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Introduction A histologic grading system for invasive lung adenocarcinoma (ADC) has been proposed by the International Association for the Study of Lung Cancer (IASLC) Pathology Committee in June 2020. This study evaluated the prognostic value of the IASLC histologic grading system (the IASLC system) in a large Japanese cohort. Methods We performed comprehensive histologic subtyping using the semiquantitative estimation of five major patterns and complex glandular patterns in patients with a completely resected lung ADC and determined the histologic grade using the IASLC system. Concordance index and receiver-operating characteristic curves were used to evaluate the clinical utility of the IASLC system for recurrence and death; the comparison was performed with the architectural-pattern system (the Arch system) and the grading system on the basis of the two most predominant patterns (the Sica’s system). Results Of 1002 patients with invasive ADC, 235 had recurrent disease and 166 died of lung cancer. The concordance index and area under the curve of the IASLC system were 0.777 and 0.807 for recurrence and 0.767 and 0.776 for death, respectively. These were similar to those of the Arch system (0.763 and 0.796 for recurrence, 0.743 and 0.755 for death) and the Sica’s system (0.786 and 0.814 for recurrence, 0.762 and 0.773 for death). Conclusions We reported that the IASLC system for invasive lung ADC has prognostic significance by evaluating a large Japanese cohort. We believe that the IASLC grading system will provide physicians with better information for postsurgery treatment.

Background Recently, histologic grade was removed from salivary tumor nomenclature by the WHO to include disease of higher grade. One such entity, cribriform adenocarcinoma (CAC), is an aggressive group of polymorphous adenocarcinoma (PAC), with frequent nodal metastasis and locoregional recurrence. We aim to examine the biologic behavior of this disease as compared with the PAC general cohort inclusive of all subtypes. Methods A systematic review of the literature on polymorphous adenocarcinoma and cribriform adenocarcinoma was completed. A descriptive analysis was performed for the following predictor variables: nodal and distant metastasis, in addition to recurrence. The outcome variables, disease free recurrence, and disease specific survival, where plotted using Kaplan-Meier curves. Results PAC and CAC both show median age of diagnosis in the sixth decade of life and a female predominance. CAC occurs most frequently in the tongue and PAC in the palate. The 2 groups show a similar biologic behavior in regards to incidence of distant metastasis (4.1 vs 5.5%), recurrence (12.5 vs 17.8%), and death from disease (3 vs 2.7%). However, there was an increased incidence of nodal metastasis in CAC (53%) as compared with that in PAC of all subtypes (14%). Conclusions CAC exhibits more aggressive biologic behavior as compared with the PAC cohort. Although CAC is not an officially recognized entity, these tumors likely comprise a significant portion of the cases of PAC with poor outcomes and are deserving of attention and consideration for escalation in oncologic treatment.

Introduction Brain metastases (BM) are frequent among lung cancer patients, affecting prognosis and quality of life. The International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS) and European Respiratory Society (ERS) lung adenocarcinoma (LADC) classification (IASLC/ATS/ERS) has prognostic impact in early-stage disease; however, its role in the advanced setting is not precise. This study aims to determine the correlation between the predominant histological subtype and the risk of developing brain metastases (BM) in locally advanced and metastatic (stages IIIB-IV) LADC. Methods A total of 710 patients with LADC were treated at our institution from January 2010 to December 2017. After excluding patients with brain metastases at diagnoses (n = 151), they were categorized according to the IASLC/ATS/ERS LADC classification to estimate the risk of developing brain metastases. A competing risk analysis was employed, considering death a competing risk event. Results From 559 patients, the mean age was 59 ± 13.2 years, women (52.4 %), and clinical-stage IV (79.2 %). LADC subtypes distribution was lepidic (11.6 %), acinar (37.9 %), papillary (10.2 %), micropapillary (6.8 %), and solid (33.5 %). A total of 27.0 % of patients developed BM, 32.9 % died without brain affection, and 40.0 % did not progress. The predominantly solid subtype showed the greatest probability of all subtypes for developing BM [HR 4.0; 95 % CI (1.80−8.91), p = 0.0006], followed by micropapillary [HR1.11; 95 % CI (0.36−3.39), p = 0.85). The solid subtype, moderately differentiated tumors, age, and ECOG PS (>2) were associated with increased hazards in the multivariate analysis. CONCLUSION According to the IASLC/ATS/ERS classification, the predominantly solid pattern was significantly associated with an increased risk of developing BM in patients with locally advanced and metastatic LADC. Its prognostic value might help explore novel clinical approaches, modify monitoring for earlier detection, prevent complications, and reduce morbidity.

Introduction PREDICT is a prognostication tool that calculates the potential benefit of various postsurgical treatments on the overall survival (OS) of patients with nonmetastatic invasive breast cancer. Once patient, tumor, and treatment details have been entered, the tool will show the estimated 5‐, 10‐, and 15‐year OS outcomes, both with and without adjuvant therapies. This study aimed to conduct an external validation of the prognostication tool PREDICT version 2.2 by evaluating its predictive accuracy of the 5‐ and 10‐year OS outcomes among female patients with nonmetastatic invasive breast cancer in Japan. Methods All female patients diagnosed from 2001 to 2013 with unilateral, nonmetastatic, invasive breast cancer and had undergone surgical treatment at Kyushu University Hospital, Fukuoka, Japan, were selected. Observed and predicted 5‐ and 10‐year OS rates were analyzed for the validation population and the subgroups. Calibration and discriminatory accuracy were assessed using Chi‐squared goodness‐of‐fit test and area under the receiver operating characteristic curve (AUC). Results A total of 636 eligible cases were selected from 1, 213 records. Predicted and observed OS differed by 0.9% (p = 0.322) for 5‐year OS, and 2.4% (p = 0.086) for 10‐year OS. Discriminatory accuracy results for 5‐year (AUC = 0.707) and 10‐year (AUC = 0.707) OS were fairly well. Conclusion PREDICT tool accurately estimated the 5‐ and 10‐year OS in the overall Japanese study population. However, caution should be used for interpretation of the 5‐year OS outcomes in patients that are ≥65 years old, and also for the 10‐year OS outcomes in patients that are ≥65 years old, those with histologic grade 3 and Luminal A tumors, and in those considering ETx or no systemic treatment., This study conducted an external validation of the online PREDICT tool version 2.2 by studying its predictive accuracy of the 5‐ and 10‐year overall survival (OS) in a population of breast cancer patients in Japan. Based on analysis of 636 eligible patients, the differences of the predicted and observed 5‐ and 10‐year OS were not statistically significant and the discriminatory accuracy results were fairly well. Hence, we can say that PREDICT tool accurately estimated the 5‐ and 10‐year overall survival in the Japanese validation population.

Objectives To develop and validate a radiomics nomogram for preoperative prediction of tumor histologic grade in gastric adenocarcinoma (GA). Methods This retrospective study enrolled 592 patients with clinicopathologically confirmed GA (low-grade: n=154; high-grade: n=438) from January 2008 to March 2018 who were divided into training (n=450) and validation (n=142) sets according to the time of computed tomography (CT) examination. Radiomic features were extracted from the portal venous phase CT images. The Mann-Whitney U test and the least absolute shrinkage and selection operator (LASSO) regression model were used for feature selection, data dimension reduction and radiomics signature construction. Multivariable logistic regression analysis was applied to develop the prediction model. The radiomics signature and independent clinicopathologic risk factors were incorporated and presented as a radiomics nomogram. The performance of the nomogram was assessed with respect to its calibration and discrimination. Results A radiomics signature containing 12 selected features was significantly associated with the histologic grade of GA (P

The most common biomarker for HCC is serum alpha-fetoprotein (AFP). AFP is used for screening and diagnosing HCC, and also, it is used for predicting prognosis and monitoring the response to treatment. AFP secretion is associated with poor tumor histologic grade and aggressive tumor biological behavior. The risk of dropout on the waiting list for liver transplantation and the risk of tumor recurrence after liver transplantation are associated with high AFP serum levels. Therefore, using AFP levels for selecting patients to include on the liver transplantation waiting lists is critical. It is also known that a low AFP serum level before liver transplantation has limited informative value, but high AFP levels prior to liver transplantation indicate a higher risk for HCC recurrence. AFP’s performance as a screening, diagnostic, and prognostic marker for HCC is not ideal, but it is the most frequently used biomarker in the management of HCC.

