability. These results suggest that an AI-powered platform could potentially transform histopathological evaluation and improve risk stratification and clinical management of prostate cancer.

Comprehensive overview of extracellular vesicle proteomics in meningioma: future strategy.

BACKGROUND: Meningioma arising from meninges is one among the various types of brain tumors. Others are, astrocytomas originating from astrocyte, oligodendrogliomas originating from oligodendrocyte, Ependymomas originating from ependymal cells and medulloblastomas originating from neurons. Current knowledge of molecular biology, genetics and epigenetics of meningioma is not sufficient. Therefore, In depth understanding of the mechanism of meningioma formation and progression is needed for its treatment and management. Grade I Grade I meningiomas are majorly classified as grade I, grade II and grade III. Meningioma can be indolent, slow growing or can be invasive and metastatic which can recurre. Grade I meningioma can be removed by surgery in comparison to invasive meningioma which may recurre with high propensity. This property of recurrence is responsible for high morbidity and mortality. Meningioma are majorly classified into three classes namely grade I, grade II, grade III. Protein biomarkers are considered as promising candidates for the diagnosis of meningioma. STUDY: Various studies done on differential expression of proteins have shown increased expression of EGFR, NEK9, EPS812, CKAP4, SET and STAT2, in all the three grades of meningioma. Additionally, some proteins like HK2 are overexpressed in grade II and grade III meningioma than in grade I meningioma. Protein Markers, found on extracellular vesicles of different grades of meningioma can serve the same purpose. A test done on a sample of any kind of body fluid like blood, tear, saliva, urine etc. for recognizing the circulating cancer cells or DNA and extracellular vesicles released from them to help detecting the early stage of cancer is known as liquid biopsy. Solid biopsy has several limitations as compared to liquid biopsy. This is because the samples can be easily collected and studied in case of liquid biopsy. Exosomes are related with liquid biopsy and hence provide platform for better diagnosis, prognosis and treatment of any type of cancer including meningioma. Exosomal tetraspanin are important example of exosomal biomarkers. The tetraspanin network is a molecular scaffold which connects various proteins for signal transduction. CONCLUSION: This study tells about the utility of proper knowledge of extracellular vesicle proteins and their profiles in different grades, which can help in better understanding of pathogenesis, diagnosis, prognosis and treatment of meningioma. In Addition to use of these proteins as biomarkers, role of exosomes in currently available therapeutic approaches has been discussed.

Adjunctive role of immunohistochemical expression of Nucleostemin in differentiation of grade II and III diffuse astrocytomas.

AIMS: Astrocytomas are common tumors and grade is an important parameter in determining the treatment modalities. Tumor proliferation activity should be determined for the differentiation of grades II and III tumors. In difficult cases, an auxiliary parameter is required. Nucleostemin (NS) is nucleolar Guanosine triphosphate (GTP)-binding protein 3. It has important roles in cell proliferation, cell cycle regulation, self-renewal, and apoptosis. In this study, we investigated whether the level of NS expression is different in grades II and III astrocytomas. SETTINGS AND DESIGN: Adults diagnosed with grades II and III astrocytomas were included in the study. MATERIAL AND METHODS: Paraffin blocks that best reflected tumor morphology were studied via immunohistochemical staining for NS. Only nuclear staining was evaluated; cytoplasmic staining was not considered. STATISTICAL ANALYSIS USED: Fisher's exact test, continuity corrections, and Pearson's Chi-square tests were used in the crosstabs. The survival analysis was based on the Kaplan-Meier method. RESULTS: Only 20% (6/30) of grade II tumors had high intensity staining, while 54,2% (13/24) of grade III tumors had high staining intensity. NS was significantly more intense in grade III tumors than grade II tumors. In cases with high NS expression, survival was significantly shorter than the cases with low expression. CONCLUSION: NS is significantly higher expressed in grade III tumors than grade II tumors. In difficult cases, it can be used as a useful proliferation marker in the differentiation of grades II and III astrocytomas.

