Low-grade Areas Research Articles

EPCO-04. SPATIAL TRANSCRIPTOMIC ANALYSIS OF MALIGNANT PERIPHERAL NERVE SHEATH TUMORS REVEALS THERAPEUTICALLY TARGETABLE MOLECULAR SIGNATURES IN REGIONS UNDERGOING HISTOPATHOLOGIC TRANSFORMATION

Abstract Malignant peripheral nerve sheath tumors (MPNSTs) evolve from plexiform neurofibromas (pNF) in patients with neurofibromatosis type-1 (NF-1) yet the cellular and transcriptomic mechanisms underlying this transformation remain unclear. Here, we perform spatial gene expression profiling on fifteen MPNSTs to correlate histologic observations with transcriptomic programs and identify mechanisms underlying malignant transformation. METHODS: Fifteen MPNSTs, including tumors with a histopathologically defined transition zone between adjacent low-grade and high-grade areas (n=3), were retrospectively identified. Spatial transcriptomic profiling was performed using Visium followed by downstream processing with SpaceRanger, Seurat, Harmony, and monocle. RESULTS: 50,807 unique spatial transcriptomes were distributed across 17 unique clusters, of which 12 were enriched for tumor cells and 5 for non-tumor microenvironment cells based on histologic evaluation, unsupervised cell-type assignment, marker gene expression, and cell signature gene sets. Transcriptomic clusters in low-grade areas were enriched for genes regulating mononuclear cell migration and cell-cell adhesion, while high-grade regions were enriched for Ras/Raf/MEK/ERK target genes, anti-apoptotic programs, and extracellular matrix reorganization genes. Trajectory inference beginning in low grade regions revealed spatially organized molecular signatures of malignant transformation enriched for cell cycle progression within histopathologically homogeneous regions. Moreover, the intermediate transformation zone between low-grade neurofibromatous and high-grade MPNST histopathologic regions was marked by loss of cell differentiation genes and increased cell cycle progression. CONCLUSIONS: Spatial transcriptomic analysis elucidates the cellular and gene expression patterns underlying progression from pNF to MPNST. Distinct cell populations exist across low-grade, transformation zone, and high-grade regions in MPNSTs highlighted by alterations in Ras/Raf/MEK/ERK signaling, cell differentiation and cell cycle programs, shedding light on targets for combinatorial molecular therapy to decrease the risk of malignant transformation and serving as a biomarker of aggressive peripheral nerve tumors to complement conventional histopathology.

Biphenotypic Sinonasal Sarcoma With High-Grade Features: A Diagnostic Challenge.

Biphenotypic sinonasal sarcoma (BSNS) is a rare neoplasm of the sinonasal tract. These tumors show neural and myogenic differentiation and are characterized by PAX3 translocations. The immunophenotypic features reflect their dual differentiation. They are low-grade sarcomas that show monomorphic spindle cells in sheets, fascicles, and herringbone patterns and are positive for S100 and smooth muscle actin. These tumors are common in elderly female patients and have a locally aggressive course. High-grade presentation or transformation was not documented until recently. Total 3 BSNSs have now been documented in the literature and we report a fourth tumor with high-grade transformation 8 years after the initial presentation. We identify the morphologic and immunohistochemical features of the high-grade areas and we highlight the stark differences with the low-grade areas based on literature and our specimen. We also discuss the diagnostic challenges that may come up with such a presentation.

High Grade Appendiceal Mucinous Neoplasm Presenting as Intussusception In an Elderly Female-A Case Report

Introduction: Appendiceal mucinous neoplasms (AMNs) are rare and account for 1% of gastrointestinal neoplasms and the diagnosis is mostly incidental. In spite of advances in the understanding of AMNs and their association with peritoneal disease, AMNs are still confusing entities in respect to their diagnosis and treatment alike.
 Case Report: We report a case of a 51year old female who presented with abdominal pain and vomiting and was diagnosed as ileo-colic intussusception on ultrasonography and CECT abdomen. Histopathological examination of right hemicolectomy specimen revealed a high grade appendicular mucinous neoplasm with low grade areas. The peri-appendiceal mucin deposition forming a mass in the cecum at the base of appendix was the lead point for intussusception in this case. No features of pseudomyxoma peritonei was seen in this case. This patient is well after 18 months of follow up period.
 Conclusion: Appendiceal mucinous neoplasms are rare and diagnosis is often difficult as presentation is mostly non-specific. Hence, awareness and further classification of these tumours is essential for diagnosis, determining the risk of recurrence and malignancy and also prognostication.

