Current Histological Classification Research Articles

The value of the current histological scores and classifications of ANCA glomerulonephritis in predicting long-term outcome

Abstract Background and Aims Three different histological scores- histopathologic classification (Berden), Renal Risk Score (RRS) and the Mayo Clinic Chronicity Score (MCCS) for ANCA associated glomerulonephritis (ANCA-GN) were compared to evaluate their association with patient and kidney prognosis of ANCA-GN. Methods Patients aged > 18 years with at least one year of follow-up and biopsy-proven ANCA-GN entered this retrospective study. Renal biopsies were classified according to Berden's classification, RRS and MCCS. The first endpoint was end-stage kidney disease (ESKD), defined as chronic dialysis or glomerular filtration rate (GFR) <15 ml/min/1.73m2. The second endpoint was ESKD or death. Results Of 152 patients 84 were males, with median age of 63.8 years and followed for 46.9 (IQR 12.8–119) months, 59 (38.8%) reached the first endpoint and 20 died. The Kaplan-Meier curves showed that Berden and RRS were associated with first (Berden: p = 0.004, RRS: p < 0.001) and second endpoint (Berden: p = 0.001, RRS: p < 0.001), MCCS with the first endpoint only when minimal + mild vs moderate + severe groups were compared (p = 0.017) and with the second endpoint (p < 0.001). Among the clinical/histological presentation features, arterial hypertension (OR = 2.75, CI = 1.50–5.06, p = 0.0011), serum creatinine (OR = 1.17, CI = 1.09–1.25, p < 0.0001), and the percentage of normal glomeruli (OR = 0.97, CI = 0.96–0.99, p = 0.009) were the independent predictors of ESKD at multivariate analysis (MA). When the three scores were included in MA, RRS (OR = 2.21, CI = 1.15–4.24, p = 0.017) and MCCS (OR = 2.03, CI = 1.04–3.95, p = 0.037), remained predictive of ESKD but Berden (OR = 1.17, CI = 0.62–2.22, p = 0.691) did not. Conclusion RRS and MCCS scores were independent predictors of kidney survival together with high serum creatinine and arterial hypertension at diagnosis, while Berden classification did not.

Enrichment of oligodendrocyte precursor phenotypes in subsets of low-grade glioneuronal tumours.

Current histological classification of low-grade glioneuronal tumours does not adequately represent their underlying biology. The neural lineage(s) and differentiation stage(s) involved and the cell state(s) affected by the recurrent genomic alterations are unclear. Here, we describe dysregulated oligodendrocyte lineage developmental programmes in three low-grade glioneuronal tumour subtypes. Ten dysembryoplastic neuroepithelial tumours, four myxoid glioneuronal tumours and five rosette-forming glioneuronal tumours were collected. Besides a comprehensive characterization of clinical features, known diagnostic markers and genomic alterations, we used comprehensive immunohistochemical stainings to characterize activation of rat sarcoma/mitogen-activated protein kinase pathway, involvement of neuronal component, resemblance to glial lineages and differentiation blockage along the stages of oligodendrocyte lineage. The findings were further complemented by gene set enrichment analysis with transcriptome data of dysembryoplastic neuroepithelial tumours from the literature. Dysembryoplastic neuroepithelial tumours, myxoid glioneuronal tumours and rosette-forming glioneuronal tumours occur at different ages, with symptoms closely related to tumour location. Dysembryoplastic neuroepithelial tumours and myxoid glioneuronal tumours contain oligodendrocyte-like cells and neuronal component. Rosette-forming glioneuronal tumours contained regions of rosette-forming neurocytic and astrocytic features. Scattered neurons, identified by neuronal nuclei antigen and microtubule-associated protein-2 staining, were consistently observed in all dysembryoplastic neuroepithelial tumours and myxoid glioneuronal tumours examined, but only in one rosette-forming glioneuronal tumour. Pervasive neurofilament-positive axons were observed only in dysembryoplastic neuroepithelial tumour and myxoid glioneuronal tumour samples. Alterations in B-Raf proto-oncogene, serine/threonine kinase, fibroblast growth factor receptor 1, fibroblast growth factor receptor 3 and platelet-derived growth factor receptor alpha occurred in a mutually exclusive manner, coinciding with strong staining of phospho-p44/42 mitogen-activated protein kinase and low apoptotic signal. All dysembryoplastic neuroepithelial tumours, myxoid glioneuronal tumours and the neurocytic regions of rosette-forming glioneuronal tumours showed strong expression of neuron-glia antigen 2, platelet-derived growth factor receptor alpha (markers of oligodendrocyte precursor cells) and neurite outgrowth inhibitor-A (a marker of developing oligodendrocytes), but lacked the expression of oligodendrocyte markers ectonucleotide pyrophosphatase/phosphodiesterase family member 6 and myelin basic protein. Notably, transcriptomes of dysembryoplastic neuroepithelial tumours were enriched in oligodendrocyte precursor cell signature, but not in signatures of neural stem cells, myelinating oligodendrocytes and astrocytes. Dysembryoplastic neuroepithelial tumour, myxoid glioneuronal tumour and rosette-forming glioneuronal tumour resemble oligodendrocyte precursor cells, and their enrichment of oligodendrocyte precursor cell phenotypes is closely associated with the recurrent mutations in rat sarcoma/mitogen-activated protein kinase pathway.