Background The 21‐gene recurrence score (RS) assay has been recommended by major guidelines for treatment decision in hormone receptor (HR)‐positive early breast cancer (EBC). However, the genomic assay is not accessible and affordable worldwide. Alternatively, an increasing number of studies have shown that traditional immunohistochemistry (IHC) can partially or even completely replace the role of the 21‐gene genomic assay. Here, we developed and validated a predictive model (IHC3 model) combining the Ki‐67 index, progesterone receptor (PR) expression, histologic grade, and tumor size to predict the recurrence risk of HR‐positive EBC. Methods The data from 389 patients (development set) with HR‐positive, human epidermal growth factor receptor 2‐negative, lymph node non‐metastasized invasive breast cancer were used to construct the IHC3 model based on the Surexam® 21‐gene RS and the TAILORx clinical trial criteria. An additional 146 patients with the same characteristics constituted the validation set. The predictive accuracy of the IHC3 model was compared with that of Orucevic et al.’s nomogram. Invasive disease‐free survival (IDFS) was analyzed in the IHC3 predictive low‐recurrence risk (pLR) group and the predictive high‐recurrence risk (pHR) group. The Pearson chi‐square test, Fisher exact test, and log‐rank test were used for analysis. Results The pLR and pHR group could be easily stratified using the decision tree model without network dependence. The accuracies of the IHC3 model were 86.1% in the development set and 87.7% in the validation set. The predictive accuracy of the IHC3 model and Orucevic et al.’s nomogram for the whole cohort was 86.5% and 86.9%, respectively. After a 52‐month of median follow‐up, a significant difference was found in IDFS between of the IHC3 pLR and the pHR groups (P = 0.001) but not in the IDFS between the low‐ and high‐recurrence risk groups according to the Surexam® 21‐gene RS and the TAILORx clinical trial criteria (P = 0.556) or 21‐gene binary RS group (P = 0.511). Conclusions The proposed IHC3 model could reliably predict low and high recurrence risks in most HR‐positive EBC patients. This easy‐to‐use predictive model may be a reliable replacement for the 21‐gene genomic assay in patients with EBC who have no access to or cannot afford the 21‐gene genomic assay.

Background Recent studies have shown a lower likelihood of locoregional recurrences in patients with a low 21-gene recurrence score (RS). In this single-institution study, we investigated whether there are any associations between different cutoff values of 21-gene RS, histopathological factors, and outcome in patients with long-term follow-up. Methods The study included 61 patients who had early-stage (I-II) clinically node-negative hormone receptor-positive and HER2-negative breast cancer and were tested with the 21-gene RS assay between February 2010 and February 2013. Demographic, clinicopathological, treatment, and outcome characteristics were analyzed. Results The median age was 48 years (range, 29–72 years). Patients with high histologic grade (HG), Ki-67 ≥ 25%, or Ki-67 ≥ 30% were more likely to have intermediate/high RS (≥ 18). Based on the 21-gene RS assay, only 19 patients (31%) received adjuvant chemotherapy. At a median follow-up of 112 months, 3 patients developed locoregional recurrences (4.9%), which were treated with endocrine therapy alone. Among patients treated with endocrine treatment alone (n = 42), the following clinicopathological characteristics were not found to be significantly associated with 10-year locoregional recurrence free survival (LRRFS): age 11. However, patients with RS ≥ 16 had significantly poorer 10-year LRRFS compared to those with RS p = 0.039). Conclusions The results suggest that patients with clinically node-negative disease and RS ≥ 16 are more likely to benefit from adjuvant chemotherapies. However, those with RS

Simple Summary Gleason grading of prostate cancer is essential for treatment strategies and patient prognosis. Previous studies showed grading variation between pathologists when grading prostate cancer. Our study analyzed the presence and extent of grading variation between and within pathology laboratories in The Netherlands. In our nationwide retrospective study, we analyzed prostate needle biopsy reports of 35,258 patients in The Netherlands graded by 40 pathology laboratories. We found a considerable variation between and within pathology laboratories, as over half of the laboratories graded significantly different from the national mean. This likely affects treatment strategy and prognosis assessment of prostate cancer patients. Abstract Purpose: Our aim was to analyze grading variation between pathology laboratories and between pathologists within individual laboratories using nationwide real-life data. Methods: We retrieved synoptic (n = 13,397) and narrative (n = 29,377) needle biopsy reports from the Dutch Pathology Registry and prostate-specific antigen values from The Netherlands Cancer Registration for prostate cancer patients diagnosed between January 2017 and December 2019. We determined laboratory-specific proportions per histologic grade and unadjusted odds ratios (ORs) for International Society of Urological Pathologists Grades 1 vs. 2–5 for 40 laboratories due to treatment implications for higher grades. Pathologist-specific proportions were determined for 21 laboratories that consented to this part of analysis. The synoptic reports of 21 laboratories were used for analysis of case-mix correction for PSA, age, year of diagnosis, number of biopsies and positive cores. Results: A total of 38,321 reports of 35,258 patients were included. Grade 1 ranged between 19.7% and 44.3% per laboratory (national mean = 34.1%). Out of 40 laboratories, 22 (55%) reported a significantly deviant OR, ranging from 0.48 (95% confidence interval (CI) 0.39–0.59) to 1.54 (CI 1.22–1.93). Case-mix correction was performed for 10,294 reports, altering the status of 3/21 (14%) laboratories, but increasing the observed variation (20.8% vs. 17.7%). Within 15/21 (71%) of laboratories, significant inter-pathologist variation existed. Conclusion: Substantial variation in prostate cancer grading was observed between and within Dutch pathology laboratories. Case-mix correction did not explain the variation. Better standardization of prostate cancer grading is warranted to optimize and harmonize treatment.

Background: The 2019 NCCN guidelines and the College of American Pathology (CAP) endorse consistent, unambiguous comprehensive pathology reporting for invasive breast cancer. Challenges surrounding inter-pathologist variability and the lack of quantitative, standardized approaches to histologic grade are significant and critical to patient management. We developed an automated multi-network machine learning platform for histologic grading and examined performance with clinical outcome. Methods: Using the Cancer Genome Atlas (TCGA) breast cancer (BCA) image dataset and clinical data as a training cohort, we evaluated 420 conventional H&E images (one slide per patient). An artificial intelligent (AI) / deep-learning based workflow is used to normalize staining differences, identify regions of tumor vs. normal and characterize individual cellular attributes of breast cancer grading systems including overall gland structure, nuclear morphology, and mitotic figures. Individual features were correlated with overall survival using the concordance index (c-index). Support vector models and Kaplan-Meier incidence curves were used to further understand feature importance. Results: Using the AI platform, 88 image features representing BCA gland morphology and cellular-nuclear attributes were generated from 420 patients with 36 events including metastasis and or death with a median overall survival (OS) of 5-years. Three clinical variables were available including AJCC stage, grade and age at diagnosis. Image features were prioritized on C-index 0.5 which reflects increased or reduced risk of poor outcome, respectively. A training model consisting of image features + clinical data produced a C-index of 0.85, Hazards ratio 11, p Conclusions: Our innovative lab-based AI / deep-learning platform produced accurate BCA risk models to predict metastasis and OS through automated H&E BCA grading. Future analyses include a multi-site validation study to confirm these initial training results. Citation Format: Marcel Prastawa, Abishek Sainath Madduri, Brandon Veremis, Alexander Shtabsky, Bahram Marami, Jack Zeineh, Michael Joseph Donovan, Gerardo Fernandez. The application of machine learning techniques to standardize breast cancer grading and develop multivariate risk outcome models [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-11.