Mucoepidermoid carcinoma may be devoid of squamoid cells by immunohistochemistry: expanding the histologic and immunohistochemical spectrum of MAML2- rearranged salivary gland tumours.

Mucoepidermoid carcinoma (MEC) is historically defined by a mix of squamoid, intermediate, and mucous cells, but we have recently encountered several cases lacking immunoreactivity for squamous markers p40, p63, and CK5/6 despite MAML2 fusions. This study will characterise these unique tumours. Ten MEC were collected arising from the parotid gland (n=4), submandibular gland (n=2), nasopharynx (n=1), base of tongue (n=1), bronchus (n=1), and trachea (n=1). Six tumours were low-grade, two intermediate-grade, one high-grade, and one demonstrated low-grade areas with high-grade transformation. Four cases were oncocytic, four had clear-cell features, two had spindle cell features, and one high-grade MEC had prominent solid, cord-like, and micropapillary features. The tumours were negative for p40 (10/10), p63 (10/10), and CK5/6 (9/9). Targeted RNA sequencing demonstrated CRTC1::MAML2 in five cases, CRTC3::MAML2 in two, and a novel MAML2::CEP126 in the unusual high-grade case. In two cases with insufficient RNA, MAML2 fluorescence insitu hybridisation (FISH) showed rearrangement. Genetically-confirmed MEC may lack overt squamous differentiation by histology and immunohistochemistry. While most cases harboured canonical fusions and fit within the spectra of MEC variants with oncocytic, clear cell, and/or spindle cell features, one had a novel MAML2::CEP126 fusion and unusual morphology. In MEC without squamoid cells, the use of immunohistochemistry may hinder, rather than aid, the correct diagnosis. In such cases, MAML2 analysis is most useful. The historical definition of MEC as a carcinoma with squamoid, intermediate and mucous cells should be revisited.

Evidence of neural crest cell origin of a DICER1 mutant CNS sarcoma in a child with DICER1 syndrome and NRAS-mutant neurocutaneous melanosis.

Evidence of neural crest cell origin of a DICER1 mutant CNS sarcoma in a child with DICER1 syndrome and NRAS-mutant neurocutaneous melanosis.

Molecular and clinicopathological analysis revealed an immuno-checkpoint inhibitor as a potential therapeutic target in a subset of high-grade myxofibrosarcoma.

This study aimed to identify differences in genetic alterations between low- and high-grade lesions in myxofibrosarcoma (MFS) and to examine the efficacy of immune checkpoint inhibitors in 45 patients with MFS. First, genetic differences between low- and high-grade components within the same tumor were analyzed in 11 cases using next-generation sequencing. Based on the obtained data, Sanger sequencing was performed for TP53 mutations in the remaining 34 patients. Loss of heterozygosity (LOH) analysis was performed at the TP53 and RB1 loci. Immunohistochemistry was performed for FGFR3, KIT, MET, programmed death receptor ligand 1 (PD-L1), CD8, FOXP3, and mismatch repair proteins. The microsatellite instability status was also evaluated in all cases. TP53 deleterious mutations and LOH at TP53 and RB1 loci were detected significantly more frequently in high-grade than in low-grade MFS (P = 0.0423, 0.0455, and 0.0455, respectively). LOH at the RB1 locus was significantly associated with shorter recurrence-free survival in both univariate and multivariate analyses. TP53 alterations, such as mutation and LOH, were more frequently observed in low-grade areas within high-grade MFS than in pure low-grade MFS. The positive PD-L1 expression rate was 35.6% (16/45), and all these 16 cases were high-grade. A high density of both CD8+ and FOXP3+ tumor-infiltrating lymphocytes was associated with PD-L1 positivity. LOH at the RB1 locus was identified an independent adverse prognostic factor for recurrence-free survival in patients with MFS. Immune checkpoint inhibitors may be a therapeutic option for a subset of high-grade MFS.