MUC1, CK20, and CDX2 immunohistochemical markers can sub-classify periampullary carcinomas into pancreaticobiliary, intestinal, and mixed subtypes.

INTRODUCTION: Pancreaticobiliary subtype of Periampullary carcinoma (PAC) has a poor prognosis in comparison to the intestinal subtype. We assessed the potential of cytokeratins and mucin markers to classify the sub-types of periampullary tumors and compared them with the survival data to identify markers that may predict prognosis. METHODOLOGY: PAC tumor tissues were obtained from 94 patients undergoing Whipples Pancreaticoduodenectomy. Paraffin-embedded tissues were immunostained with cytokeratins CK7, CK20), mucins (MUC1, MUC2, MUC5Ac), and CDX2 antibodies. The survival status of patients was obtained as follow-up up to 5-years of surgery. The Receiver Operating Character Curve (ROC) analysis was used for detecting sensitivity and specificity. The survival data were analyzed using the Kaplan-Meier survival curve. RESULTS: Tumors were initially categorized on the basis of histological classification as pancreaticobiliary (n = 46), intestinal (n = 35) and indeterminate (n = 13). Further, using immunohistochemical markers (MUC1, CK20, and CDX2), we gave systematic classification of IHC-PB (n = 51), IHC-Int (n = 30) and IHC-Mixed (n = 13). The interobserver analysis showed good agreement between histologic and IHC type with a kappa value of 0.554. Combined expression of CK20, MUC1 and CDX2 accurately classify the mixed type of tumor. Overall survival rate and duration were 74.4% and 44.95 ± 2.29 months. Survival analysis for subtypes reveal, pancreaticobiliary tumors have low survival (27.9 ± 1.63 months) than mixed type (35.5 ± 0.45 months) and intestinal-type (52.92 ± 2.18 months). Among these, intestinal-type have better survival. Only TNM Stage III (tumor staging as per American Joint Committee on Cancer classification) and perineural invasion have been associated with predicting poor survival in PAC patients. CONCLUSION: Our results suggest that the combined expression of MUC1, CK20 and CDX2 could serve as markers to diagnose histological inconclusive specimens as mixed subtype tumors.

Approach to Resectable Biliary Cancers.

OPINION STATEMENT: Biliary malignancies, although rare, can be some of the most challenging to manage surgically. Intrahepatic cholangiocarcinomas are resectable if there is no evidence of metastatic disease. These tumors are managed with anatomic resection and portal lymphadenectomy when centrally located or multiple in a single lobe. Non-anatomic resection can be performed for solitary peripheral tumors with minimally invasive techniques. It is not our practice to routinely employ neoadjuvant chemotherapy prior to resection of these tumors. Hepatic arterial infusion chemotherapy is utilized at our institution in highly selected patients in the context of an ongoing clinical trial for unresectable tumors. Hilar cholangiocarcinomas, when resectable (i.e., ipsilateral arterial involvement or lack of vascular involvement), are managed with right or left (extended) hepatectomy, caudate resection, and portal lymphadenectomy. Distal cholangiocarcinomas are managed with pancreaticoduodenectomy. Neoadjuvant chemotherapy is not routinely used in our treatment algorithm of extrahepatic cholangiocarcinomas. Nodal involvement and positive margin (R1) resection necessitates adjuvant chemotherapy. Finally, gallbladder carcinoma is managed with radical cholecystectomy, anatomic segment IVb/V resection, and portal lymphadenectomy. Adjuvant chemotherapy is employed routinely amongst patients with T2 or higher tumors and those with positive lymph nodes.

Tumor size may influence the prognosis of solitary hepatocellular carcinoma patients with cirrhosis and without macrovascular invasion after hepatectomy.

