Histologic Categories Research Articles

Validation of a renal risk score in a cohort of ANCA-associated vasculitis patients with severe kidney damage.

To validate the renal risk score in a cohort of patients with advanced kidney damage. A total of 72 patients with biopsy-proven ANCA glomerulonephritis with >12months of follow-up were studied. The renal risk score was calculated and evaluated by survival analysis for time of renal survival. Cohort-specific clinical, histopathologic, and post-treatment factors associated with renal survival were determined by Cox regression analysis. Kidney biopsies were classified as focal, crescentic, mixed, and sclerotic classes in 6 (8%), 4 (6%), 25 (35%), and 37 (51%) patients, respectively. The 1-, 3-, and 5-year renal survival rates were 79%, 73%, and 68%, respectively. Patients were segregated by the risk score in low- (18%), medium- (47%), and high-risk (35%) groups. Patients in the low-risk group had 36-, 60-, and 84-month renal survival of 100%; those in the medium risk 85% (95% CI 72-92), 81% (95% CI 66-95), and 76% (95% CI 60-92), respectively; and those in the high risk 37% (95% CI 17-57), 26% (95% CI 7-45), and 18% (95% CI 1-36), respectively. Six (43%) of the 14 patients in the high-risk group recovered renal function after the initial episode, and 2 (14%) remained dialysis-free. Other parameters associated with renal survival included age, proteinuria, general symptoms, cellular crescents, glomerulosclerosis, tubulointerstitial lesions, best post-treatment eGFR, and renal relapses. We validated the renal risk score as a prognostic tool in a cohort with predominantly mixed and sclerotic histologic categories. Since patients in the high-risk group still benefited from immunosuppressive therapy, this score should be used in conjunction with other predictive parameters to aid therapeutic decisions.Key Points• The ANCA renal risk score is validated in a cohort with advanced kidney damage.• Patients in the high-risk group still benefited from immunosuppressive therapy.• Parameters not included in the risk score are associated with renal survival and may be useful.

Thyroid follicular cell tumors: cytohistological comparisons in the context of the new international classification

To carry out a correlation retrospective analysis of the histological and cytological findings of follicular cell neoplasms over a two-year period after the publication of the new WHO classification of thyroid tumors (2017), which identifies a category of follicular tumors of uncertain malignant potential (T-UMP). The investigators of the Clinic, National Medical Research Center for Endocrinology, Ministry of Health of Russia, made a cytohistological comparison of morphological findings, by using the material of surgically removed follicular cell neoplasms. The investigation showed the lack of unreasonably common usage of the histological classification category of T-UMP (3.08%). Non-invasive follicular neoplasm with papillary-like nuclei predominantly diagnosed in the T-UMP category was more frequently (83.3) assigned to Diagnostic Category IV of the 2017 Bethesda system for the cytological diagnosis of thyroid tumors. Cytology showed the highest (98.1%) sensitivity, including classic (97.8%), encapsulated (100%), and follicular (97.7%) options in diagnosing papillary cancer, being substantially inferior in diagnosing follicular and Hürthle cell neoplasms, in which diagnostic category IV category was more frequently established for adenomas (81.4%) and carcinomas (69.5%). The morphological differential diagnosis of follicular cell neoplasms seems to be a relevant problem.

Primary Tumor Histology Affects Oncological Outcomes Independently of the Anatomical Extent of Disease in Colorectal Liver Metastasis.

Introduction: Growing evidence indicates the prognostic importance of the crosstalk between cancer cells and stroma through the induction of epithelial-mesenchymal transition (EMT). This study aimed to clarify the prognostic value of evaluating primary tumor histology with the anatomical extent of disease in patients with colorectal liver metastasis (CRLM). Methods: Prognostic analyses were performed in 411 CRLM patients who underwent hepatectomy at two institutions. Tumors were graded into one of three histological categories based on integrated assessment of EMT-associated histology (HistologyEMT) in primary tumors, i.e., poorly differentiated clusters (PDCs) and desmoplastic reaction (DR). Results: A prognostic grouping system for the anatomical extent of disease (N stage, liver metastasis number and size, and extrahepatic disease; Gradeanatomical) stratified patients into three groups with different five-year relapse-free survival (RFS) rates after hepatectomy: A, 31% (191 patients); B, 15% (124 patients); and C, 6% (96 patients; P < 0.0001). HistologyEMT (A, G1 PDC and mature-type DR; C, G3 PDC and immature-type DR; and B, others) identified 49, 120, and 242 patients with 46%, 5%, and 22% five-year RFS, respectively (P < 0.0001). Among prognostic factors, the Akaike information criterion was most favorable in Gradeanatomical, followed by HistologyEMT. Multivariate analysis demonstrated that these two factors independently impacted RFS; two-year RFS after hepatectomy in different patient groups had a wide range (10%-76%). Conclusions: Histological assessment of dedifferentiation and the stromal environment of primary tumors contributed to effective risk stratification of early relapse after hepatectomy, which could be useful to determine clinical management for CRLM patients.