Histopathological features for coexistent invasive cancer in large colorectal adenomatous polyps.

BackgroundHistopathological features associated with coexistent invasive adenocarcinoma in large colorectal adenomas have not been described. This study aimed to determine the association of histopathological features in areas of low-grade dysplasia with coexistent invasive adenocarcinoma.MethodsHigh-grade lesions (containing high-grade dysplasia or adenocarcinoma) from a cohort of large (at least 20 mm) colorectal adenomas removed by endoscopic resection were subjected to detailed histopathological analysis. The histopathological features in low-grade areas with coexistent adenocarcinoma were reviewed and their diagnostic performance was evaluated.ResultsSeventy-four high-grade lesions from 401 endoscopic resections of large adenomas were included. In the low-grade dysplastic areas, a coexistent invasive adenocarcinoma was associated significantly with a cribriform or trabecular growth pattern (P < 0.001), high nuclear grade (P < 0.001), multifocal intraluminal necrosis (P < 0.001), atypical mitotic figures (P = 0.006), infiltrative lesion edges (P < 0.001), a broad fibrous band (P = 0.001), ulceration (P < 0.001), expansile nodules (P < 0.001) and an extensive tumour-infiltrating lymphocyte pattern (P = 0.04). Lesions with coexistent invasive adenocarcinoma harboured at least one of these features. The area under the receiver operating characteristic curve (AUROC) for coexistent invasive adenocarcinoma, using frequencies of adverse histopathological factors in low-grade areas, was 0.92. The presence of two or more of these adverse histopathological features in low-grade areas had a sensitivity of 86 per cent and a specificity of 84 per cent for coexistent invasive adenocarcinoma.ConclusionSeveral histopathological features in low-grade dysplastic areas of adenomas could be predictive of coexistent adenocarcinoma.

A Rare Case of Dedifferentiated Solitary Fibrous Tumor

Abstract Casestudy: Dedifferentiated solitary fibrous tumor is a rare malignant subtype of the common benign mesenchymal neoplasm with fibroblastic differentiation known as solitary fibrous tumor (SFT). These account for less than 2% of all soft masses; and about 20% of SFTs turn aggressive. They feature bland spindle cells creating a classic “pattern-less pattern” in collagenous stroma with prominent staghorn vessels. They can dedifferentiate into a biphasic tumor with low grade areas that are spindle cell rich and high-grade areas with epithelioid cells, mitotic figures and necrosis. Here we present an 84-year-old female who came from an outside institution for a pathology review. The patient’s clinical history was lacking and biopsies from the right lower and middle lobes of the lung, azygous and hilar lymph nodes were investigated. The pathology revealed multiple areas with epithelioid cells that were pleomorphic and had high nuclear to cytoplasmic ratio. These areas also contained numerous mitotic figures, necrosis and giant cells; with lymphovascular space invasion. There was a clear demarcation between the epithelioid area and an area rich in spindle cells. The spindled areas revealed a fascicular architecture with intervening sclerotic stoma and prominent rounded and dilated blood vessels. Immunohistochemistry analysis of the epithelioid and spindle cell areas were positive for STAT6. Additional testing for CD34 was diffusely positive in the spindle cell component and only focally positive in the high-grade portion of the tumor. Ki-67stain was utilized to estimate the proliferative index which was up to 80 percent in the high-grade epithelioid component and about 15% in the spindle cell portion. These morphological and histochemical findings were consistent with the diagnosis of a dedifferentiated solitary fibrous tumor.