Hepatocellular carcinoma (HCC) is usually associated with varying degrees of cirrhosis. Among cirrhotic patients with solitary HCC in the absence of macro-vascular invasion, whether tumor size drives prognosis or not after hepatectomy remains unknown. This study aimed to investigate the prognostic impact of tumor size on long-term outcomes after hepatectomy for solitary HCC patients with cirrhosis and without macrovascular invasion. A total of 813 cirrhotic patients who underwent curative hepatectomy for solitary HCC and without macrovascular invasion between 2001 and 2014 were retrospectively studied. We set 5 cm as the tumor cut-off value. Propensity score matching (PSM) was performed to minimize the influence of potential confounders including cirrhotic severity that was histologically assessed according to the Laennec staging system. Recurrence-free survival (RFS) and overall survival (OS) were compared between the two groups before and after PSM. Overall, 464 patients had tumor size ≤ 5 cm, and 349 had tumor size > 5 cm. The 5-year RFS and OS rates were 38.3% and 61.5% in the ≤ 5 cm group, compared with 25.1% and 59.9% in the > 5 cm group. Long-term survival outcomes were significantly worse as tumor size increased. Multivariate analysis indicated that tumor size > 5 cm was an independent risk factor for tumor recurrence and long-term survival. These results were further confirmed in the PSM cohort of 235 pairs of patients. In cirrhotic patients with solitary HCC and without macrovascular invasion, tumor size may significantly affect the prognosis after curative hepatectomy.

Defining tumor-associated vascular heterogeneity in pediatric high-grade and diffuse midline gliomas.

The blood-brain barrier (BBB) plays important roles in brain tumor pathogenesis and treatment response, yet our understanding of its function and heterogeneity within or across brain tumor types remains poorly characterized. Here we analyze the neurovascular unit (NVU) of pediatric high-grade glioma (pHGG) and diffuse midline glioma (DMG) using patient derived xenografts and natively forming glioma mouse models. We show tumor-associated vascular differences between these glioma subtypes, and parallels between PDX and mouse model systems, with DMG models maintaining a more normal vascular architecture, BBB function and endothelial transcriptional program relative to pHGG models. Unlike prior work in angiogenic brain tumors, we find that expression of secreted Wnt antagonists do not alter the tumor-associated vascular phenotype in DMG tumor models. Together, these findings highlight vascular heterogeneity between pHGG and DMG and differences in their response to alterations in developmental BBB signals that may participate in driving these pathological differences.

Visual assessment of mitotic figures in breast cancer: a comparative study between light microscopy and whole slide images.

BACKGROUND AND AIMS: Visual assessment of mitotic figures in breast cancer (BC) remains a challenge. This is expected to be more pronounced in the digital pathology era. This study aims to refine the criteria of mitotic figure recognition, particularly in whole slide images (WSI). METHOD AND RESULTS: Haematoxylin and eosin (H&E)-stained BC sections (n = 506) were examined using light microscopy (LM) and WSI. A set of features for identifying mitosis in WSI and to distinguish true figures from mimickers was developed. Changes in the mitotic count between the two platforms was explored. Morphological features of mitoses were recorded separately, including absence of nuclear membrane, chromatin hairy-like projections, shape, cytoplasmic features, mitotic cell size and relationship to surrounding cells. Each mitotic phase has its own mimickers. Fifty-eight per cent of mitoses showed absent hairy-like projection in WSI; however, 89% retained their ragged nuclear border, which distinguished them from mimickers including apoptotic cells, lymphocytes and dark elongated hyperchromatic structures. Mitosis in WSI showed loss of fine details, and there was a 20% average reduction rate of mitotic counts when compared to the same area on LM. Using refined mitosis recognition criteria in WSI resulted in a twofold improvement of interobserver concordance. However, when compared to LM, 19% of cases were underscored in WSIs. CONCLUSIONS: All morphological features of mitosis should be considered to enable recognition and differentiation from their mimickers, particularly in WSI, to ensure reliable BC grading. Refining mitotic cut-offs per specific area when using WSI, based on the degree of reduction and association with outcome, is warranted.

Diagnostic performance of diffusion tensor imaging for preo- perative glioma grading.