A Forgotten Entity following Breast Implant Contracture: Does Baker Need a Change?

Introduction: Breast augmentation is one of the most common operative procedures in Plastic and Reconstructive surgery. However, it is associated with different postoperative complications. Local inflammation around the implant is followed by loss of cellular activity, shrinkage and necrosis. In very rare cases, the ultimate step of the process is capsular contracture and calcification (CC). Here we present the clinical case of a female patient with capsular calcification. In this patient we performed different examinations and the surgical removal of the implant. Although CC is traditionally staged with the Baker classification system, there is smarted heterogeneity between the objective contracture severity and patients’ subjective symptoms. Considering our clinical case and the need for a more comprehensive classification, we present an upgrade of the traditional Baker classification. Materials and Methods: We performed ultrasonography, RX-array and magnetic resonance imaging. In addition we performed a core needle biopsy and the surgical removal of breast implants. After a deep analysis of the history and the etiopathogenesis of capsular calcification and considering the heterogeneity of patients’ clinical signs and symptoms, we upgraded the traditional Baker classification system. Results: The addition of “(A)” (without symptoms) and “(B)” (with symptoms) should be added to all stages of the classification. Both for classification purposes and to potentially match patients’ objective data to clinical and histological parameters. The addition of a grade V within the classification will allow surgeons to report any neoformations present within the capsular microenvironment and better predict patients’ outcomes. Conclusion: By analyzing the current histological and clinical classification systems for CC by Wilflingseder and Baker, we additionally provide a “symptomatic” modification of the traditional Baker stages. The introduction of a symptomatic classification with the addition of grade within the Baker classification will allow surgeons to better report the clinical presentation of patients with CC.

Update on lobular lesions of the breast.

The current histological classification of in-situ and invasive lobular carcinomas (ILCs) includes different morphological variants, some of which have been recently described. In this review, we will focus upon: (i) the diagnostic criteria of non-invasive lobular neoplasia and treatment implications across different countries; (ii) utility and limitations of immunohistochemistry; (iii) recently described variants of ILC; and (iv) the significance of lobular differentiation in invasive carcinoma for clinical management.

Systematic analysis of MCM3 in pediatric medulloblastoma via multi-omics analysis.

Minichromosome maintenance proteins are DNA-dependent ATPases that bind to replication origins and allow a single round of DNA replication. One member of this family, MCM3, is reportedly active in most cancers. To systematically elucidate the mechanisms affected by aberrant MCM3 expression and evaluate its clinical significance, we analyzed multi-omics data from the GEO database and validated them in cell lines and tumor samples. First, we showed the upregulation of MCM3 in medulloblastoma (MB) at bulk and single-cell RNA sequence levels and revealed the potential role of MCM3 via DNA replication. Then we found the dysregulation of MCM3 might result from abnormal methylation of MCM3. Moreover, we discovered that MCM3 might affect varied biological processes such as apoptosis, autophagy, and ferroptosis and that MCM3 was correlated with immune components such as fibroblast and neutrophils, which were associated with overall survival in different medulloblastoma subtypes. Furthermore, we found that MCM3 expression was correlated with the IC50 values of cisplatin and etoposide. The nomogram of MCM3-related genes showed the reliable and better prediction of 1- and 5-year survival compared to current histological and molecular classifications. Overall, the results of our study demonstrated that MCM3 might serve as a potential biomarker with clinical significance and better guidance than current histological and molecular classifications for clinical decision-making.