Molecular and clinicopathological features of appendiceal mucinous neoplasms

Appendiceal mucinous tumors (AMTs) include low-grade mucinous appendiceal neoplasms (LAMNs), high-grade mucinous appendiceal neoplasms (HAMNs), and mucinous adenocarcinomas (MACs). We collected 51 AMT samples (LAMN: 34, HAMN: 8, MAC: 9). Three of the eight HAMN cases contained LAMN components, and four out of nine MAC cases contained LAMN and/or HAMN components within the tumor. A next-generation sequencing (NGS) cancer hotspot panel was used to analyze 11 pure LAMN, 4 HAMN, and 3 MAC cases. The results revealed KRAS and GNAS as the most frequently mutated genes. Sanger sequencing was then performed to detect KRAS, GNAS, and TP53 mutations in the remaining 31 cases and RNF43 mutations in all cases. KRAS/GNAS and TP53 mutations occurred exclusively in pure LAMNs; however, five LAMN cases had mutations in both KRAS and GNAS. RNF43 mutations almost exclusively occurred with KRAS/GNAS mutations in pure LAMNs. In MAC and HAMN, KRAS/GNAS mutation status was nearly preserved between lower-grade areas. Most of the detected RNF43 mutations was missense type. RNF43 mutations were detected in both components of MAC with lower-grade area; however, RNF43 mutations detected in these two lesions were entirely different. RNF43 mutations were detected in only one of the eight HAMN patients, which was the sole case without pseudomyxoma peritonei (PMP). None of the four MAC patients with RNF43 mutation showed PMP. These findings suggest that RNF43 mutations occur at a later stage of MAC development and do not associate with PMP. Furthermore, a gradual transition from LAMN to MAC via HAMN could be considered.

Su1070 – Morphological and Molecular Risk Markers for Coexistent Adenocarcinoma in Low-Grade Dysplastic Areas of Highgrade Colorectal Adenomas

Su1070 – Morphological and Molecular Risk Markers for Coexistent Adenocarcinoma in Low-Grade Dysplastic Areas of Highgrade Colorectal Adenomas

Melt Reintegration Modelling: Testing against a Subsolidus Reference Assemblage

Phase equilibria modelling incorporating melt reintegration offers a methodology to create hypothetical rock compositions that may have existed prior to melt loss, allowing the potential prograde evolution of rocks to be explored. However, melt reintegration modelling relies on assumptions concerning the volume of melt that was lost and is generally restricted by the absence of direct constraints on the pre-anatectic mineral assemblages. Mg-rich granulite in the 514–490 Ma Delamerian Orogen in southern Australia contains spinel–cordierite symplectic intergrowths that surround rare, coarse blocky domains of sillimanite. These sillimanite cores, as well as the widespread presence of andalusite in lower grade areas of the southern Delamerian Orogen, suggest that the subsolidus precursor to the granulite contained andalusite. This provides the opportunity to test if melt reintegration modelling of the granulite predicts subsolidus andalusite. Stepwise down-temperature melt reintegration modelling produces a water-saturated solidus after the addition of 12 mol% melt. When modelled at subsolidus conditions, the resulting rock composition produces andalusite-bearing assemblages with andalusite modes similar to the abundance of the sillimanite-cored spinel–cordierite intergrowths. The modelling results from this case study suggest that melt reintegration modelling is a valid method to recreate prograde subsolidus bulk rock compositions.

BRM/SMARCA2-negative clear cell renal cell carcinoma is associated with a high percentage of BRM somatic mutations, deletions and promoter methylation.

The aim of this study was to investigate potential molecular mechanisms associated with loss of BRM expression in poorly differentiated clear cell renal cell carcinoma (ccRCC). Nineteen previously selected BRM-negative RCC tissues were examined by DNA sequencing, fluorescence in-situ hybridization (FISH) and methylation-specific polymerase chain reaction (PCR) of the BRM gene. BRM mutation was identified in 78.9% (15 of 19) cases, chromosome 9 monosomy or BRM deletion in 43.8% (seven of 16) and BRM promoter region cytosine-phosphate-guanine (CpG) methylation in 42.8% (six of 14). These results indicated that 89.5% (17 of 19) of the cases harboured at least one type of BRM genetic alteration, with two or more types of alteration in 47.4% (nine of 19). Such alterations were found rarely in adjacent non-neoplastic tissues and low-grade areas of composite tumours. BRM gene mutation, chromosome 9 monosomy or BRM deletion and CpG methylation contribute collectively to the loss of BRM expression in ccRCC. This work focusing on composite tumours indicated that BRM abnormality occurred during tumour progression.