Sex Differences and Adverse Effects between Chemotherapy and Immunotherapy for Non-Small Cell Lung Cancer.

Introduction: Lung cancer remains the leading cause of cancer mortality in men and women and around the world. Approximately 90% of cases of lung cancer are caused by smoking and the use of tobacco products. However, other factors such as asbestos, air pollution and chronic infections can contribute to pulmonary carcinogenesis. Lung cancer is divided into two broad histological categories, which develop and spread different small cell lung carcinomas and non-small cell lung carcinomas. The treatment options for lung cancer include surgery, radiotherapy, chemotherapy and targeted treatments. Tumor induced immune suppression is vital for malignant progression. Immunotherapies act by strengthening the patient's innate tendency for an immune response and give positive promise to patients with non-small cell lung cancer and small cell lung cancer. Immune checkpoint inhibitors are a new approach to cancer therapies. Just as immune therapies include a new approach to cancer biology, the toxicities associated with these factors have created new challenges in clinical practice.Materials & Methods: Patients (218) aged 40-80 years were treated with either chemotherapy or immunotherapy. Their response to treatment and any subsequent adverse drug reactions were studied.Results: 69% of patients were treated with chemotherapy and 31% were treated with immunotherapy. The type of treatment had a statistically significant effect on the undesirable effects of the treatment.Conclusions: The type of treatment was statistically significant in responding to the treatment and treatment side effects but not in the rate of death.

Clinical Interest of LMO2 Testing in Aggressive Large B-Cell Lymphomas

Introduction: MYC rearrangements (MYCr) occur in 5 to 15% of diffuse large B-cell lymphomas (DLBCL) and 20 to 35% of high-grade B-cell lymphoma, NOS (HGBL-NOS), are a defining criterion of the category HGBL with rearrangements of MYC and/or BCL2/BCL6 (HGBL, with MYCr and BCL2/BCL6), and may be present in 90% of Burkitt lymphoma. The current WHO classification considers cytogenetic techniques as the appropriate tool to detect MYCr but does not define how to approach to the identification of such alteration. As the global incidence of MYCr in large B-cell lymphomas (LBCL) is low, it is necessary to clarity whether FISH or other cytogenetic methods have to be applied to all LBCL or only in selected cases. We previously identified LMO2 as a potential surrogate marker of MYCr in LBCL (Colomo L, Am J Surg Pathol 2017). Our aim with this study is to confirm this observation and evaluate the clinical impact of this marker in the survival of patients with LBCL. Methods: We have prospectively studied between September 2014 and July 2019 a new series of 180 LBCL including patients with DLBCL, HGBL, with HGBL, with MYCr and BCL2/BCL6, HGBL-NOS and transformed low-grade lymphomas into DLBCL (tDLBCL) diagnosed according to WHO criteria. LMO2 (clone 1A9-1), MYC (clone Y69) and a common immunohistochemistry (IHC) panel of B and T-cell markers have been used for the histological categorization of the cases, using whole tissue sections. The cutoff for LMO2 and MYC were 30% and 40%, respectively. MYC and BCL6 genes were studied using break apart probes, and BCL2 gene using dual-color dual-fusion probes (IGH/BCL2), all from Vysis-Abbott. We have statistically correlated the loss of expression of LMO2 and the overexpression of MYC with the presence or absence of MYCr. Moreover, we performed survival analyses assessing the clinical impact of LMO2 in a series of 162 LBCL patients (112 DLBCL, 20 HGBL, with MYCr and BCL2/BCL6, 4 HGBL-NOS and 26 tDLBCL). The survival series included cases diagnosed before 2014 with IHC and FISH data. Results: The prospective series included 132 patients with DLBCL (78M/52F; median age 67 years, range 35-95), 9 HGBL, with MYCr and BCL2/BCL6 (5M/4F; median age 67 years, range 42-85), 4 HGBL-NOS (2M/2F; median age 58 years, range 42-89), and 35 tDLBCL (31 transformed follicular lymphomas, 3 marginal zone lymphoma and 1 lymphoplasmacytic lymphoma; 23M/20F; median age 64 years, range 40-82). LMO2 and MYC were expressed as follows, respectively: 84/130 (65%) and 46/132 (35%) in DLBCL; 1/9 (11%) and 8/9 (89%) in HGBL, with MYCr and BCL2/BCL6; 0/4 and 3/4 (75%) HGBL-NOS; 25/34 (73%) and 7/33 (21%) tDLBCL. MYCr were identified in 9/132 (7%) DLBCL; all HGBL, with MYCr and BCL2/BCL6; 4/4 HGBL-NOS; 7/35 (20%) tDLBCL. The table shows the comparisons between LMO2 and MYC protein expression for the identification of the presence of MYCr in the series of LBCL. Whereas in the whole series LMO2 and MYC had similar results, among CD10-positive cases, LMO2 had better results than MYC and identified better the presence of MYCr than MYC protein expression. The 5-year progression-free survival (PFS) according the diagnostic categories was 59% for DLBCL, 28% for HGBL, with MYCr and BCL2/BCL6, 25% for HGBL-NOS and 22% for tDLBCL (P=0.015). In addition, PFS was significantly lower for the presence of MYCr (26% vs 53%, P=0.02) and MYC IHC expression (35% vs 53%, P=0.005), and showed a positive trend for LMO2 loss of expression (39% vs 52%, P=0.1). The 5-year overall survival (OS) according the diagnostic categories was 67% for DLBCL, 23% for HGBL, with MYCr and BCL2/BCL6, 50% for HGBL-NOS and 77% for tDLBCL (P&lt;0.001). In addition, OS was significantly shorter for the presence of MYCr (37% vs 71%, P=0.002), MYC protein expression (46% vs 75%, P=0.001), and for LMO2 loss of expression (46% vs 74%, P=0.005). In a Cox regression survival analysis including IPI and LMO2 for the 68 CD10-positive cases, IPI (HR: 1.61 P=0.03) was the most important variable for predicting OS, and LMO2 showed a significant trend (HR: 0.44 P=0.06). However, the addition of MYC IHC and MYCr did not add predictive accuracy to IPI score (HR: 1.6 P=0.31; HR: 1.8 P=0.19, respectively). Conclusions: LMO2 detection by IHC is a useful tool to detect MYCr in aggressive LBCL, particularly in CD10-positive cases. Moreover, LMO2 protein expression captures the prognostic significance of the different diagnostic histological categories and the presence of MYCr in this group of lymphomas. Disclosures Sanchez-Gonzalez: Alexion: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Salar:Celgene: Consultancy; Gilead: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau.