Karcinom endometrijuma - angiogeneza i osvrt na uloge vaskularnog endotelnog faktora rasta

Endometrial carcinomas (EC) represent the most common malignant tumors of the female reproductive system and the sixth most common in the female population with an increased incidence of morbidity and mortality over the past three decades. In addition to stage, grade and type of tumor, these are the most significant prognostic factors of the biological behavior of EC and in current clinical practice are based on pathohistological examination. The shortcomings of the current histological classification are cited as one of the key limiting factors in further research, as well as in the understanding of EC carcinogenesis and improving therapeutic protocols. A new molecular classification of EC was formulated, based on the analysis of molecular biological features, recognized as highly related to the specific clinical course. Considerable efforts have been made to understand the process of angiogenesis as one of the key processes in tumor growth. The vascular endothelial growth factor (VEGF) family is a group of proangiogenic ligands that play a central role in the process of physiological and pathological angiogenesis. This factor is the most widely investigated angiogenic one as a potential biomarker and target for targeted therapy. After vast research, clinical studies have shown significant advances in the development of anti-angiogenic therapy directed at VEGF, predominantly in the form of combined therapy. In defining therapeutic groups, this therapy relies on the molecular classification of EC. Antiangiogenic therapy is limited to small specific groups of patients, associated with side effects, and numeorus patients who initially responded to targeted therapy develop resistance over time, which indicates the further need for a better understanding of the mechanisms and factors involved in the angiogenic process of EC. Potentially promising advances in the development of targeted therapeutic options for EC can be expected within the integration of molecular features of EC as a factor in the context of histological classification.

TRIPLE NEGATIVE BREAST CANCER, EXPERIENCE OF MILITARY HOSPITAL RABAT: ABOUT 52 CASES

Objective: to review the epidemiological, clinical, anatomopathological, biological, therapeutic and prognostic characteristics of this histo-prognostic subgroup, namely triple-negative breast cancer Material and Method: Our work consists of a retrospective study carried out at the military hospital of instruction Med v rabat between January 2010 and December 2017 on 52 cases of invasive breast carcinoma with a triple negative phenotype. Result: From an epidemiological point of view: a peak in frequency was noted between 45 and 50 years old, and 48.1% of patients still in genital activity. On the anatomo-pathological level: invasive ductal carcinoma is the most predominant type representing 68.3% of cases with an average tumor size of 30mm. Histopronostic grades II and III each represent 43.2% and 56.8% of cases. Therapeutically: more than 42.3% received conservative treatment and 57.7% underwent radical surgery of the Pateytype.Adjuvant systemic chemotherapy was given in 86.5% of cases and 5.8% received neoadjuvant chemotherapy On the evolutionary level, 17.3% or 9 cases developed systemic metastases with predilection for the lungs. Conclusion: Despite advances in treatments and the emergence of targeted therapies, breast cancer remains the leading cause of death in women. Current clinical and histological classifications do not fully establish the prognostic and predictive parameters of response to treatment.

Establishing Novel Molecular Subtypes of Appendiceal Cancer.

Appendiceal cancer is a rare disease process with complex treatment strategies. The objective of this study was to identify mutation-based genetic subtypes that may differ from the current histological classification, compare the genetic make-up of primaries and metastases, and find novel targetable alterations. The analyses involved the curation and normalization of gene mutation panels from appendiceal adenocarcinoma and mucinous adenocarcinoma (n = 196) stored in the AACR GENIE Database v6.0. Genes mutated in less than one patient and tumors profiled with incomplete mutation panels were excluded from the study. The optimal number of AC subtypes was established using the Nonnegative Matrix Factorization algorithm. Statistical comparisons of mutation frequencies were performed using Pearson's χ2 test. AC patients were stratified into five mutation subtypes, based on a final set of 41 cancer-related genes. AC0 had no mutations. The most frequently mutated genes varied between the subtypes were: AC1: KRAS (91.9%) and GNAS (77.4%); AC2: KRAS (52.5%), APC (32.5%), and GNAS (30%); AC3: KMT2D (38.7%), TP53 (38.7%), KRAS (35.5%), EP300 (22.6%); and AC4: TP53 (97.2%), KRAS (77.8%), and SMAD4 (36.1%). Additionally, AC3 was less likely to be mucinous (22.6% vs. 50.0-74.2%, p < 0.001) and had a higher mutation frequency (3.6 vs. 0-3.1, p < 0.001). There were no significant differences between primary tumors and metastases in the 41 assessed genes (p = 0.35). The characterization of these subtypes suggests a need for molecular approaches to complement anatomical and histopathological staging for AC. A prospective comparison of subtype prognosis and response to surgery and adjuvant treatment is needed to identify the clinical applications of the novel molecular subtypes.