Background/aim Liposarcomas (LS) are one of the most common entities within the heterogenous group of soft tissue sarcomas. The aim of this study was to identify prognostic indicators in patients with LS of the extremities and truncal wall. Patients and methods We analysed the influence of potential prognostic factors on local recurrence-free survival (LRFS) and overall survival (OS) in 181 patients who were suitable for surgical treatment with curative intent. Results The median follow-up period was 7.1 years. The 5-year LRFS and OS rates were 79.1 and 93.3%. The 5-year OS rate was 94.7% in patients with R0-resected primary tumors and 72.7% in patients with R1/R2-status (p=0.023). In multivariate analysis, only histologic grade was found to be an independent prognostic factor of OS. Conclusion Negative margins were not an independent prognostic factor in our series. Tumor biology reflected by histologic grade dictated the outcome.

Due to the aggressive biological behavior, a large number of studies attempt to identify the prognostic indicators for feline mammary carcinoma (FMC). In this study, we retrospectively identified the prognostic indicators and evaluated the effect of surgery with or without adjuvant chemotherapy on 47 cats with FMCs. Over a two-year follow-up period, surgical removal was significantly associated with greater overall survival time (OST). In cats that underwent surgical treatment, median OST was longer in cats that underwent surgery with adjuvant chemotherapy (540 days) than cats that underwent surgery without chemotherapy (398 days). In addition, cats with FMCs in early stage (I or II) had longer OST than cats in advanced stages. Further, through multivariate analyses, the histological grade was found to be significantly associated with a survival of two years. Cats with FMCs at high grade were most likely to have a mean or median OST of less than one year. In summary, stage, grade and the size of tumor were all prognostic factors, in which histological grade was found to be the only significant factor in cats with mammary carcinomas through multivariate analysis.

Background Despite the overall diagnostic utility of core needle biopsy (CNB) comparable to incisional biopsy, increased diagnostic errors have been suggested of CNB for myxoid soft tissue tumors. This study compared the diagnostic performance of CNB between myxoid and non-myxoid soft tissue tumors. Methods 369 patients who underwent ultrasound-guided CNB prior to resection for soft tissue tumors were classified into two groups according to resection pathology; myxoid group (n = 75) and non-myxoid group (n = 294). One-hundred and ninety-three patients were male and the median age of the patients was 40 years. Two-hundred and sixty-three tumors were malignant. Results CNB correctly diagnosed malignancy in 84% (58 of 69) for the myxoid group and 95% (184 of 194) for the non-myxoid group. For diagnosing histologic grade of soft tissue sarcoma, CNB correctly identified high grade in 78% (18 of 23) for the myxoid group and 74% (94 of 128) for the non-myxoid group. Correct diagnosis rate of histological type was significantly lower in the myxoid group (63% [47 of 75] in the myxoid group and 83% [242 of 294] in the non-myxoid group, p = 0.013). Conclusion Our study suggests that CNB is useful for myxoid soft tissue tumors of the extremity, with regard to diagnosing malignancy and histologic grade. However, CNB was less useful for identifying histologic subtype in myxoid tumors than in non-myxoid tumors.

Historically, ductal carcinoma in situ (DCIS) of the breast has been managed aggressively with surgery and radiotherapy because of a risk of progression to invasive ductal carcinoma. However, this treatment paradigm has been challenged by overtreatment concerns and evidence that suggests that DCIS can be stratified according to risk of recurrence or risk of progression to invasive disease. Traditional methods of risk stratification include histologic grade and hormone receptor status. Recent technological advancements have enabled an era of precision medicine, where DCIS can be molecularly analyzed by tools, such as next-generation DNA and RNA sequencing, to identify molecular biomarkers for risk stratification. These findings have led to the development of tools such as the Oncotype DX Breast DCIS Score, a gene expression–based assay with the potential to prevent overtreatment in low-risk disease.

Accurate, consistent and reproducible grading by pathologists is of key‐importance for identification of individual patients with invasive breast cancer (IBC) that will or will not benefit from adjuvant systemic treatment. We studied the laboratory‐specific grading variation using nationwide real‐life data to create insight and awareness in grading variation. Synoptic pathology reports of all IBC resection‐specimens, obtained between 2013 and 2016, were retrieved from the nationwide Dutch Pathology Registry (PALGA). Absolute differences in laboratory‐proportions of Grades I–III were compared to the national reference. Multivariable logistic regression provided laboratory‐specific odds ratios (ORs) for high‐ vs. low‐grade IBC. 33,792 IBC pathology reports of 33,043 patients from 39 laboratories were included, of which 28.1% were reported as Grade I (range between laboratories 16.3–43.3%), 47.6% as Grade II (38.4–57.8%), and 24.3% as Grade III (15.5–34.3%). Based on national guidelines, the indication for adjuvant chemotherapy was dependent on histologic grade in 29.9% of patients. After case‐mix correction, 20 laboratories (51.3%) showed a significantly deviant OR. Significant grading differences were also observed among pathologists within laboratories. In this cohort of 33,043 breast cancer patients, we observed substantial inter‐ and intra‐laboratory variation in histologic grading. It can be anticipated that this has influenced outcome including exposure to unnecessary toxicity, since choice of adjuvant chemotherapy was dependent on grade in nearly a third of patients. Better standardization and training seems warranted., What's new? Histologic grade serves a critical prognostic role in invasive breast cancer (IBC) and is used to guide therapeutic decisions. Evidence indicates, however, that IBC grading varies considerably. Here, grading variation in clinical practice was evaluated using real‐life data from laboratories in the nationwide Dutch Pathology Registry. Laboratories varied in IBC grade I, II, and III reporting. Among grading components, nuclear polymorphism showed the greatest difference between laboratories. Within laboratories, one‐third of pathologists deviated significantly from national proportions for IBC grade I. Despite deployment of uniform guidelines across laboratories, IBC histologic grading is not necessarily performed in a consistent manner.

Purpose Double heterozygosity (DH) for BRCA1 and BRCA2 variant is very rare with only a few cases reported, and most those in Caucasians. In this article, we present seven unrelated cases of DH for BRCA1/2 identified from a single institution in Korea, and describe the characteristics and phenotype of DH individuals compared to those with a single BRCA variant.Materials and Methods This study included 27,678 patients diagnosed with breast cancer and surgically treated at Samsung Medical Center (SMC) between January 2008 and June 2020. In total, 4,215 high-risk breast cancer patients were tested for the BRCA1/2 genes, and electronic medical records from 456 cases with pathogenic/likely pathogenic variants (PVs/LPVs) were reviewed.ResultsA younger mean age at diagnosis was associated with DH than a single variant of BRCA1/2. More triple-negative breast cancer (TNBC) and higher nuclear and histologic grade cancer occurred with DH than BRCA2 variant. All 7 cases of DH were unrelated, and their mutation combinations were different. There were no Ashkenazi founder variants detected.ConclusionWe suggest that patients with DH for BRCA1/2 variants develop breast cancer at a younger age, but the histopathologic features are similar to those of BRCA1.