Expression of p53 & epidermal growth factor receptor in glioblastoma.

Background & objectives:Glioblastoma (GB) is the most frequent brain tumour, manifesting at any age, with a peak incidence between 45 and 75 years. Primary and secondary GBs constitute relatively distinct disease entities in evolution, in expression profiles and in therapeutic response. Histopathologically, primary and secondary GBs are indistinguishable. The aim of this investigation was to study the immunohistochemical (IHC) expression of p53 and epidermal growth factor receptor (EGFR) in GB with the objective of categorizing the morphological variants of GB into primary and secondary based on the presence of low-grade areas and knowing the variable expression of p53 and EGFR in primary and secondary GB.Methods:A total of 28 patients with GB were studied and categorized into primary and secondary based on the presence of low-grade areas, i.e. discernible astrocytic morphology, gemistocyte and oligodendroglia. Tumours with the presence of combination of the above features or any one of the above features were taken as secondary GB, whereas tumours with highly pleomorphic areas were considered as primary GB. IHC was done on the representative tissue blocks for p53 and EGFR.Results:Majority of the patients were in the fifth and sixth decades of life with a mean age of 46.96±13 yr with male preponderance (male:female 2.5:1). Mean age of presentation was 48.93±12 yr in primary and 44.69±15 yr in secondary GB. All cases of GB were classified into primary (53.57%) and secondary (46.43%) based on morphology. EGFR was more frequently expressed than p53. Based on IHC, 50 per cent of cases were classified into primary, three per cent into secondary and 47 per cent as unclassified.Interpretation & conclusions:Histopathological features, i.e. presence of low-grade areas, may play a role in classifying GB into primary and secondary. EGFR has a pivotal role in gliomagenesis. Combination of p53 and EGFR alone may not be sufficient to clarify GB into primary and secondary.

Tumor budding at the invasive front of colorectal cancer may not be associated with the epithelial-mesenchymal transition

Tumor budding is thought to reflect the epithelial-mesenchymal transition (EMT). However, the molecular mechanism linking tumor buds and the EMT remains unclear. Here, we examined the induction of tumor budding and EMT and their association with EMT-related proteins (ZEB1, TWIST, SNAIL, and SLUG) in colorectal cancer (CRC). Immunohistochemical expression of pan-cytokeratin was examined for identification of tumor budding in 101 CRCs. Grading of tumor budding was classified into low- and high-grade groups. Tissue microarray was conducted to identify tumor budding sites. The expression of E-cadherin, ZEB1, TWIST, SNAIL, and SLUG was examined in areas of tumor budding and the surrounding tumor stroma using a double-immunostaining method. Specifically, pan-cytokeratin and EMT-related proteins were assessed by double immunostaining. Low or no expression of E-cadherin was found in areas of tumor budding. Moreover, ZEB1, TWIST, SNAIL, and SLUG were not expressed in regions of tumor budding. However, the expression level of ZEB1 in the stromal cells surrounding tumor budding was significantly more frequent than that of TWIST, SNAI, and SLUG. In addition, the expression of EMT-related proteins in surrounding stromal cells was significantly greater in areas of high-grade tumor budding than in low-grade areas. Our present results suggest that EMT-related proteins play a minor role in forming tumor buds. In addition, our findings suggest the existence of subtypes of stromal cells in CRC with phenotypical and functional heterogeneity.

Analysis of papillary urothelial carcinomas of the bladder with grade heterogeneity: supportive evidence for an early role of CDKN2A deletions in the FGFR3 pathway.