Ovarian Cancer and Cancer Stem Cells-Cellular and Molecular Characteristics, Signaling Pathways, and Usefulness as a Diagnostic Tool in Medicine and Oncology.

Simple SummaryOvarian cancer is still a high-risk, metastatic disease, often diagnosed at a late stage. Difficulties in its treatment are associated with high resistance to chemotherapy and recurrence. Responsible for the malignant features of cancer are considered to be cancer stem cells (CSCs), which generate new cells by modifying various signaling pathways. Signaling pathways are crucial for the regulation of epithelial-mesenchymal transition, metastasis, and self-renewal of CSCs. New therapies based on the use of inhibitors that block CSC growth and proliferation signals are being investigated. The current histological classification of ovarian tumors, their epidemiology, and the recent knowledge of ovarian CSCs, with particular emphasis on their molecular basis, are important considerations.Despite the increasing development of medicine, ovarian cancer is still a high-risk, metastatic disease that is often diagnosed at a late stage. In addition, difficulties in its treatment are associated with high resistance to chemotherapy and frequent relapse. Cancer stem cells (CSCs), recently attracting significant scientific interest, are considered to be responsible for the malignant features of tumors. CSCs, as the driving force behind tumor development, generate new cells by modifying different signaling pathways. Moreover, investigations on different types of tumors have shown that signaling pathways are key to epithelial-mesenchymal transition (EMT) regulation, metastasis, and self-renewal of CSCs. Based on these established issues, new therapies are being investigated based on the use of inhibitors to block CSC growth and proliferation signals. Many reports indicate that CSC markers play a key role in cancer metastasis, with hopes placed in their targeting to block this process and eliminate relapses. Current histological classification of ovarian tumors, their epidemiology, and the most recent knowledge of ovarian CSCs, with particular emphasis on their molecular background, are important aspects for consideration. Furthermore, the importance of signaling pathways involved in tumor growth, development, and metastasis, is also presented.

Thymic carcinoma in a 2-year-old child: case description and literature review

Thymic carcinoma (TC) belongs to a group of rare thymic epithelial tumours (TETs) arising from the anterior mediastinum. One of the most relevant established prognostic factors is complete surgical resection. Given the high invasive potential of TC a lot of patents at the diagnosis present with a locally advanced or metastatic disease, therefore complete resection could not be achieved, and a role of systemic therapy is increasing. Due to the rarity of this tumor type in children and adolescents, treatment approaches based on the guidelines for management of TETs in adults. In this article we report a case of TC in a 2-year-old boy. The literature review describes the current histological classification of the TET, approaches for systemic chemotherapy and local control in patients with TC.

Multivariate analysis reveals differentially expressed genes among distinct subtypes of diffuse astrocytic gliomas: diagnostic implications