BACKGROUND: This study aimed to determine the diagnostic per-formance of fractional anisotropy (FA) and mean diffusivity (MD) values for glioma grading. CONCLUSION: The tMD, rMDt/w, and rFAp/w values represent useful indices for the differentiation between LGG and HGG. The combination of these indices can improve diagnostic specificity. METHODS: A total of 42 patients who underwent biopsy or surge-ry and were histologically diagnosed with glioma from September 2019 to December 2020 were enrolled in this retrospective study. Diffusion tensor imaging (DTI) and conventional magnetic resonance imaging (MRI) were performed preoperatively using 3 Tesla MRI in all cases. The FA and MD values were measured in the solid portion of the tumor, the peritumoral area, and the normal white matter. The diagnostic performances of the absolute and relative FA and MD values for glioma grading were analyzed using the receiver operating characteristic (ROC) curve. RESULTS: The MD value in the solid portion of the tumor (tMD), the MD value of the solid portion of the tumor relative to that in the normal white matter (rMDt/w), and the FA value for the peritumoral region relative to that of the normal white matter (rFAp/w) showed significant differences between the low-grade (LGG) and high-grade glioma (HGG) groups. The combination of these three parameters provided the largest area under the curve value of 89% with sensitivity, specificity, accuracy, negative predictive, and positive predictive values of 72%, 100%, 81%, 62%, and 100%, respectively, for distinguishing between the LGG and HGG groups.

Clinical assessment of tumor regression grade systems in gastroesophageal adenocarcinoma following neoadjuvant chemotherapy.

BACKGROUND: The standard treatment for gastroesophageal cancer is neoadjuvant chemotherapy, followed by surgery, which has been shown to increase survival compared with surgery alone. Evidence is mounting that characterization of the oncologically induced tumor regression is of prognostic importance. However, no consensus regarding the optimal system for describing tumor regression exists. Thus, this study aims to explore three validated/promising tumor regression systems with a focus on their interobserver reliability and usability. METHODS: We included 100 consecutive patients with gastroesophageal adenocarcinoma who had undergone neoadjuvant oncological treatment followed by surgery. The tumors underwent tumor regression grade (TRG) assessment according to the Standard Mandard-, Modified Mandard-, and Becker systems to assess the interobserver reliability between two consultant pathologists. The interobserver reliability was determined by both Fleiss kappa and weighted kappa metrics. Besides, a semi-quantitative usability questionary was completed and it was expanded with usability comments. RESULTS: The Fleiss kappa interobserver agreement was 0.67 [95% CI, 0.55-0.79], 0.88 [95% CI, 0.73-1.00], and 0.88 [95% CI, 0.73-1.00] for Standard Mandard-, Modified Mandard-, and the Becker systems, respectively. The weighted kappa (linear) was 0.80 [95% CI, 0.72-0.89], 0.91 [95% CI, 0.84-0.98], and 0.91 [95% CI, 0.84-0.98] for the Standard Mandard-, Modified Mandard-, and the Becker systems, respectively. The usability was scored on a scale of 8-24 by both raters. The systems were scored accordingly: 47 (Modified Mandard system), 43 (Becker system), and 37 (Standard Mandard system). CONCLUSION: The Modified Mandard- and Becker systems had excellent interobserver reliability and usability. However, the systems could be improved by a better characterization of the different tiers and tumor morphology.

PDIA6 promotes pancreatic cancer progression and immune escape through CSN5-mediated deubiquitination of ß-catenin and PD-L1.