Purpose The large variation in histologic grading of invasive breast cancer (IBC) that has been reported likely influences tailoring adjuvant therapy. The role of grading in therapeutic decision-making in daily practice, was evaluated using the Dutch national guidelines for IBC-management. Methods Synoptic reports of IBC resection-specimens, obtained between 2013 and 2016, were extracted from the nationwide Dutch Pathology Registry, and linked to treatment-data from the Netherlands Cancer Registry. The relevance of grading for adjuvant chemotherapy (aCT) was quantified by identifying patients for whom grade was the determinative factor. In addition, the relation between grade and aCT-administration was evaluated by multivariate logistic regression for patients with a guideline-aCT-indication. Results 30,843 patients were included. Applying the guideline that was valid between 2013 and 2016, grade was the determinative factor for the aCT-indication in 7744 (25.1%) patients, a percentage that even increased according to the current guideline where grade would be decisive for aCT in 10,869 (35.2%) patients. Also in current practice, the indication for adjuvant endocrine therapy (aET) would be based on grade in 9173 (29.7%) patients. Finally, as patients with lower-grade tumors receive aCT significantly less often, grade was also decisive in tailoring aCT de-escalation. Conclusions In the largest study published so far we illustrate the increasing importance of histologic grade in tailoring adjuvant systemic breast cancer therapy. Next to playing a key-role in aCT-indication and de-escalation, the role of grading has expanded to the indication for aET. Optimizing histologic grading by pathologists is urgently needed to diminish the risk of worse patient outcome due to non-optimal treatment.

BackgroundTo develop and validate nomogram models for the preoperatively prediction of the histologic grade of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) to provide appropriate treatments.MethodsA total of 1014 participants, including 211 healthy controls, 293 patients with benign diseases, 299 patients with cancers, and 211 patients with GEP-NETs were included in the final analysis. Their sociodemographic and laboratory information, including serum tumor markers such as AFP, CEA, CA19-9, CA72-4, Cyfra21-1 and NSE were collected. Nomogram models were developed to preoperatively predict histologic grades of GEP-NETs.ResultsAmong six serum tumor markers, only NSE was found to have a statistically significant association with the histologic grades in GEP-NETs (G1 vs. G2: p < 0.05; G2 vs. G3: p < 0.001; G1 vs. G3: p < 0.0001), which was combined with sex and age to develop the nomogram models. The first nomogram (to differentiate grade 1(G1) and grade 2/3 tumor (G2/G3)) showed a strong association to differentiate with an AUC of 0.747 (95% CI: 0.663-0.832) and 0.735 (95% CI: 0.624-0.847) in the training and validation datasets, respectively. The second nomogram (to differentiate G1/G2 and G3 tumors) showed a strong association to differentiate with an AUC of 0.827 (95% CI: 0.744-0.911) and 0.847 (95% CI: 0.744-0.950) in the training and validation datasets, respectively. The ROC, area under ROC curve (AUC), calibration curve and decision curve analysis (DCA) demonstrated the clinical usefulness of both models.ConclusionsWe proposed two novel nomogram models based on sex, age and serum NSE levels to preoperatively predict the histologic grades in GEP-NETs to assist the clinical decision-making.

Simple Summary Survivin, coded by the BIRC5 gene, is the cell death preventing protein, which is important for cell division in normal and cancer cells. It is intensively studied as a cancer biomarker and target for antitumor therapy. In this study we asked if we could get clinically helpful information on how active BIRC5 is in breast cancer patients? We studied the BIRC5 protein level in tumor samples for breast cancer patients from a West Swedish cohort and its mRNA level in two different public gene expression databases. Survival analysis demonstrated that a higher BIRC5 protein or mRNA level was associated with poor survival in all cohorts and for different cancer subtypes. We show that BIRC5 is a promising independent cancer survival marker. Abstract Breast cancer (BC) histological and molecular classifications significantly improved the treatment strategy and prognosis. Inhibitor of apoptosis BIRC5/survivin is often overexpressed in cancers, however, indications of its importance in BC are inconsistent. We integrate BIRC5 protein and mRNA measures with clinical associates and long-term outcome in three independent cohorts Protein levels of BIRC5 were measured in primary lysates of 845 patients of the West Swedish BC cohort (VGR-BC) and linked to 5- and 27-years survival. The results were externally validated in transcriptomic data from METABRIC and SCAN-B cohorts. Survival analysis showed that high levels of BIRC5 were consistently associated with a poor probability of 5-year overall survival. High BIRC5 in VGR-BC contributed negatively to the disease-specific survival at 5 and 27 years. Subsets with different status by ER (estrogen receptor) expression and presence of nodal metastasis supported independent association of high BIRC5 with poor prognosis in all cohorts. In METABRIC and SCAN-B cohorts, high levels of BIRC5 mRNA were associated with the basal-like and luminal B molecular BC subtypes and with increasing histologic grade. BIRC5 is a sensitive survival marker that acts independent of ER and nodal status, and its levels need to be considered when making treatment decisions.

OBJECTIVES Pancreatic neuroendocrine neoplasms include well-differentiated tumors (PanNETs) and poorly differentiated carcinomas (PanNECs). Previous reports suggested a role for platinum-based therapy largely in PanNEC. We sought to investigate the role of platinum-based therapy in pancreatic neuroendocrine neoplasms regardless of tumor grade and differentiation. METHODS Patients with pancreatic neuroendocrine neoplasms treated with platinum-based therapy at Memorial Sloan Kettering (1994-2016) and Verona University Hospital (2008-2016) were retrospectively identified. Response to treatment by RECIST v1.1, overall survival, and progression-free survival were defined. Among patients with available tissue, DAXX, ATRX, Rb, and p53 expression was evaluated to support the histologic grade of differentiation. RESULTS Fifty PanNETs, 29 PanNECs, and 22 high-grade tumors with undeterminable differentiation were included. No patients achieved complete response. Overall rate of partial response was 31%, 41% for PanNEC, and 20% for PanNETs. Among PanNETs, partial response was achieved in 33% of G1 (2/6), 10% of G2 (2/19), and 24% of G3 (6/25) tumors. Median overall survival was 29.3 months for PanNETs and 10.9 months for PanNEC (P < 0.001). There was no significant difference in median progression-free survival (P = 0.2). CONCLUSIONS Platinum-based therapies demonstrated increased activity in PanNEC; however, promising efficacy was also observed in PanNETs, irrespective of grade.

Purpose: Although tumor-infiltrating lymphocytes (TIL) assessment has been acknowledged to have both prognostic and predictive importance in triple-negative breast cancer (TNBC), it is subject to inter and intraobserver variability that has prevented widespread adoption. Here we constructed a machine-learning based breast cancer TIL scoring approach and validated its prognostic potential in multiple TNBC cohorts. Experimental Design: Using the QuPath open-source software, we built a neural-network classifier for tumor cells, lymphocytes, fibroblasts, and “other” cells on hematoxylin–eosin (H&E)–stained sections. We analyzed the classifier-derived TIL measurements with five unique constructed TIL variables. A retrospective collection of 171 TNBC cases was used as the discovery set to identify the optimal association of machine-read TIL variables with patient outcome. For validation, we evaluated a retrospective collection of 749 TNBC patients comprised of four independent validation subsets. Results: We found that all five machine TIL variables had significant prognostic association with outcomes (P ≤ 0.01 for all comparisons) but showed cell-specific variation in validation sets. Cox regression analysis demonstrated that all five TIL variables were independently associated with improved overall survival after adjusting for clinicopathologic factors including stage, age, and histologic grade (P ≤ 0.0003 for all analyses). Conclusions: Neural net-driven cell classifier-defined TIL variables were robust and independent prognostic factors in several independent validation cohorts of TNBC patients. These objective, open-source TIL variables are freely available to download and can now be considered for testing in a prospective setting to assess clinical utility. See related commentary by Symmans, p. 5446

The purpose of this study was to investigate whether ultra-high-field dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) of the breast at 7T using quantitative pharmacokinetic (PK) analysis can differentiate between benign and malignant breast tumors for improved breast cancer diagnosis and to predict molecular subtypes, histologic grade, and proliferation rate in breast cancer. In this prospective study, 37 patients with 43 lesions suspicious on mammography or ultrasound underwent bilateral DCE-MRI of the breast at 7T. PK parameters (KTrans, kep, Ve) were evaluated with two region of interest (ROI) approaches (2D whole-tumor ROI or 2D 10 mm standardized ROI) manually drawn by two readers (senior reader, R1, and R2) independently. Histopathology served as the reference standard. PK parameters differentiated benign and malignant lesions (n = 16, 27, respectively) with good accuracy (AUCs = 0.655&ndash, 0.762). The addition of quantitative PK analysis to subjective BI-RADS classification improved breast cancer detection from 88.4% to 97.7% for R1 and 86.04% to 97.67% for R2. Different ROI approaches did not influence diagnostic accuracy for both readers. Except for KTrans for whole-tumor ROI for R2, none of the PK parameters were valuable to predict molecular subtypes, histologic grade, or proliferation rate in breast cancer. In conclusion, PK-enhanced BI-RADS is promising for the noninvasive differentiation of benign and malignant breast tumors.