The dual pathway model of urothelial carcinogenesis does not fully explain grade and stage progression in patients with initial low-grade, non-muscle invasive urothelial carcinomas. Fibroblast growth factor receptor 3 (FGFR3) mutations are a hallmark of the low-grade pathway, with subsequent progression to muscle invasion occurring when FGFR3 mutant tumours exhibit a homozygous CDKN2A deletion. We hypothesized that grade heterogeneity represents the morphological manifestation of molecular changes associated with disease progression. We identified retrospectively 29 non-muscle invasive papillary urothelial carcinomas with grade heterogeneity (<20% high grade). Nineteen had sufficient material for immunohistochemistry, CDKN2A fluorescence in-situ hybridization and FGFR3 mutation analysis. Eight pure low-grade urothelial carcinomas (PLGUC) were also analysed. FGFR3 mutation was seen in 10 of 19 cases. A homozygous CDKN2A deletion was identified in the low-grade areas of eight of nine (88%) technically suitable FGFR3 mutant cases (including five pTa cancers), in five of nine FGFR3 wild-type carcinomas and in none of the PLGUC. Increased MIB-1 expression was seen in low-grade areas of 12 of 19, in high-grade areas of 17 of 19 cases with grade heterogeneity and in none of the PLGUC. p53 staining was increased in one of 19 low-grade and seven of 19 high-grade areas. Our findings show that grade heterogeneity in urothelial carcinoma is characterized by increased MIB-1 labelling, and particularly in the FGFR3 mutant pathway, with homozygous deletions of CDKN2A in low- and high-grade areas. This would suggest that CDKN2A deletion occurs prior to grade progression and supports the current convention to assign the highest grade to urothelial carcinomas with grade heterogeneity.

Concurrent TERT promoter and BRAF V600E mutation in epithelioid glioblastoma and concomitant low‐grade astrocytoma

Epithelioid glioblastoma (E-GBM) is a rare variant of glioblastoma (GBM), characterized by epithelioid cells with eosinophilic round cytoplasm devoid of stellate cytoplasmic processes. A number of studies have demonstrated that more than half of E-GBMs harbor a valine to glutamic acid substitution at position 600 of the serine/threonine-protein kinase BRAF (BRAF V600E). However, there are no previous reports on E-GBM with telomerase reverse transcriptase (TERT) promoter mutation in addition to BRAF V600E mutation. Here, we report an E-GBM case in an 18-year-old man with BRAF V600E and TERT promoter mutations. The tumor composed of 80% E-GBM and 20% diffuse astrocytoma-like components, and BRAF V600E and TERT promoter mutations were detected in both. E-GBM generally arises as a primary lesion; however, a few previous cases have been demonstrated to accompany low-grade areas. Demonstration of concurrent BRAF V600E and TERT promoter mutations in low- and high-grade lesions strongly suggested their identical origin, and acquisition of each mutation may be an early event, possibly playing a pivotal role in the genesis and subsequent progression to E-GBM.

영남지역의 토지피복에 따른 열쾌적성평가도 구축

The purpose of this study is to analyze the thermal comfort in Yeongnam area using climatic data and GIS data in order to determine regions necessary to improve thermal environment policies. The results of the calculated PET show that Daegu city is high and Bonghwa-gun is low compared to other regions. PET was compared with the typical classification according to regional characteristics. As a result, PET value of rural areas such as Changnyeong-gun, Haman-gun and Goryeong-gun was high but Green space was too low compared to other rural areas. Yeongnam area was classified according to the value of PET using cluster analysis. As a result, more low grade areas show that green space ratio was low and facility area was high. It is determined that there is a relationship between thermal comfort and land cover. The thermal comfort evaluation map in Yeongnam area will be useful for urban planning in order to establish a sustainable city in climate change.

Chemical composition of Late Svecofennian granite in the Bothnian Basin, central Sweden