Iron deficiency in children at the time of initial neuroblastoma diagnosis.

ABSTRACTImportanceThere is a high incidence of iron deficiency in children worldwide. Notably, however, while iron deficiency is the most common cause of anemia, little is known about the prevalence and different types of iron deficiency in neuroblastoma patients.ObjectiveThe aim of the present study was to investigate the prevalence of iron deficiency in patients newly diagnosed with neuroblastoma.MethodsA total of 195 newly diagnosed neuroblastoma patients from November 2015 to January 2018 were analyzed retrospectively. The survival analysis was estimated by the Kaplan‐Meier method.ResultsOf the 195 neuroblastoma patients included in the study, 121 (62.1%) had iron deficiency, 55 (28.2%) had absolute iron deficiency, and 66 (33.9%) had functional iron deficiency. Being aged ≥ 18 months, tumor originating in the abdomen, International Neuroblastoma Risk Group Staging System M, high‐risk neuroblastoma, lactate dehydrogenase ≥ 1500 U/L, neuron‐specific enolase ≥ 100 U/L, unfavorable histologic category, MYCN amplification, chromosome 1p loss, and bone marrow metastasis were associated with significantly higher rates of functional iron deficiency (P < 0.05).InterpretationFunctional iron deficiency at the time of initial neuroblastoma diagnosis predicted lower event‐free survival. Long‐term effects of iron supplementation in neuroblastoma patients with different types of iron deficiency need to be further studied.

Cancer Progress and Priorities: Lung Cancer.

In the United States, lung cancer is the second most common diagnosed cancer and the leading cause of cancer-related death. Although tobacco smoking is the major risk factor accounting for 80% to 90% of all lung cancer diagnoses, there are numerous other risk factors that have been identified as

269 Colorectal Cancer Annual Percent Change Incidence Analysis in 40–49 and 50–54 Year-Olds Utilizing 2000–2016 SEER 18 Data and Stratified by Histology