Diagnosis and classification of gliomas mostly relies on histopathology and a few genetic markers. Here we interrogated microarray gene expression profiles (GEP) of 268 diffuse astrocytic gliomas—33 diffuse astrocytomas (DA), 52 anaplastic astrocytomas (AA) and 183 primary glioblastoma (GBM)—based on multivariate analysis, to identify discriminatory GEP that might support precise histopathological tumor stratification, particularly among inconclusive cases with II–III grade diagnosed, which have different prognosis and treatment strategies. Microarrays based GEP was analyzed on 155 diffuse astrocytic gliomas (discovery cohort) and validated in another 113 tumors (validation set) via sequential univariate analysis (pairwise comparison) for discriminatory gene selection, followed by nonnegative matrix factorization and canonical biplot for identification of discriminatory GEP among the distinct histological tumor subtypes. GEP data analysis identified a set of 27 genes capable of differentiating among distinct subtypes of gliomas that might support current histological classification. DA + AA showed similar molecular profiles with only a few discriminatory genes overexpressed (FSTL5 and SFRP2) and underexpressed (XIST, TOP2A and SHOX2) in DA vs AA and GBM. Compared to DA + AA, GBM displayed underexpression of ETNPPL, SH3GL2, GABRG2, SPX, DPP10, GABRB2 and CNTN3 and overexpression of CHI3L1, IGFBP3, COL1A1 and VEGFA, among other differentially expressed genes.

Establishing novel mutation subtypes in peritoneal carcinomatosis of appendiceal origin.

200 Background: Appendiceal cancer (AC) is a rare disease process with complex treatment strategies. The objective of this study was to identify mutation-based genetic subtypes that may differ from the current histological classification, compare genetic make-up of primaries and metastases, and to find novel targetable alterations. Methods: The analysis involved the curation and normalization of mutation panels from adenocarcinoma and mucinous adenocarcinoma (n = 196) stored in the AACR GENIE Database v6.0. Genes mutated in less than two patients and tumors profiled with incomplete mutation panels were excluded from the study. The optimal number of AC subtypes was established using the Non-negative Matrix Factorization algorithm. Statistical comparisons of mutation frequencies were performed by using the Pearson’s χ2 test. Results: AC patients were stratified into five mutation subtypes. AC0 had no mutations in the 41 genes in the study. The most frequently mutated genes varied between the subtypes. AC1: KRAS (91.9%) and GNAS (77.4%); AC2: KRAS (52.5%), APC (32.5%), and GNAS (30%); AC3: KMT2D (38.7%), TP53 (38.7%), KRAS (35.5%), EP300 (22.6%); and AC4: TP53 (97.2%), KRAS (77.8%), and SMAD4 (36.1%). Additionally, AC3 was less likely to be mucinous (22.6% v 50.0-74.2%, p &lt; 0.001) and had a higher mutation frequency (3.6 v 0-3.1, p &lt; 0.001). There were no differences between primaries and metastases (p = 0.35). Conclusions: Characterization of these subtypes suggest a need for molecular rather than anatomic staging for AC. Histone regulation by KMT2D and EP300 may be considered for targeted therapy for patients with AC3. A prospective comparison of subtype prognosis and response to surgery and adjuvant treatment is needed.

PAS stain based histological classification and severity grading of toenail onychomycosis.

Onychomycosis is a common world-wide health issue. Accurate detection is essential for treatment. Multiple studies have shown that PAS-stain based histological visualization of fungal elements is superior to either direct microscopy with 20% potassium hydroxide, or fungal culture. However, PAS stain based histological classification and severity grading of onychomycosis are lacking in the literature. Here we reported a fungal detection rate of 47.87% based on an analysis of 13,805 toenails processed for H&E and PAS stains over a three year period. Based on the analysis of fungal density, distribution and infiltrating depth level in 858 PAS-positive toenails, we created a novel PAS stain based histological classification system to classify onychomycosis as occult onychomycosis (OO), focal or diffuse subungual onychomycosis (FSO or DSO), focal or diffuse plate onychomycosis (FPO or DPO), focal or diffuse subungual and plate onychomycosis (FSPO or DSPO) and superficial onychomycosis (SO). The severities of OO, FSO and FPO were graded as mild, DSO and DPO as moderate, FSPO and DSPO as severe infections, which revealed that more than 75% PAS positive toenails were severe infections. Evaluation of 97 paired toenails biopsied pre- and post-treatment from 47 patients demonstrated that the severity of infection was significantly reduced from severe to mild and moderate levels. These data indicate that the current histological classification evaluates not only the severity of the fungal infection but also the response to treatment. We further propose a guideline for treatment of onychomycosis based on the histological classification and severity.

Novel immunological and clinical insights in vascularized composite allotransplantation.

