Clinicopathological features of dedifferentiated liposarcomas with meningothelial-like whorls: report of six cases / 中华病理学杂志

To investigate the histopathologic, immunohistochemical, molecular genetic characteristics of dedifferentiated liposarcomas with meningothelial-like whorls(DDLMW). Six cases of DDLMW diagnosed at Jiangsu Province Hospital(the First Affiliated Hospital of Nanjing Medical University) from March 2012 to August 2018 were enrolled. The cases were analyzed by routine HE staining, immunohistochemistry(MDM2, CDK4 and p16) and fluorescent in-situ hybridization(FISH) on MDM2 gene. Related literatures were also reviewed. Three of the 6 patients were male.The patient ages ranged from 40 to 77 years (mean, 58 years). Four tumors occurred in the retroperitoneum and two in the mediastinum. Histologically, the tumors showed, in addition to foci of well-differentied liposarcoma, characteristic, scattered meningothelial-like concentrical whorls. The whorls were composed of tightly, concentrically arranged, spindle to ovoid cells with mild to mederate cytological atypia. Metaplastic bone was present within or in their immediate vicinity in four case. The tumors cell also showed strong and diffuse immunoreactivity to MDM2, CDK4 and p16, but no immunoreactivity to S-100 protein, SMA, SOX10, EMA, CD21, CD23 or CD35. The Ki-67 labeling indexes were low, while FISH showed high levels of MDM2 amplification in all cases. DDLMW is a rare morphologic variant of dedifferentiated liposarcoma. The whorls in DDLMW do not represent perineurial or follicular dendritic differentiation. Recognition and familiarity with its existence, as well as combined application of immunohistochemical staining and MDM FISH, are important to avoid confusion with other lesions.

Clinicopathological features of dedifferentiated liposarcomas with meningothelial-like whorls: report of six cases / 中华病理学杂志

Objective@#To investigate the histopathologic, immunohistochemical, molecular genetic characteristics of dedifferentiated liposarcomas with meningothelial-like whorls(DDLMW).@*Methods@#Six cases of DDLMW diagnosed at Jiangsu Province Hospital(the First Affiliated Hospital of Nanjing Medical University) from March 2012 to August 2018 were enrolled. The cases were analyzed by routine HE staining, immunohistochemistry(MDM2, CDK4 and p16) and fluorescent in-situ hybridization(FISH) on MDM2 gene. Related literatures were also reviewed.@*Results@#Three of the 6 patients were male.The patient ages ranged from 40 to 77 years (mean, 58 years). Four tumors occurred in the retroperitoneum and two in the mediastinum. Histologically, the tumors showed, in addition to foci of well-differentied liposarcoma, characteristic, scattered meningothelial-like concentrical whorls. The whorls were composed of tightly, concentrically arranged, spindle to ovoid cells with mild to mederate cytological atypia. Metaplastic bone was present within or in their immediate vicinity in four case. The tumors cell also showed strong and diffuse immunoreactivity to MDM2, CDK4 and p16, but no immunoreactivity to S-100 protein, SMA, SOX10, EMA, CD21, CD23 or CD35. The Ki-67 labeling indexes were low, while FISH showed high levels of MDM2 amplification in all cases.@*Conclusions@#DDLMW is a rare morphologic variant of dedifferentiated liposarcoma. The whorls in DDLMW do not represent perineurial or follicular dendritic differentiation. Recognition and familiarity with its existence, as well as combined application of immunohistochemical staining and MDM FISH, are important to avoid confusion with other lesions.

Primary colonic liposarcomatosis: report of a case with review of literature

The colon is a rare site of occurrence of liposarcoma, as either the primary site or by secondary involvement from a retroperitoneal liposarcoma. Liposarcomatosis denotes simultaneous occurrence of multiple liposarcomas. There are only 17 cases of primary colonic liposarcoma reported in the English literature­one of which was primary colonic liposarcomatosis. We depict the second case of primary colonic liposarcomatosis in a 57-year-old female who presented with abdominal swelling and pain. On exploratory laparotomy, two large masses were seen arising from the wall of the right colon along with multiple smaller masses attached to the colon. Right hemicolectomy with en bloc excision of the masses was performed along with hysterectomy and pelvic floor repair. Macroscopically, multiple exophytic masses and one endophytic mass were identified. The exophytic masses were of variable size and were found to hang from the colon by a thin pedicle simulating variable-sized appendices epiploicae. Histopathologically, the lesions showed the morphology of well-differentiated liposarcoma. This appears to be a case of primary colonic liposarcomatosis. There is only one other similar case reported in the English literature, to the best of our knowledge.