INTRODUCTION: SEER 9 analysis has revealed rising incidence of early-onset colorectal cancer (EOCRC) in 40–49 year-olds and within 50–54 year-olds. We seek to analyze SEER 18 EOCRC rates as this represents a greater percentage of the U.S. population compared to SEER 9 (28% vs. 9%). Furthermore, given evidence carcinoid (CN) rates are increasing and these tumors may potentially be broadly categorized as “colorectal cancer,” we aimed to sub-stratify analysis by histology. METHODS: Age-specific CRC, colon only and rectal only incidence rates from SEER 18 (2000–2016) were generated in yearly intervals using SEER*Stat. Age 40–49 and 50–54 blocks were analyzed, and Joinpoint regression was used to calculate annual percent changes (APC). Histologic categories included all CRCs, adenocarcinomas (AC), CNs, and CRCs without CNs. RESULTS: Age 40–49 overall CRC APC was 1.45% from 2000–2016. Colon AC APC was 1.08% from 2000–2016, and rectal AC APC was 1.49% 2000–2016. Age 50–54 overall CRC APCs was 1.06% from 2000–2016. Age 50–54 2000–2016 CRC AC APCs was 0.55% with a colon AC APC of 0.27% and rectal AC APC of 1.09%. Age 40–49 CRC CN APC was 4.58% from 2000–2016. Age 50–54 CRC CN APCs were 10.35% from 2000–2008, −1.09% from 2008–2012, and 9.41% from 2012–2016. All results were statistically significant except Age 50–54 colon AC APC 2000–2016 (0.27%) and Age 50–54 CRC CN APC 2008–2012 (−1.09%). CONCLUSION: Age 40–49 and 50–54 overall CRC rate increases in SEER 18 appear to be driven by all histology sub-types, including AC and CN. Although there was significant increase in colorectal AC APC of 0.55% in 50–54 year-olds, there was no significant APC increase in colon ACs, but significant increase in rectal ACs. In both age groups, colon and rectal CNs incidences have been increasing faster than ACs. Importantly, rising CN incidence is significantly factoring into the increase in CRC in ages 40–49 and 50–54. Reasons are unclear but could potentially represent increased use of colonoscopy which can detect proximal lesions. Overall, findings support rises in CRC incidence in EOCRC and ages 50–54. Despite these findings, ACs are still rising in 40–54 year-olds, and concerning symptoms should trigger diagnostic evaluations.

268 Early-Onset Colorectal Cancer Annual Percent Change Incidence Analysis in 20–29 and 30–39 Year-Olds Utilizing 2000–2016 SEER 18 Data and Stratified by Histology

INTRODUCTION: SEER 9 analysis has revealed rising early-onset colorectal cancer (EOCRC) incidence. We seek to analyze SEER 18 EOCRC rates as this represents a greater percentage of the U.S. population compared to SEER 9 (28% vs. 9%). Furthermore, given evidence carcinoid (CN) rates are increasing and these tumors may potentially be broadly categorized as “colorectal cancer,” we aimed to substratify analysis by histology. METHODS: Age-specific CRC, colon only and rectal only incidence rates from SEER 18 (2000–2016) were generated in yearly intervals using SEER*Stat. Age 20–29 and 30–39 blocks were analyzed and Joinpoint regression was used to calculate annual percent changes (APC). Histologic categories included all CRCs, adenocarcinomas (AC), CNs and CRCs without CNs. RESULTS: Age 20–29 overall CRC APC was 3.39% from 2001–2013 and 14.55% from 2013–2016. Colon AC APCs (1.03% from 2000–2016) and rectal AC APCs (7.42% 2000–2006, −0.24% 2007–2016) in 20–29 year-olds were not statistically significant. However, colorectal combined ACs had a statistically significant, modest APC of 1.12%. In contrast, 2007–2016 age 20–29 colon CN APC was 41.05%. Rectal CN APCs were not significantly changed. Age 30–39 overall CRC APCs were 1.58% from 2000–2010 and 4.03% from 2010–2016. Age 30–39 2000–2016 colorectal AC APCs were 1.89% with a colon AC APC of 1.59% and rectal AC APC of 2.40%. Age 30–39 colonic CN APCs were 32.81% from 2010–2016. Rectal CN APCs were 2.90% from 2000–2016. CONCLUSION: Age 20–29 overall CRC rate increases in SEER 18 appear to be driven in large part by increasing CN incidence. Although there was a significant colorectal AC APC of 1.12% in 20–29 year-olds, there was no significant APC increase in colon ACs. There appeared to be an increased APC trend in rectal ACs from 2000–2006 (7.42%), however this was non-significant and there was a negative trend from 2006–2016. In contrast, colon and rectal ACs in the 30–39 age group have been steadily increasing. In both age groups, colon CNs have been increasing faster than rectal CNs. Reasons are unclear but could potentially represent increased use of colonoscopy which can detect proximal lesions. Study limitations include underreported age 20–29 CN rates from 2000–2006. Overall, findings support rises in CRC incidence in young adults, however this is less from ACs in 20–29 year-olds. Despite these findings, ACs are still present in 20–29 year-olds and concerning symptoms should trigger diagnostic evaluations.