Background Endometrial cancer is the fifth most common malignant disorder in women, with its incidence increasing. A biomarker with diagnostic and prognostic value remains to be found. The HABP2 protein, or Factor VII-activating protease, encodes a hyaluronic acid-binding protein. Methods Patient data including clinical characteristics and RNAseq information of HABP2 was obtained from The Cancer Genome Atlas (TCGA), and analyzed by R statistic packages. A total of 370 women with endometrial cancer were enrolled in the study. To study the diagnostic value of HABP2 in patients with endometrial cancer, receiver operating characteristic (ROC) curves were plotted by the pROC package. To study the prognostic value of HABP2 in patients with endometrial cancer, the survival package in R was used and the Cox model was established. Results HABP2 expression was lower in endometrial cancer compared with normal endometrial tissues. HABP2 showed moderate diagnostic value for endometrial cancer, with HBP2 expression associated with vital status, histologic grade, and residual tumor. HABP2 was an independent prognostic factor, with low HABP2 expression indicating a better overall survival. Conclusions HABP2 has diagnostic and prognostic value and maybe a novel biomarker for endometrial cancer.

Background and objectives: Our aim is to explore the relationship between the levels of protein encoded by Ki67 and the histopathological aspects regarding the overall survival and progression-free survival in a single university center. A secondary objective was to examine other factors that can influence these endpoints. New approaches to the prognostic assessment of breast cancer have come from molecular profiling studies. Ki67 is a nuclear protein associated with cell proliferation. Together with the histological type and tumor grade, it is used to appreciate the aggressiveness of the breast tumors. Materials and Methods: We conducted a retrospective single-institution study, at Elias University Emergency Hospital, Bucharest, Romania, in which we enrolled women with stage I to III breast cancer. The protocol was amended to include the immunohistochemistry determination of Ki67 and the histological aspects. The methodology consisted in using a Kaplan&ndash, Meier analysis for the entire sample and restricted mean survival time up to 36 months. Results: Both lower Ki67 and low tumor grade are associated with better prognosis in terms of overall survival (OS) and progression-free survival (PFS) for our patients&rsquo, cohort. In our group, the histological type did not impact the time to progression or survival. Conclusions: Both overall survival and progression-free survival may be influenced by the higher value of Ki67 and less differentiated tumors. Further studies are needed in order to establish if the histologic type may impact breast cancer prognostic, probably together with other histologic and molecular markers.

Pyknons are specific human/primate-specific DNA motifs at least 16 nucleotides long that are repeated in blocks in intergenic and intronic regions of the genome and can be located in a new class of non-coding RNAs of variable length. Recent studies reported that pyknon deregulation could be involved in the carcinogenesis process, including colorectal cancer. We evaluated the expression profile of a set of 12 pyknons in a set of molecularly characterized colorectal cancer (CRC) patients. The pyknons (PYK10, PYK14, PYK17, PYK26, PYK27, PYK40, PYK41, PYK42, PYK43, PYK44, PYK83, and PYK90) expression was determined by qRT-PCR. A pilot analysis of 20 cases was performed, and consistent results were obtained for PYK10, PYK17, PYK42, PYK44, and PYK83. Further, the expression of the selected pyknons was evaluated in 73 CRC cases. Moreover, in 52 patients, we compared the expression profile in both tumor and normal tissues. All five pyknons analyzed showed significantly lower expression levels in the tumor compared to normal tissue. It was observed an association between expression of PYK10 with TP53 mutations (p = 0.029), PYK17 to histologic grade (p = 0.035), and PYK44 to clinical staging (p = 0.016). Moreover, levels of PYK44 were significantly associated with the patient's poor overall survival (p = 0.04). We reported the significant downregulation of pyknons motifs in tumor tissue compared with the normal counterpart, and the association of lower PYK44 expression with worse patient outcome. Further studies are needed to extend and validate these findings and determine the clinical-pathological impact.

Background: Preoperative grading of hepatocellular carcinoma (HCC) is an important factor associated with prognosis after liver resection. The promising prediction of the differentiation of HCC remains a challenge. The purpose of our study was to investigate the value of amide proton transfer (APT) imaging in predicting the histological grade of HCC, compared with the intravoxel incoherent motion (IVIM) imaging.Methods: From September 2018 to February 2020, 88 patients with HCC were enrolled and divided into four groups (G1, G2, G3, and G4) based on the histologic grades. Preoperative APT signal intensity (SI), apparent diffusion coefficient (ADC), true molecular diffusion coefficient (D), pseudo-diffusion coefficient (D*), and perfusion fraction (f ) of HCC were independently measured by two radiologists. The averaged values of those parameters were compared using an analysis of variance. The Spearman rank analysis was used to compare the correlation between those imaging parameters and the histological grades. Receiver operating characteristic (ROC) curve analysis was used to explore the predictive performance.Results: There were significant differences in APT SI, ADC, D, and f among the four grades of HCC (all P < 0.001). A moderate to good relationship was found between APT SI and the histologic grade of HCC (r = 0.679, P < 0.001). APT SI had an area under the ROC curve (AUC) of 0.890 (95% CI: 0.805–0.947) for differentiating low- from high-grade HCC, and the corresponding sensitivity and specificity were 85.71% and 82.05%, respectively. Comparison of ROC curves demonstrated that the AUC of APT SI was significantly higher than those of IVIM-derived parameter (Z = 2.603, P = 0.0092; Z = 2.099, P = 0.0358; Z = 4.023, P = 0.0001; Z = 2.435, P = 0.0149, compared with ADC, D, D*, and f , respectively). Moreover, the combination of both techniques further improved the diagnostic performance, with an AUC of 0.929 (95% CI: 0.854–0.973).Conclusion: APT imaging may be a potential noninvasive biomarker for the prediction of histologic grading of HCC and complements IVIM imaging for the more accurate and comprehensive characterization of HCC.