Vascularized composite allotransplantation (VCA) is a promising approach to restore the quality of life of carefully selected patients that suffered extensive injury. Although acute rejection occurs very frequently, still little is known about the specific characteristics of the VCA immune response. This review aims to highlight the current development in the field of VCA concerning the immunobiology and management of upper extremity and face transplant recipients. T-cell mediated rejection is the predominant mechanism of allograft injury in VCA. As current histological classification does not differentiate types of rejection, novel evidence using NanoString has determined a molecular signature that helps identify antibody-mediated rejection in comparison to T-cell mediated rejection. Additionally, long-term follow-up of VCA patients progressively reveals various features of chronic rejection, and novel immunosuppressive approaches such as costimulation blockade found its way into immunosuppressive regimens of VCA recipients, unraveling its potential benefits as well as limitations. Finally, novel noninvasive biomarkers were recently evaluated and showed promise to differentiate the severity of acute rejection, and consequently, the intensity of treatment required. With growing knowledge about the immunobiology in VCA, novel approaches to immunosuppressive therapy and immune monitoring will help better manage patients and improve long-term VCA outcomes.

Computational development of a molecular-based approach to improve risk stratification of endometrial cancer patients.

Histological classification and staging are the gold standard for the prognosis of endometrial cancer (EC). However, in morphologically intermediate and doubtful cases this approach results largely insufficient, defining the need for better classification criteria.In this work we developed an algorithm that based on EC genetic alterations and in combination with the current histological classification, improves EC patients prognostic stratification, in particular in doubtful cases. A panel of 26 cancer related genes was analyzed in 89 EC patients and somatic functional mutations were investigated in association with different histology and outcome.An unsupervised hierarchical clustering analysis revealed that two groups of patients with different tumor grade and different prognosis can be distinguished by mutational profile. In particular, the mutational status of APC, CTNNB1, PIK3CA, PTEN, SMAD4 and TP53 resulted to be principal drivers of prognostic clustering. Consistently, a decisional tree generated by a data mining approach summarizes the consequential molecular criteria for patients prognostic stratification.The model proposed by this work provides the clinician with a tool able to support the prognosis of EC patients and consequently drives the choice of the most appropriated therapeutic strategy and follow up.

The prognostic significance of ATRX in pulmonary carcinoid tumors.

e20543 Background: Loss of ATRX, a transcriptional regulator, has been associated with reduced survival in patients with pancreatic neuroendocrine tumors. We aimed to evaluate the prognostic role of ATRX in patients with pulmonary carcinoid tumors in addition to the histological classification. Methods: Resected pulmonary carcinoid tumors and clinical information from 1995 to 2017 were retrospectively identified and recorded. ATRX expression by immunohistochemistry was recorded as percentage of tumor nuclei staining by two pathologists independently. Logistic regression and receiver operating characteristic curve (ROC) were used to establish the cutoff for ATRX expression. Kaplan-Meier method and Cox proportional hazards model were used for survival analysis. Results: 120 patients (38% male) with median age of 59.7 years (range, 14.8-87) were included. The median follow-up was 4.2 years. 52 (43%) patients had atypical carcinoid; 68 (57%) patients had typical carcinoid. 74 (62%) tumors had < 2 mitoses per 10 high-power field. 15 (12%) tumors had necrosis. Loss of ATRX nuclear expression was defined as less than 7.5%, a cutoff identified from ROC curves with area under the curve (AUC) of 0.61. Loss of ATRX nuclear expression was independently associated with atypical pulmonary carcinoid tumor with odds ratio 8.6 (95% CI: 3.0-29, p = 0.0002), after adjusting for lymphovascular invasion and perineural invasion. Although histological classification (atypical vs. typical histology) remains to be the best prognostic predictor for the survival of patients with pulmonary carcinoid tumors, loss of ATRX nuclear expression was also independently associated with shorter disease specific overall survival with hazard ratio 8.6 (95% CI 1.6-46, p = 0.01), after adjusting for tumor necrosis, lymphovascular invasion, and the presence of metastatic disease at diagnosis. Conclusions: Loss of ATRX nuclear expression has significant diagnostic and predictive roles in patients with pulmonary carcinoid tumors in addition to the current histological classification. Further studies on the function of ATRX in the pathogenesis of pulmonary carcinoid tumors and larger outcome studies are needed.

Gastric Cancer: Recent Molecular Classification Advances, Racial Disparity, and Management Implications.