Evaluation of HER2/neu Expression in High-Grade Endometrial Carcinoma and Its Clinicopathological Correlation.

Background & Objective:Endometrial carcinoma (EC) has been traditionally classified into two distinct categories of low-grade and high-grade. Type I (low grade) EC, which constitutes the majority of cases, is linked to estrogen-related molecular pathways. But type II (high-grade) EC accounts for 10-20% of cases and behaves in an aggressive way. Pathologic and biological features of type II EC have not been fully elucidated yet. Several investigations have demonstrated HER2/neu expression and amplification in type II EC, especially papillary serous carcinoma (PSC). This study assessed HER2/neu expression in high-grade EC as well as its association with other clinical and histopathological prognostic factors.Methods:In this cross-sectional study, we performed HER2/neu immunohistochemical (IHC) staining in 37 high-grade EC cases with histological diagnostic categories of PSC (n=23), clear cell carcinoma (CCC) (n=9), and carcinosarcoma with high-grade carcinomatous component (PSC, CCC, grade 3 endometrioid carcinoma, or unclassified high-grade adenocarcinoma) (n=5). All patients were followed for 2-9 years in order to evaluate their disease-free survival (DFS) and overall survival (OS) during study period (2005-2014).Results:HER2/neu IHC staining was positive in 12 patients (32.4%) including 8/23 (34.8%) PSC, 2/9 (22.2%) CCC, and 2/5 (40%) carcinosarcoma cases. There was no statistically significant difference between HER2/neu expression and DFS or OS of the patients (P>0.05).Conclusion:We observed that HER2/neu is expressed in one-third of high-grade ECs. This ancillary test is supportive in follow-up of patients with high-grade ECs.

Structured light imaging for breast-conserving surgery, part II: texture analysis and classification.

.Subdiffuse spatial frequency domain imaging (sd-SFDI) data of 42 freshly excised, bread-loafed tumor resections from breast-conserving surgery (BCS) were evaluated using texture analysis and a machine learning framework for tissue classification. Resections contained 56 regions of interest (RoIs) determined by expert histopathological analysis. RoIs were coregistered with sd-SFDI data and sampled into subimage samples of confirmed and homogeneous histological categories. Sd-SFDI reflectance textures were analyzed using gray-level co-occurrence matrix pixel statistics, image primitives, and power spectral density curve parameters. Texture metrics exhibited statistical significance () between three benign and three malignant tissue subtypes. Pairs of benign and malignant subtypes underwent texture-based, binary classification with correlation-based feature selection. Classification performance was evaluated using fivefold cross-validation and feature grid searching. Classification using subdiffuse, monochromatic reflectance (illumination spatial frequency of , optical wavelength of ) achieved accuracies ranging from 0.55 (95% CI: 0.41 to 0.69) to 0.95 (95% CI: 0.90 to 1.00) depending on the benign–malignant diagnosis pair. Texture analysis of sd-SFDI data maintains the spatial context within images, is free of light transport model assumptions, and may provide an alternative, computationally efficient approach for wide field-of-view () BCS tumor margin assessment relative to pixel-based optical scatter or color properties alone.

Lymph node metastasis in lung squamous cell carcinoma and identification of metastasis-related genes based on the Cancer Genome Atlas.

Squamous cell carcinoma (SCC) is a unique clinical and histological category that accounts for about 30% of total lung cancer. To identify risk factors for lymph node metastasis and analyze the molecular features of these metastases in lung SCC, a retrospective study was performed for 170 lung SCC patients who underwent surgical treatment. The overall survival of these patients with or without lymph node metastasis (LM/NLM) was analyzed using the Kaplan‐Meier method. We also used the TCGA database to compare the differentially expressed genes (DEGs) in patients with stage T1‐2 and T3‐4 lung SCC. Data from both our retrospective study and the TCGA database demonstrated a correlation between age and stage T1‐T2 LM (P = .002). There were significant differences between the LM and NLM groups in both mean survival time and median survival time for different T‐stages (P = .031). There were 176 upregulated and 177 downregulated DEGs between the LM and NLM groups in the stage T1‐2 group and 93 upregulated and 34 downregulated DEGs in the stage T3‐T4 group. These differentially expressed genes were predicted to participate in five cellular components, five molecular functions, and five biological processes. There were 20 genes, including GCG, CASR, NPY, CGA, TAC1, ALB, APOA1, CRH, CHRH, TRH, and GHSR, located at the core of the protein‐protein interaction network in the stage T1‐2 group and 11 genes, including F2, CASR, GRM1, GNRHR, GRPR, NTSR1, PROKR2, UTS2D, PTH, ALB, and FGA, in the stage T3‐4 group. Overall, LM plays a key role in the treatment response and prognosis of SCC patients. Several risk factors, including age and stage, were identified for LM. There was a previously undiscovered enrichment of significant novel genes in lung SCC between the LM and NLM groups, which may have the potential for predicting prognosis and targeting.