IDH-mutant astrocytomas have a more indolent natural history and better prognosis than their IDH-wild type counterparts, but are still graded according to schemes developed prior to the recognition of this type of neoplasm as a distinct entity. Homozygous deletion of CDKN2A has been proposed as a molecular correlate of aggressive behavior in these tumors, and may be incorporated into future grading systems in an effort to improve prognostic stratification. Fluorescence in situ hybridization (FISH) is a common ancillary testing modality used to assess CDKN2A status, but the specifics of how to best interpret FISH results for prognostication of gliomas have not been clearly defined in the literature. To address this issue, we performed a retrospective analysis of prospectively collected CDKN2A FISH data from 108 primary and 43 recurrent IDH-mutant astrocytomas diagnosed between 2007–2020 at the University of Pittsburgh Medical Center. High level CDKN2A homozygous deletion was rare in primary tumors and was identified more frequently in recurrent tumors. Multivariate Cox Proportional-Hazards analysis demonstrated that histologic grade and CDKN2A status are independent predictors of survival, and the prognostic value of CDKN2A is maximized by applying a threshold of ≥ 30% of tumor cells with homozygous deletion by FISH to define a positive result. At this threshold, CDKN2A deletion significantly stratified survival of histologic grade 4 tumors, but grade 2 and 3 tumors rarely exceeded this cutoff value and did not show worse survival. Lower thresholds identified additional lower grade tumors, but were not prognostically useful. Compared to prior studies, the lack of prognostic significance of CDKN2A homozygous deletion by FISH in grade 2–3 IDH-mutant astrocytomas may reflect differences in cohort populations or technical differences between testing modalities. Definitive criteria for determining CDKN2A homozygous deletion by various methodologies will be critical if this is to be included in future grading schemes.

Breast cancer treatment is largely guided by the results of tumor tissue analyses, i.e. evaluation of so called biomarkers, by pathologists. These biomarkers determine whether the tumor is sensitive to treatment with hormone therapy or treatment against the HER2-protein. Histologic grade represents the degree of aggressiveness and (co)determines whether additional treatment, for example with chemotherapy, is required. Given the importance of these biomarkers with regard to breast cancer treatment, we investigated whether there are differences in the results of biomarker assessment between pathology laboratories and between pathologists within individual laboratories. These analyses were performed with data from over 33.000 patients treated for breast cancer in the Netherlands between 2013 and 2016. Variation in biomarker assessment was limited, with exception of variation in grading, which was substantial, both between laboratories and between pathologists within the same laboratory. Realizing that grade is decisive for the indications for additional chemotherapy and hormone therapy in 35% and 30% of breast cancer patients, it seems likely that variation in grading lead to variation in treatment. This could potentially affect survival of breast cancer patients, which is still under investigation. To promote uniform grading, these data were reported back to the laboratories by means of feedback reports. An e-learning module, in which pathologists were trained in grading of breast cancer, was also developed. Both initiatives showed promising results. Additional initiatives, such as artificial intelligence, should be developed with priority to limit the variation in grading as much as possible.

Diffuse gliomas are among the most common adult central nervous system tumors with an annual incidence of more than 16,000 cases in the United States. Until very recently, the diagnosis of these tumors was based solely on morphologic features, however, with the publication of the WHO Classification of Tumours of the Central Nervous System, revised 4th edition in 2016, certain molecular features are now included in the official diagnostic and grading system. One of the most significant of these changes has been the division of adult astrocytomas into IDH-wildtype and IDH-mutant categories in addition to histologic grade as part of the main-line diagnosis, although a great deal of heterogeneity in the clinical outcome still remains to be explained within these categories. Since then, numerous groups have been working to identify additional biomarkers and prognostic factors in diffuse gliomas to help further stratify these tumors in hopes of producing a more complete grading system, as well as understanding the underlying biology that results in differing outcomes. The field of neuro-oncology is currently in the midst of a “molecular revolution” in which increasing emphasis is being placed on genetic and epigenetic features driving current diagnostic, prognostic, and predictive considerations. In this review, we focus on recent advances in adult diffuse glioma biomarkers and prognostic factors and summarize the state of the field.

Follicular lymphoma comprises approximately 20-30% of all cases of B-cell lymphomas. Median survival has improved significantly in the modern era. Prognostic factors include histologic grade, cytogenetics, molecular mutations, the tumor microenvironment, and tumor burden. Clinical prognostic indices are available and increasingly incorporate genetic information. Prognostic factors also arise during the course of treatment. Early progression within 24 months of initial chemoimmunotherapy is an adverse prognostic marker of inferior survival. Other high-risk populations include those with double refractory disease or those with high risk of transformation to diffuse large B-cell lymphoma.

Liver-directed therapy should be considered for patients with unresectable liver metastases from neuroendocrine tumor if symptomatic or progressing despite medical management. Our experience and current literature shows that the bland embolization, chemoembolization, and radioembolization are very effective in controlling symptoms and disease burden in the liver, and that these embolization modalities are similar in terms of efficacy and radiologic response. Their safety profiles differ, however, with recent studies suggesting an increase in biliary toxicity with drug-eluting bead chemoembolization over conventional chemoembolization, and a risk of long-term hepatotoxicity with radioembolization. For this reason, we tailor the type of embolotherapy to each patient according to their clinical status, symptoms, degree of tumor burden, histologic grade, and life expectancy. We do not recommend a “one-size-fits-all” approach. Our general strategy is to use bland embolization as first-line embolotherapy, and radioembolization for patients with high-grade tumors or who have failed other embolotherapy.

Pathologic variables play an important role in prognostication in urologic malignancies. Histologic subtype, histologic grade, and anatomic extent of disease (pathologic tumor and nodal staging) influence treatment decisions in both the adjuvant and metastatic settings. This article discusses treatment paradigms for the most common urologic malignancies, followed by the evidence base to support the relationship between pathologic assessment and decision making by the medical oncologist.

This consensus statement is a joint initiative of the Spanish Society of Pathology (SEAP) and the Spanish Society of Medical Oncology (SEOM). It revises and updates the recommendations for the use of biomarkers in the diagnosis and treatment of breast cancer. The group of experts recommends that, in all cases of breast cancer, the histologic grade and the alpha-estrogen receptor (ER), progesterone receptor, Ki-67 and HER2 status should be determined, in order to assist prognosis and establish therapeutic options, including hormone therapy, chemotherapy and anti-HER2 therapy. One of the four available genetic prognostic platforms (MammaPrint ® , Oncotype DX ® , Prosigna ® or EndoPredict ® ) may be used in node-negative ER-positive patients to establish a prognostic category and decide, together with the patient, whether adjuvant treatment be limited to hormonal therapy. Newer technologies, including next generation sequencing, liquid biopsy, tumour infiltrating lymphocytes or PD-1 determination, are still investigational.

Objective This study aimed to investigate the incidence of ovarian malignant involvement in young and premenopausal endometrioid endometrial cancer and study the possible risk factors. Methods Premenopausal patients 45 years of age or younger with endometrioid endometrial cancer treated at the OB/GYN Hospital of Fudan University between 2009 and 2013 were identified. The incidence of ovarian malignant involvement in young and premenopausal endometrioid endometrial cancer patients were calculated and the possible risk factors were investigated. Results A total of 144 younger (age ≤ 45, premenopausal) patients with endometrioid endometrial cancer were identified and coexisting malignant ovarian neoplasms were detected in 6 patients. Univariate analysis revealed that deeper myometrial invasion, positive lymphonode metastasis, positive LVSI, and high histologic grade (G2-G3) were associated with ovarian involvement in younger endometrial cancer patients. However, multivariate analysis revealed that only deep myometrial invasion was an independent risk factors for ovarian involvement (OR = 12.81, P = 0.046). Conclusion In conclusions, the incidence of coexisting ovarian malignant neoplasms in young and premenopausal patients with endometrioid endometrial cancer is low, and these findings may facilitate preoperative counseling of patients and decision making at the time of surgery.