Protein Disulfide Isomerase Family A Member 6 (PDIA6) is an endoplasmic reticulum protein that is capable of catalyzing protein folding and disulfide bond formation. Abnormally elevated expression of PDIA6 has been reported to predict poor outcomes in various cancers. Herein, gain-of- and loss-of-function experiments were performed to investigate how PDIA6 participated in the carcinogenesis of pancreatic cancer (PC). By analyzing the protein expression of PDIA6 in 28 paired PC and para carcinoma specimens, we first found that PDIA6 expression was higher in PC samples. Both the overall survival and disease-free survival rates of PC patients with higher PDIA6 expression were poorer than those with lower PDIA6 (n = 178). Furthermore, knockdown of PDIA6 impaired the malignancies of PC cells - suppressed cell proliferation, invasion, migration, cisplatin resistance, and xenografted tumor growth. PDIA6-silenced PC cells were more sensitive to cytotoxic natural killer (NK) cells. Overexpression of PDIA6 had opposite effects on PC cells. Interestingly, COP9 signalosome subunit 5 (CSN5), a regulator of E3 ubiquitin ligases known to promote deubiquitination of its downstream targets, was demonstrated to interact with PDIA6, and its expression was increased in PC cells overexpressing PDIA6. Additionally, PDIA6 overexpression promoted deubiquitination of ß-catenin and PD-L1 and subsequently upregulated their expression in PC cells. These alterations were partly reversed by CSN5 shRNA. Collectively, the above results demonstrate that PDIA6 contributes to PC progression, which may be associated with CSN5-regulated deubiquitination of ß-catenin and PD-L1. Our findings suggest PDIA6 as a potential target for the treatment of PC.

Interobserver agreement of a gastric adenocarcinoma tumor regression grading system that incorporates assessment of lymph nodes.

Perioperative chemotherapy is increasingly used in combination with surgery for the treatment of patients with locally advanced, resectable gastric cancer. Histologic tumor regression grade (TRG) has emerged as an important prognostic factor; however, a common standard for its evaluation is lacking. Moreover, the clinical significance of regressive changes in metastatic lymph nodes (LNs) remains unclear. We conducted an international study to examine the interobserver agreement of a TRG system that is based on the Becker system for the primary tumors and additionally incorporates regression grading in LNs. Twenty observers at different levels of experience evaluated the TRG in 60 histologic slides (30 primary tumors and 30 LNs) based on the following criteria: for primary tumors, grade 1 represented complete response (no residual tumor), grade 2 represented <10%, grade 3 represented 10-50%, and grade 4 represented >50% residual tumor, as described by Becker et al. For LNs, grade "a" represented complete, grade "b" represented partial, and grade "c" represented no regression. The interobserver agreement was estimated using the Kendall's coefficient of concordance (W). Regarding primary tumors, agreement was good irrespective of the level of experience, reaching a W-value of 0.70 overall, 0.71 among subspecialized, and 0.71 among nonsubspecialized observers. Regarding LNs, interobserver agreement was moderate to good, with W-values of 0.52 overall, 0.64 among subspecialized, and 0.45 among nonsubspecialized observers. These findings indicate that the combination of the Becker TRG system with a three-tiered grading of regression in LNs generates a system that is reproducible. Future studies should investigate whether the additional information of TRG in LNs adds to the prognostic value of histologic regression grading in gastric cancer specimens.

Intratumoral budding is associated with poor clinical outcome in early-stage clear cell carcinoma of ovary.

AIMS: Clear cell carcinoma of ovary (CCC) is considered a high-grade malignancy by default and the role of histological grading for assessing clinical outcome is not established. We aimed to evaluate histopathological features associated with clinical outcome in CCC patients. METHODS AND RESULTS: Seventy-six cases of CCC with available clinical follow-up information were studied. Histopathological features, including tumour size, architectural patterns, nuclear atypia, mitotic activity, intratumoral and peritumoral inflammation, presence of endometriosis, peritumoral and intratumoral budding, were evaluated. Multivariate analysis was performed with logistic regression and Kaplan-Meier survival curves with the log-rank test were used for survival analysis. Forty cases (53%) presented at stage I. Complete response to treatment was achieved in 65%, while 35% of patients had tumour recurrence or progression of disease despite treatment. At last follow-up, 13% had died of disease, 20% were alive with disease and 67% had no evidence of disease. Higher stage (P = 0.0016) and presence of intratumoral budding (P = 0.0454) were independently associated with recurrence/disease progression. Advanced stage (P = 0.0011), presence of lymph node involvement (P = 0.0003), intratumoral budding (P = 0.0023) and peritumoral budding (P = 0.0334) were significantly associated with shorter survival. Intratumoral budding was significantly associated with recurrent/progressive disease (P = 0.0195) and also shorter survival (P = 0.0277) within the cohort of low-stage (I/II) patients as well. CONCLUSION: We have shown that besides the classic prognostic factors of stage and lymph node status, the presence of tumour budding is associated with poorer outcome in patients with CCC. Specifically, evaluation of intratumoral budding may help to more clearly predict prognosis in patients with early-stage disease.