Clustering patterns of type‐type combination in multiple genotypes infections of human papillomavirus in cervical adenocarcinoma

Coinfections with multiple types of human papillomavirus (HPV) occur in cervical adenocarcinoma (ADC). However, it remains unclear the clustering patterns of multiple types in HPV coinfections and relevant factors in ADC. A total of 718 paraffin-embedded ADC specimens were collected in China and tested for HPV genotypes using SPF10-INNO-LIPA. The prevalence of HPV coinfections and clustering patterns by geographical regions, histological subtypes and ages were assessed. Type-specific attribution of HPV to ADC adjusted by HPV coinfections were calculated. The prevalence of HPV coinfections was found to be 8.4% in ADC cases with slight variation by geographic regions between 2.2% and 12.5%. The 88.3% of all HPV multiple infections in ADC were two types of HPV coinfections with predominant combination of HPV 16 and HPV 18. The attribution to ADC was 88.0% for HPV 16/18 targeted by bivalent and quadrivalent vaccine and 96.8% for HPV 16/18/31/33/45/52/58 targeted by nonavalent vaccine. Clustering patterns of multiple types were related with histological categories and age at diagnosis. In conclusion, HPV coinfections are uncommonly prevalent in ADC cases with slight variation by geographic regions and distinct clustering patterns of multiple types by histological subtypes and ages at diagnosis. The high attribution of carcinogenic HPV types to ADC predicts potential protection of HPV vaccine against ADC.

Survival of patients with thyroid papillary and follicular carcinoma: similarity and difference of prognostic factors (cohort retrospective study).

While analyzing the causes supposed to be important for disease prognosis and to impact on the patient’s survival of malignant thyroid tumors, the researches examine many factors. The aim of the study was to determine the indices of cumulative patients survival with differentiated thyroid carcinoma that belong to different histological types depending on biological properties of neoplasm and some clinical factors. Materials and methods : Retrospective study of the cohort of patients after surgical intervention. The information of patients (age and sex, histological type, size and categories of carcinomas (TNM), their invasive properties, the presence of multifocal growth), as well as the clinical characteristics of the disease (stage, volume of surgical intervention and radioiodine treatment, risk of relapse group, number of points in the system MACIS) was analysed. Results : In cases of papillary or follicular thyroid carcinoma the analyzed factors are important for further prognosis. The most essential factor for papillary carcinoma is the tumor size, which associated with other ones – metastasizing, multifocal growth, intra- and extra-thyroid invasion, relapse development. In patients below 45, which were operated because of cancer, without extra-thyroid tumor spreading and metastases, the favorable disease prognosis does not depend on the neoplasm type. Under other circumstances the impact of carcinoma histological type (for follicular carcinoma versus papillary ones) is more important, and in some cases – for men, for patients above 60, patients with tumors above40 mm, for multifocal neoplasm with intra- and especially extra-thyroid invasion, for cases of distant metastases, thyroidectomy with lymph nodes dissection, with relapses the histological tumor type, is extremely important. Conclusion : The obtained results confirm the conclusion that histological subtype of differentiated thyroid carcinoma, tumor size, age and patient gender are the most important predictor of diseases persistence/disease relapse or patients mortality

Identification of ZYG11A as a candidate IGF1-dependent proto-oncogene in endometrial cancer

The insulin-like growth factors (IGF) have a key role in the development of gynecological cancers, including endometrial tumors. Uterine serous carcinoma (USC) constitutes a defined histological category among endometrial cancers. Laron syndrome (LS) is a genetic type of dwarfism that results from mutation of the growth hormone receptor (GHR) gene, and is the best characterized entity under the spectrum of the congenital IGF1 deficiencies. Epidemiological studies have shown that LS patients are protected from cancer development. Recent genome-wide association studies conducted on LS-derived lymphoblastoid cells led to the identification of a series of metabolic genes whose over-representation in this condition might be linked to cancer protection. Our analyses led to the identification of ZYG11A, a potential cell cycle regulator, as a new downstream target for IGF1 action. The aim of the present paper was to investigate the regulation of ZYG11A gene expression by IGF1 and insulin in endometrial cancer cell lines and to assess the impact of tumor suppressor p53 on ZYG11A expression and biological action. Using USC-derived cell lines expressing a wild type or a mutant p53 gene, we demonstrate that IGF1 inhibited ZYG11A mRNA and protein levels in cells containing a wild type p53. On the other hand, IGF1 potently stimulated ZYG11A expression in mutant p53-expressing cells. Data presented here links the IGF1 and p53 signaling pathways with ZYG11A action. The clinical implications of the present study in endometrial and other types of cancer must be further investigated.