Background We aimed to demonstrate the prognostic value of TGF-β1 in triple negative breast cancer (TNBC) and its association with clinicopathological characteristics of TNBC. Materials and methods A total of 180 women were randomly selected from non-metastatic invasive TNBC patients diagnosed at two hospitals between 2003 and 2012. Lmmunohistochemistry was performed to semi-quantify the expression of TGF-β1. Relationship between TGF-β1 expression and clinicopathological features was performed by Chi-square test. Univariate and multivariate survival analyses were performed to identify the prognostic role of TGF-β1 expression on survival outcomes. Results Of the 180 women included in this study, 67 (37.2%) patients expressed high level of TGF-β1. High expression of cytoplasmic TGF-β1 was correlated with higher histologic tumor grade ( P P P = 0.029). High cytoplasmic TGF-β1 expression was associated with reduced disease-free survival (DFS) and overall survival (OS) by log-rank test ( P DFS P OS = 0.045). However, multivariate survival analyses showed that high TGF-β1 was marginally correlated with unfavorable DFS (hazard ratio (HR) 1.796, 95% CI 0.995–3.242, P = 0.052), while it was not significantly associated with OS (HR 0.747, 95% CI 0.367–1.522, P = 0.422). Conclusions This multi-centered retrospective study highlights the high expression of cytoplasmic TGF-β1 in TNBC is associated with higher histologic grade and lymph node status, more axillary lymph node dissection, as well as reduced DFS. Our observation that the prognostic role of TGF-β1 in TNBC suggests potential rationale for using therapeutic strategies based on targeting TGF-β1 in advanced tumors.

The aim of this study was to access the prognostic value of 4 histopathologic grading systems of oral squamous cell carcinoma (OSCC): The World Health Organization (WHO), Anneroth, Bryne (1989), and Bryne (1992).Eighty-five cases of OSCC diagnosed between 1996 and 2010 at the Clinics Hospital of Porto Alegre (Porto Alegre, Brazil) were included. Slides stained with hematoxylin and eosin were obtained, and a histologic grade was assigned on the basis of the consensus of 3 expert oral pathologists, who were blinded to the clinicopathologic factors. Each system was correlated with proliferative labeling index, accessed through Ki67 immunostaining, clinicopathologic factors, patient outcome (alive or deceased), and survival time.The increase in Bryne (1992) histologic grades was accompanied by an increase in proliferative labeling index. Moreover, this system was the only one associated with patient outcome (P = .01) and survival. Bryne (1992) grading system grade III tumors were associated with poor disease-specific survival according to univariate and multivariate cox regression analyses and the log-rank test (P .05). The other systems evaluated presented no association with patients' outcome or survival.The Bryne (1992) grading system is more effective in predicting survival in OSCC compared with the systems proposed by the WHO, Anneroth, or Bryne (1989).

Brain metastasis from breast cancer generally represents a catastrophic event yet demonstrates substantial biological heterogeneity. There have been limited studies solely focusing on the prognosis of patients with such metastasis. In this study, we carried out a comprehensive analysis in 108 consecutive patients with breast cancer brain metastases between 1997 and 2012 to further define clinicopathological factors associated with early onset of brain metastasis and survival outcomes after development of them. We found that lobular carcinoma, higher clinical stages at diagnosis, and lack of coexisting bone metastasis were significantly associated with a worse brain relapse-free survival when compared with brain-only metastasis. High histologic grade, triple-negative breast cancer, and absence of visceral involvement were unfavorable prognostic factors after brain metastasis. Furthermore, high histologic grade, advanced tumor stages, and lack of coexisting bone involvement indicated a worse overall survival. Thus, the previously established prognostic factors in early stage or advanced breast cancers may not entirely apply to patients with brain metastases. Furthermore, the prognostic significance of the clinicopathological factors differed before and after a patient develops brain metastasis. This knowledge might help in establishing an algorithm to further stratify patients with breast cancer into prognostically significant categories for optimal prevention, screening, and treatment of their brain metastasis.

Background: The aim of this retrospective analysis is to understand the natural history of myxofibrosarcoma (MFS), in particular whether the prognosis can be influenced by histologic grade. Methods: We reviewed 229 adult patients with primary MFS of the limbs. We analyzed disease-specific survival (overall survival [OS]) and local recurrence (LR). Results: Median age was 70 years (range, 19–92). Sixteen (7.0%) were grade 1, 38 (16.6%) grade 2, and 175 (76.4%) grade 3. A worse OS was found in grade 3 MFS (73.1%) than in grade 2 and 1 MFS (91.9 and 100%, respectively) at 5 years (p = 0.031). Locally recurred MFS had a worse OS (p = 0.018). A better LR-free rate (100% at 5 years) was observed in grade 1 MFS; however, a similar rate was observed between grade 2 and 3 tumors (77.1 and 80.0% at 5 years, respectively, p = 0.412). Conclusions: Grade 3 MFS has the worst prognosis. Grade 1 MFS have the lowest risk of LR. These data could help identify a high-risk patient group, thus selecting a more careful follow-up for higher-risk patients. Since MFS mostly affects the elderly population, it might be useful to reserve adjuvant treatments (radiotherapy and chemotherapy) to higher-risk patients.

Objective: To investigate the application value of apparent diffusion coefficient value in the pathological type, histologic grade, and presence of lymph node metastases of esophageal carcinoma. Materials and Methods: Eighty-six patients with pathologically confirmed esophageal carcinoma were divided into different groups according to pathological type, histological grade, and lymph node status. All patients underwent conventional magnetic resonance imaging and diffusion-weighted imaging scan, and apparent diffusion coefficient values of tumors were measured. Independent sample t test and 1-way variance were used to compare the difference of apparent diffusion coefficient value in different pathological types, histologic grades, and lymph node status. Correlation between the apparent diffusion coefficient value and the histologic grade was evaluated using Spearman rank correlation test. Receiver operating characteristic curve of apparent diffusion coefficient value was generated to evaluate the differential diagnostic efficiency of poorly and well/moderately differentiated esophageal carcinoma. Results: No significant difference was observed in apparent diffusion coefficient value between esophageal squamous cell carcinoma and adenocarcinoma and in patients between those with and without lymph node metastases ( P > .05). The differences of apparent diffusion coefficient value were statistically significant between different histologic grades of esophageal carcinoma ( P < .05). The apparent diffusion coefficient value was positively correlated with histologic grade ( rs = 0.802). The apparent diffusion coefficient value ≤1.25 × 10−3 mm2/s as the cutoff value for diagnosis of poorly differentiated esophageal carcinoma with the sensitivity of 84.3%, and the specificity was 94.3%. Conclusions: The performance of apparent diffusion coefficient value was contributing to predict the histologic grade of esophageal carcinoma, which might increase lesions characterization before choosing the best therapeutic alternative. However, they do not correlate with pathological type and the presence of lymph node metastases of esophageal carcinoma.

Aim: Breast cancer histologic grade (HG) is a well-established prognostic factor. This study aimed to select methylomic biomarkers to predict breast cancer HGs. Materials & methods: The proposed algorithm BioDog firstly used correlation bias reduction strategy to eliminate redundant features. Then incremental feature selection was applied to find the features with a high HG prediction accuracy. The sequential backward feature elimination strategy was employed to further refine the biomarkers. A comparison with existing algorithms were conducted. The HG-specific somatic mutations were investigated. Results & conclusions: BioDog achieved accuracy 0.9973 using 92 methylomic biomarkers for predicting breast cancer HGs. Many of these biomarkers were within the genes and lncRNAs associated with the HG development in breast cancer or other cancer types.

Our study's goal was to screen novel biomarkers that could accurately predict the progression and prognosis of bladder cancer (BC). Firstly, we used the Gene Expression Omnibus (GEO) dataset GSE37815 to screen differentially expressed genes (DEGs). Secondly, we used the DEGs to construct a co-expression network by weighted gene co-expression network analysis (WGCNA) in GSE71576. We then screened the brown module, which was significantly correlated with the histologic grade (r = 0.85, p = 1e-12) of BC. We conducted functional annotation on all genes of the brown module and found that the genes of the brown module were mainly significantly enriched in "cell cycle" correlation pathways. Next, we screened out two real hub genes (ANLN, HMMR) by combining WGCNA, protein-protein interaction (PPI) network and survival analysis. Finally, we combined the GEO datasets (GSE13507, GSE37815, GSE31684, GSE71576). Oncomine, Human Protein Atlas (HPA), and The Cancer Genome Atlas (TCGA) dataset to confirm the predict value of the real hub genes for BC progression and prognosis. A gene-set enrichment analysis (GSEA) revealed that the real hub genes were mainly enriched in "bladder cancer" and "cell cycle" pathways. A survival analysis showed that they were of great significance in predicting the prognosis of BC. In summary, our study screened and confirmed that two biomarkers could accurately predict the progression and prognosis of BC, which is of great significance for both stratification therapy and the mechanism study of BC.