Primary high-grade myoepithelial carcinoma of the lung: A study of three cases illustrating frequent SMARCB1-deficiency and review of the literature.

Primary myoepithelial carcinoma of the lung is exceptionally rare and, hence, remained poorly characterized. We present 3 tumors affecting 2 males and 1 female aged 60 to 84 years. Tumor size ranged from 4 to 10 cm. All presented as well circumscribed non-encapsulated peripheral solitary masses. One patient died postoperatively. The other two were lost to follow-up. Histologically, all tumors were high-grade with predominance of myxoid/chordoid (2) and rhabdoid (1) pattern. Immunohistochemistry (IHC) showed reactivity with vimentin, pankeratin, EMA and smooth muscle actin. Two tumors were SMARCB1-deficient (one with additional loss of SMARCA2 and PBRM1). RNA sequencing revealed no gene fusions. Review of reported cases (total: 16) showed that pulmonary myoepithelial carcinoma affects both sexes equally at a median age of 60 years (24-84), presents predominantly as peripheral masses (69%) in the lower lobes (66%) of smokers (70%) with a median size of 6 cm (1.5-13), and originates as high-grade de novo carcinoma. Forty percent of patients died of disease at a median of 12.5 months (0 to 62). Only 40% of patients were disease free at last follow-up (median, 9.5 months). Prominent lobulation and myxoid stroma were frequent histological features. Most tumors displayed variable combinations of epithelioid, spindle, plasmacytoid, clear, ovoid or round cells. Three of 6 tumors subjected to different RNA panels showed EWSR1 rearrangements (fused to PBX1, ZNF444 or to unknown partner). Two of 3 tumors lacking gene fusions were SMARCB1-deficient (both showed secondary EWSR1 FISH abnormalities due to 22q deletion). Primary pulmonary myoepithelial carcinoma is a rare aggressive malignancy that recapitulates its soft tissue and salivary counterpart. Exclusion of metastasis from other primaries is mandatory and can only be achieved by detailed clinical history and imaging.

Secondary parenchymal CNS involvement by lymphoma including rare types: Follicular and EBV-positive NK/T cell lymphoma, nasal type.

BACKGROUND: Secondary CNS involvement by systemic lymphomas (SCNSL) is uncommon, but when it occurs, is usually due to diffuse large B cell lymphoma (DLBCL). Three recent unusual cases serve to highlight diagnostic challenges. OBJECTIVE: To report SCNSL from DLBCL and two unusual lymphoma types: follicular lymphoma with high-grade transformation to DLBCL and NK/T cell lymphoma, nasal type (ENKL), nasal type. RESULTS: SCNSL in the DLBCL case occurred at 7-year interval from primary in a 54-year-old woman who presented with stroke-like symptoms and a right postcentral gyrus 2.6 × 2.9 × 2.6 cm. mass. The follicular lymphoma occurred at 6-month interval in a 69-year-old woman with 1 month of diplopia and 2 weeks of cognitive decline; multifocal lesions involved temporal lobe, subependymal periventricular areas, brainstem, cerebellum, hypothalamus, corpus callosum and gyrus rectus. The ENKL occurred at 25-month interval from nasal biopsy in a 45-year-old man with 1 week of altered mental status; multifocal cerebral and brainstem lesions were identified. Histological features in cases 1 and 3 were identical to the primary lymphoma, with high-grade transformation to DLBCL in the follicular lymphoma. CONCLUSION: Unusual features in our series include longer interval from primary to relapse in case 1 with DLBCL (usually <2 years of diagnosis), and SCNSL occurring from either follicular lymphoma or EKNL, nasal type (<6% of cases). Pathologists play an important role in excluding infectious, especially in cases with parenchymal lesions and characterizing the lymphoma type in SCNSL.