An audit of mammographic screen detected lesions of uncertain malignant potential (B3) diagnosed on initial image guided needle biopsy: how has our practice changed over 10 years?

To review all cases of B3 lesion diagnosed at initial image-guided needle biopsy over two 5-year cohorts to identify upgrade rates to malignancy and the effect of changing guidance on the management of such lesions. Data was collected retrospectively. Mammographic features, biopsy type and management were recorded for each lesion. Upgrade rates for each B3 histological category were quantified. Statistical analysis was performed using SPSS. There were 224 cases in 2005-2010 and 240 cases in 2010-2015. Mammographically 211 lesions were microcalcifications, 182 masses, 65 distortions and six asymmetric densities with no difference in the mammographic features in the two cohorts. Two hundred and eight 14 G core biopsies and 256 initial vacuum-assisted biopsies were performed. There was a statistically significant reduction in benign surgical biopsies and an increase in second-line vacuum biopsy/excision in the latter cohort, with no significant change in the upgrade rate. There was an overall 6% upgrade to invasive malignancy and 13% upgrade to ductal carcinoma in situ (DCIS). The upgrade rates for the following histological categories were atypical intraductal epithelial proliferation (AIDEP) 33.2% (21/63); classical (not pleomorphic) in situ lobular neoplasia (ISLN) 18.2% (6/33); flat epithelial hyperplasia (FEA) 21.7% (20/92); papilloma with atypia 53.8% (7/13), without atypia 12.1% (8/66); and radial scar/complex sclerosing lesion with atypia 16.7% (2/12), and without atypia 7.9% (6/76). Upgrade rates remain high for some histological categories even with first-line use of vacuum biopsy. Management of borderline lesions should be considered carefully in a multidisciplinary meeting. In many cases, the need for diagnostic surgical excision has been replaced by image-guided vacuum sampling.

Keratin 17 is a sensitive and specific biomarker of urothelial neoplasia

There is a clinical need to identify novel biomarkers to improve diagnostic accuracy for the detection of urothelial tumors. The current study aimed to evaluate keratin 17 (K17), an oncoprotein that drives cell cycle progression in cancers of multiple anatomic sites, as a diagnostic biomarker of urothelial neoplasia in bladder biopsies and in urine cytology specimens. We evaluated K17 expression by immunohistochemistry in formalin-fixed, paraffin embedded tissue specimens of non-papillary invasive urothelial carcinoma (UC) (classical histological cases), high grade papillary UC (PUC-LG), low grade papillary UC (PUC-HG), papillary urothelial neoplasia of low malignant potential (PUNLMP), and normal bladder mucosa. A threshold was established to dichotomize K17 status in tissue specimens as positive vs. negative, based on the proportion of cells that showed strong staining. In addition, K17 immunocytochemistry was performed on urine cytology slides, scoring positive test results based on the detection of K17 in any urothelial cells. Mann–Whitney and receiver operating characteristic analyses were used to compare K17 expression between histologic diagnostic categories. The median proportion of K17 positive tumor cells was 70% (range 20–90%) in PUNLMP, 30% (range 5–100%) in PUC-LG, 20% (range 1–100%), in PUC-HG, 35% (range 5–100%) in UC but staining was rarely detected (range 0–10%) in normal urothelial mucosa. Defining cases in which K17 was detected in ≥10% of cells were considered positive, the sensitivity of K17 in biopsies was 89% (95% CI: 80–96%) and the specificity was 88% (95% CI: 70–95%) to distinguish malignant lesions (PUC-LG, PUC-HG, and UC) from normal urothelial mucosa. Furthermore, K17 immunocytochemistry had a sensitivity of 100% and a specificity of 96% for urothelial carcinoma in 112 selected urine specimens. Thus, K17 is a sensitive and specific biomarker of urothelial neoplasia in tissue specimens and should be further explored as a novel biomarker for the cytologic diagnosis of urine specimens.

Melanized focal changes in skeletal muscle in farmed Atlantic salmon after natural infection with Piscine orthoreovirus (PRV).