Gastric adenocarcinoma remains an aggressive and poorly understood malignancy with a heterogeneous presentation and tumor biology. The current histologic and anatomic classification has been ineffective in guiding therapy, with only marginal improvement in outcome over time. Furthermore, the variation in presentation and disease among racial and ethnic groups amplifies the complexity of this cancer. An understanding of the clinical and molecular variability is important for effective treatment. Recent advances in molecular biology have better defined gastric cancer subtypes. We systematically review recent literature on the molecular classification of gastric adenocarcinoma and the associated management implications, with an emphasis on Hispanic and Native American populations.

Rhabdomyosarcoma in children - current pathologic and molecular classification.

The last 25 years have brought significant progress in the treatment of sarcomas in children, especially rhabdomyosarcoma (RMS). Nevertheless, treatment failure in some patients results from considerable biological heterogeneity noted in these tumours. RMS, the most common malignant soft tissue neoplasm in children, includes two main subtypes: embryonal (ERMS) and alveolar (ARMS). Due to greater aggressiveness and worse prognosis of ARMS in comparison to ERMS, discrimination between different rhabdomyosarcoma subtypes is of crucial clinical importance. This paper presents the current histological classification of RMS, up-to-date immunohistochemical and biological research regarding RMS, and its associated clinical and prognostic significance.

Updated Histologic Classification of Adenomas and Carcinomas in the Colon of Carcinogen-treated Sprague-Dawley Rats.

Recent studies have disclosed novel histological phenotypes of colon tumours in carcinogen-treated rats. The aim of this study was to update the current histological classification of colonic neoplasias in Sprague-Dawley (SD) rats. Archival sections from 398 SD rats having 408 neoplasias in previous experiments were re-evaluated. Of the 408 colonic neoplasias, 11% (44/408) were adenomas without invasive growth and 89% (364/408) invasive carcinomas. Out of the 44 adenomas, 82% were conventional (tubular or villous), 14% traditional serrated (TSA; with unlocked serrations or with closed microtubules) and 5% gut-associated lymphoid tissue (GALT)-associated adenomas. Out of 364 carcinomas, 57% were conventional carcinomas, 26% GALT carcinomas, 8% undifferentiated, 6% signet-ring cell carcinomas, and 4% traditional serrated carcinomas (TSC). Thus, conventional adenomas, conventional carcinomas and GALT-associated carcinomas predominated (p<0.05). The updated classification of colonic tumours in SD rats includes conventional adenomas, TSA, GALT-associated adenomas, conventional carcinomas, TSC, GALT-associated carcinomas, signet-ring cell carcinomas and undifferentiated carcinomas. Several of the histological phenotypes reported here are not included in any of the current classifications of colonic tumours in rodents. This updated classification fulfils the requirements for an animal model of human disease, inasmuch as similar histological phenotypes of colon neoplasias have been documented in humans.

Comprehensive molecular characterisation of epilepsy-associated glioneuronal tumours

Glioneuronal tumours are an important cause of treatment-resistant epilepsy. Subtypes of tumour are often poorly discriminated by histological features and may be difficult to diagnose due to a lack of robust diagnostic tools. This is illustrated by marked variability in the reported frequencies across different epilepsy surgical series. To address this, we used DNA methylation arrays and RNA sequencing to assay the methylation and expression profiles within a large cohort of glioneuronal tumours. By adopting a class discovery approach, we were able to identify two distinct groups of glioneuronal tumour, which only partially corresponded to the existing histological classification. Furthermore, by additional molecular analyses, we were able to identify pathogenic mutations in BRAF and FGFR1, specific to each group, in a high proportion of cases. Finally, by interrogating our expression data, we were able to show that each molecular group possessed expression phenotypes suggesting different cellular differentiation: astrocytic in one group and oligodendroglial in the second. Informed by this, we were able to identify CCND1, CSPG4, and PDGFRA as immunohistochemical targets which could distinguish between molecular groups. Our data suggest that the current histological classification of glioneuronal tumours does not adequately represent their underlying biology. Instead, we show that there are two molecular groups within glioneuronal tumours. The first of these displays astrocytic differentiation and is driven by BRAF mutations, while the second displays oligodendroglial differentiation and is driven by FGFR1 mutations.