Objectives To identify prognostic factors of endometrial cancer patients assisted in the Instituto do Câncer do Estado de Sao Paulo (ICESP), Brazil. Methods A retrospective analysis of 703 patients with endometrial cancer diagnosis referred to surgical treatment in ICESP between January 2009 and October 2016 was performed. Data has been exported from the REDCap database. Cox regression was used to identify parameters related to worse prognosis. Results The following parameters were included in the analysis: tumor histology, histologic grade, lymph-vascular space invasion (LVSI), tumor size (cutoff: 2 and 4 cm) and myometrial infiltration. In the univariate analysis all studied parameters had RR>2. When multivariate analysis was performed the parameters with independent prognostic factors were histologic grade and LVSI (table 1). Conclusions High grade tumors and the presence of lymph-vascular space invasion are worse prognostic factors in endometrial cancer patients.

Purpose A considerable part of ductal carcinoma in situ (DCIS) lesions may never progress into invasive breast cancer. However, standard treatment consists of surgical excision. Trials aim to identify a subgroup of low-risk DCIS patients that can safely forgo surgical treatment based on histologic grade, which highlights the importance of accurate grading. Using real-life nationwide data, we aimed to create insight and awareness in grading variation of DCIS in daily clinical practice. Methods All synoptic pathology reports of pure DCIS resection specimens between 2013 and 2016 were retrieved from PALGA, the nationwide Dutch Pathology Registry. Absolute differences in proportions of grade I-III were visualized using funnel plots. Multivariable analysis was performed by logistic regression to correct for case-mix, providing odds ratios and 95% confidence intervals for high-grade (III) versus low-grade (I–II) DCIS. Results 4952 DCIS reports from 36 laboratories were included, of which 12.5% were reported as grade I (range 6.1–24.4%), 39.5% as grade II (18.2–57.6%), and 48.0% as grade III (30.2–72.7%). After correction for case-mix, 14 laboratories (38.9%) reported a significantly lower (n = 4) or higher (n = 10) proportion of high-grade DCIS than the reference laboratory. Adjusted ORs (95%CI) ranged from 0.52 (0.31–0.87) to 3.83 (1.42–10.39). Significant grading differences were also observed among pathologists within laboratories. Conclusion In this cohort of 4901 patients, we observed substantial inter- and intra-laboratory variation in DCIS grading, not explained by differences in case-mix. Therefore, there is an urgent need for nationwide standardization of grading practices, especially since the future management of DCIS may alter significantly depending on histologic grade. Electronic supplementary material The online version of this article (10.1007/s10549-018-05082-y) contains supplementary material, which is available to authorized users.

Somatic leiomyosarcoma (LMS) is an aggressive soft tissue sarcoma entity with a high metastatic potential. The purpose of this study was to identify prognostic indicators of survival in patients with somatic LMS of the soft tissues.We retrospectively assessed the relationship between local recurrence-free survival (LRFS), disease-specific survival (DSS), overall survival (OS) and potential prognostic factors in 164 patients who were suitable for surgical treatment in curative intent. Patients with soft tissue LMS of the extremities, the truncal wall and the head and neck area were included. The median follow-up time was 4.9 years.In the entire cohort, the 5-year estimate of the DSS, OS and LRFS rate were 74.5% (95% confidence interval [CI] 65.0-81.8), 70.6% (95% CI: 60.9-78.3) and 63.4% (95% CI 53.4-71.9), respectively. Thirty-eight patients (23.2%) developed distant metastases with a median survival time of 1.5 years after diagnosis of metastasis. Surgical margins attained at the initial oncologic resection and eventual re-excisions did not influence DSS, OS and LRFS significantly. Within the R0 subgroup, close and wide negative margins led to similar outcomes. High histologic grade (P 0.001), size5 cm (P = 0.002) and subfascial localisation (P = 0.002) were associated with significantly diminished DSS in univariate analysis. In multivariate analysis, only histologic grade was found to be an independent prognostic factor of DSS.The data from this study could not determine a prognostic significance of surgical margins suggesting that tumour characteristics other than margin status are important. Tumour biology reflected by the histologic grade dictates the final outcome.

Soft tissue sarcomas comprise tumors originating from mesenchymal or connective tissue. Histologic grade is integral to prognosis. Because sarcoma management is multimodal, histologic subtype should inform optimum treatment. Appropriate biopsy and communication between surgeon and pathologist can help ensure a correct diagnosis. Treatment often involves surgical excision with wide margins and adjuvant radiotherapy. There is no consensus on what constitutes an adequate margin for histologic subtypes. An appreciation of how histology corresponds with tumor biology and surgical anatomic constraints is needed for management of this disease. Even with the surgical goal of wide resection being obtained, many patients do not outlive their disease.

Objective: To investigate the relationship between F box/WD-40 domain protein 7 (FBXW7) and cervical squamous cancer.Methods: We investigated the FBXW7 expression in 136 cervical squamous carcinoma cases through immunohistochemistry and Western-blot analysis to evaluate the clinical significance of FBXW7 and to elucidate the relationship of FBXW7 expression with progression-free survival (PFS) and overall survival (OS).Results: Low FBXW7 expression was associated with high histologic grade, lymphovascular space invasion and lymph node metastasis, among other parameters. Patients with low FBXW7 expression exhibited poor OS and PFS.Conclusions: FBXW7 is related to the susceptibility and prognosis of cervical squamous carcinoma, indicating FBXW7 may be a potentially important target for the prediction of prognosis.

Background: Salivary Adenoid Cystic Carcinoma (ADCC), also known as “Wolf in Sheep's clothing,” is associated with poor prognosis. Regardless of the vigorous treatment, ADCC has been known to recur and metastasize. Hence, identifying informative prognostic biomarkers for Salivary ADCC is of great importance to better predict tumor behavior and to guide treatment planning. Various immunohistochemical biomarkers along with other factors like the histologic grade of the tumor, site of tumor, and age have been studied to establish their correlation with the prognosis of ADCC. Aim: The aim of the systematic review was to identify various markers that have the potential to predict the prognosis in salivary ADCC. Materials and Methods: A literature search was conducted using PubMed and Scopus as database and Google Scholar as an additional source. Studies that performed immunohistochemical analysis predicting the overall survival of patients with salivary ADCC were included in this review. Studies published from 1977 to August 2018 were included. Case reports, review, letter to editors, and articles in languages other than English were excluded from the review. The following outcomes were examined: overall/disease-free survival, metastasis, and recurrence using immunohistochemistry as a prognostic marker. Results: A number of biomarkers were identified by the evaluation of 68 studies, which predicted overall survival and prognosis in terms of recurrence and metastasis. Out of these biomarkers, four markers most frequently assessed markers were Ki-67, p53, vascular endothelial growth factor (VEGF), and cyclin D1, which showed reproducible results. Many other markers showed significant results, but since only a single study was carried out with these markers, it was difficult to assess their predictability. Conclusion: The review thus identified that Ki-67, p53, VEGF could effectively predict metastasis and recurrence in salivary ADCC. More research work is, however, required to validate the accuracy of these markers for their prognostic significance. Many other markers also showed a significant correlation to prognosis; however, multiple studies are required to establish their prognostic value.