Late Svecofennian granite is frequent in the Bothnian Basin, especially in zones of rapidly changing metamorphic grade but also in areas, where the metamorphic grade is elevated. The granite is essentially undeformed, but weakly foliated or lineated rocks are common; more rarely are rocks strongly foliated. X-ray fluorescence was used for major-element and ICP-MS for trace-element analyses. The chemical composition is almost invariably peraluminous, calc-alkaline and strict granitic. The mean of the molecular ratio Al2O3/(CaO+Na2O+K2O) is 1.3 with an almost normal distribution. It straddles the boundary between S- and I-type granites (where the value 1.1 is used as the boundary). The source is made up of mixtures in any proportions of igneous and sedimentary rocks, and this boundary is not a strict boundary between source rocks. Trace-element variation is immense. Rare earth element patterns are somewhat different for I- and S-type granites, but otherwise no systematic difference depending on the I/S character has been found. The metasedimentary rocks in the source were probably enriched in Sr and show evidence of oxidation. Breakdown of biotite and, probably to some extent, muscovite delivered the necessary volatiles for melting. Volatiles were important for the evolution of the granite giving non-CHARAC effects among others tetrad effects to the low-temperature granite. Degrees of melting were moderate and probably variable but cannot be quantified. Zr-saturation temperatures vary (820 ± 148°C (2σ)), but are higher for I-type than for S-type granites. The lowest temperatures occur in low-grade areas probably representing high intrusion levels.

Survivin Expression in Renal Epithelial Tumors: It's Usage in the Differential Diagnosis of Eosinophilic Renal Epithelial Tumors

Objective: The differential diagnosis of renal tumors can be problematic due to overlapping morphologic features. The purpose of this study was to assess the potential contribution of survivin expression in the differential diagnosis and determination of therapy modalities of these tumors. Methods: This study consisted of 15 chromophobe (ChRCC), 15 clear cell (CCRCC) and 9 papillary (PRCC) renal cell carcinomas, and 13 oncocytomas. Sections were stained against survivin antibody. Results: PRCCs and CCRCCs showed diffuse and strong survivin expression. Survivin expression was strikingly prominent in type1 PRCCs and cystic CCRCCs. In CCRCCs, survivin expression was more pronounced in low grade areas than high grade and sarcomatoid areas. In ChRCC, survivin expression was more limited and weaker than that of oncocytomas and other malignant renal tumors. In non-neoplastic renal tissue, survivin expression was more pronounced in podocytes and atrophic tubules than other nephron parts. Conclusions: Our results suggested that survivin may helpful in the differential diagnosis of renal tumors despite limited number of our cases. Experimental studies have revealed that inhibition of survivin induces apoptosis and enhance radiosensitivity of RCC cells. Taken together, to be known the proportion of survivin expression in subtypes of renal tumors may contribute to determine new therapeutic strategies for RCCs. This needs to be proven in more wide series.

Loss of ARID1A Expression Correlates With Stages of Tumor Progression in Uterine Endometrioid Carcinoma

ARID1A is a recently identified tumor suppressor that functions in chromatin remodeling. Inactivating mutations of ARID1A and loss of its expression most frequently occur in ovarian clear cell carcinoma, ovarian endometrioid carcinoma, and uterine endometrioid carcinoma. In this study, we performed a detailed immunostaining analysis of ARID1A in 246 cases including benign endometrium and endometrioid carcinoma at different stages of progression. Special attention was paid to recording intratumoral heterogeneity of clonal loss of ARID1A immunoreactivity. All normal endometria (n=51) and endometrial polyps (n=14) retained ARID1A expression. Among complex atypical hyperplasias (n=38), 16% exhibited clonal loss of ARID1A, but none showed complete loss. Among low-grade endometrioid carcinomas (n=88), 25% exhibited complete loss and 24% exhibited clonal loss. In contrast, 44% of high-grade endometrioid carcinomas (n=55) showed complete loss of ARID1A, and 9% exhibited clonal loss. We found that 19 high-grade carcinomas also contained concurrent low-grade carcinomas. In the high-grade areas, 63% exhibited complete loss and 11% exhibited clonal loss, whereas in the low-grade areas, 37% exhibited complete loss and 42% clonal loss. In 5 of these 19 cases, progressive loss of ARID1A from retention or clonal loss to complete loss was observed between the low-grade and high-grade areas. Overall, the percentage of complete ARID1A loss increased from 0% in complex atypical hyperplasia, to 25% in low-grade endometrioid carcinoma, to 44% in high-grade endometrioid carcinoma. These findings suggest that loss of ARID1A expression, presumably due to mutation, plays an important role in tumor progression of uterine endometrioid carcinoma.