Melanized focal changes in skeletal muscle of farmed Atlantic salmon (Salmo salar) are a major quality problem. The aetiology is unknown, but infection with Piscine orthoreovirus (PRV) has been associated with the condition. Here, we addressed the pathogenesis of red and melanized focal changes and their association with PRV. First, a population of farmed fish (PRV‐negative prior to sea transfer) was sequentially investigated throughout the seawater period. The fish were autopsied and tested for PRV infection. Muscular changes were described by macroscopy and histology, and a classification system was established. Second, in an experimental infection trial, PRV was injected intramuscularly to induce changes. The farmed fish was gradually infected with PRV. Red focal changes occurred throughout the observation period with a low prevalence regardless of PRV status. Melanized changes were highly diverse and their prevalence increased during the trial. Changes of low macroscopic grade and histological category were more prevalent in PRV‐negative fish. Diffuse granulomatous melanized changes only occurred after PRV infection. No muscular changes were observed in the experimentally challenged fish. Our studies do not indicate that PRV infection causes red focal changes, but seems important in the development of granulomatous melanized changes.

Gene Expression in Formalin-Fixed Paraffin-Embedded Lung Transplant Biopsies: Correlation between Molecular and Histologic Phenotypes

Purpose Transbronchial lung transplant biopsies (TBBx) are limited by non-specific histologic lesions and suboptimal interobserver reproducibility. Gene expression offers a potentially more precise, objective and mechanistic diagnostic approach, but it has not yet been fully utilized in lung transplants. The aim of this study was to assess the feasibility of gene expression in formalin-fixed paraffin-embedded (FFPE) TBBx. Methods All TBBx performed at our institution from 01/2015 to 12/2017 were retrieved (n=43). Those without alveolar parenchyma (n=9) or residual FFPE tissue (n=2) were excluded. Concurrent mucosal biopsies (MBx) were also retrieved (n=11). Review diagnoses were assigned by a pathologist blinded to molecular results. NanoString was used to analyze a literature-derived 136-gene set, including previously-described allograft rejection and acute lung injury transcripts. Gene expression results were correlated with histology and biopsy characteristics. Results 30/32 TBBx and 11/11 MBx passed quality control and were included in the final analysis. TBBx were reclassified as acute cellular rejection (n=5), infection (n=5), possible antibody-mediated rejection (n=2) and normal (n=18). There were no significant differences in patient or biopsy characteristics between diagnostic groups (p>0.05). Unsupervised principal component analysis demonstrated gene expression patterns to generally correlate with histology diagnoses in TBBx (Figure 1) but not MBx. Surfactant gene expression correlated with the presence (p Conclusion These results suggest that, for TBBx with alveolar parenchyma, gene expression patterns do generally correlate with histologic categories. Molecular analysis of FFPE TBBx can potentially be used to identify and validate molecular signatures of clinical significance, refine histologic criteria and provide adjunct diagnostic tools.

Natural History and Treatment Trends in Pancreatic Cancer Subtypes

BackgroundWhile pancreatic ductal adenocarcinoma is the most common form of pancreatic cancer, many other histologic forms of pancreatic cancer are also recognized. These histologic variants portray unique characteristics in terms of patient demographics, tumor behavior, survival, and responsiveness to treatments. Materials and MethodsPatients who underwent surgical resection of the pancreas for non-metastatic, invasive pancreatic cancer between 2004 and 2014 were selected from the National Cancer Data Base and categorized by histologic variant according to WHO classification guidelines. Patient demographics, tumor variables, treatment characteristics, and survival were compared between histologic groups and subgroups. ResultsA total of 57,804 patients met inclusion and exclusion criteria and were grouped into eight major histologic categories. Survival analysis by the histologic group showed median overall survival of 20.2 months for ductal adenocarcinoma, 20.5 months for squamous cell carcinoma, 26.8 months for mixed acinar-neuroendocrine carcinomas, 52.6 months for cystic mucinous neoplasms with an associated invasive carcinoma, 67.5 months for acinar cell carcinoma, and 69.3 months for mesenchymal tumors. Median survival was not reached for neuroendocrine tumors and solid-pseudopapillary neoplasms, with 5-year overall survival rates of 84% and 97% respectively. ConclusionsRare subtypes of pancreatic cancer present unique clinicopathologic characteristics and display distinct tumor biologies. This study presents data on demographic, prognostic, treatment, and survival outcomes between rare forms of pancreatic neoplasms in order to aid understanding of the natural history and behavior of these neoplasms, with the hope of serving as a reference in clinical decision-making and ability to provide accurate prognostic information to patients.