Dedifferentiated liposarcoma with inflammatory myofibroblastic tumor-like features: a clinicopathological analysis of five cases / 中华病理学杂志

Objective@#To investigate the clinicopathological features, diagnosis and differential diagnosis of dedifferentiated liposarcoma (DDLPS) with inflammatory myofibroblastic tumor (IMT)-like features.@*Methods@#Five cases of DDLPS with IMT-like features were collected from the First Affiliated Hospital of Nanjing Medical University, the Affiliated Hospital of Nanjing University of Traditional Chinese Medicine and the First People′s Hospital of Qinzhou between 2013 and 2018. EnVision method and fluorescence in situ hybridization (FISH) were used to detect the immunophenotype of the tumor cells and the profile of MDM2 gene amplification respectively.@*Results@#All five cases were male and the median age was 61 (range 53 to 65) years. The clinical symptoms were mainly related to the space-occupying lesions. The tumors were located in duodenal mesentery (two cases), intestinal wall (one case), retroperitoneum (one case), and spermatic cord (one case). Grossly, the tumors were not well encapsulated, ranging from 3 to 13 cm (median 6.7 cm) in diameter, with tan to gray and firm cut surface. Histologically, the dedifferentiated component closely resembled inflammatory myofibroblastic tumor (IMT), with spindle/polygonal/stellate-shaped cells arranged in storiform, sheet-like, or random pattern, with varying degrees of chronic inflammation and fibrosis. All three major patterns seen in IMT (myxoid, cellular and hypocellular fibrous) were observed, the hypocellular fibrous pattern was the most common. Well-differentiated liposarcomatous component was found in the peripheral areas of all the tumors. One case had high grade dedifferentiated component. Four cases were strongly positive for MDM2 and p16. Two cases were positive for SMA, and one case was focally positive for desmin and one for CD34. None of the cases stained for ALK-1. FISH demonstrated MDM2 gene amplification in all five cases. Clinical follow-ups were available in all five cases and the interval ranged from 3 to 66 months (median 23 months). Two patients developed recurrences and one patient had metastasis. The remaining two patients were alive with no evidence of tumor recurrence at 3 and 14 months after surgery respectively.@*Conclusions@#DDLPS with IMT-like features is a more aggressive neoplasm than its histological mimic (IMT), and should not be misdiagnosed as other intermediate or low-grade malignant tumors, such as IMT, sclerosing liposarcoma, inflammatory liposarcoma, aggressive fibromatosis, solitary fibrous tumors, low-grade myofibroblastic sarcoma, and low-grade fibrosarcoma.

Effect of Helicobacter pylori Lipopolysaccharide on Malignant Transformation of Gastric Epithelial Cells by Regulating MDM2 Expression / 胃肠病学

Background: Helicobacter pylori lipopolysaccharide (Hp-LPS) plays an important role in gastric carcinogenesis. Aims: To investigate the regulatory effect of Hp-LPS on MDM2 gene expression and its impact on malignant transformation of gastric epithelial cells. Methods: After stimulated with Hp-LPS 1 μg/mL or Escherichia coli (E. coli)-LPS 1 μg/mL for 24 hours, expression of MDM2 in human gastric epithelial cell line (GES-1) and gastric cancer cell line (HGC-27 and MKN45) was detected by Western blotting. Plasmid containing MDM2 promoter luciferase reporter gene was constructed and transfected into HGC-27 cells, and the relative luciferase activity was measured after treated with Hp-LPS for 24 hours. RNA interference plasmid targeting to MDM2 was constructed and transfected into GES-1, HGC-27, and MKN45 cells, then changes in cell apoptosis and invasiveness were analyzed by flow cytometry and Transwell invasion assay. Growth inhibition of MKN45 and HGC-27 xenograft tumors in nude mice was observed after receiving caudal vein injection of siRNA-hMDMA2-3 for silencing MDM2 expression. Results: Hp-LPS enhanced the transcriptional activity of MDM2 promoter and up-regulated MDM2 protein expression in gastric epithelial and gastric cancer cells. In GES-1, HGC-27, and MKN45 cells transfected with siRNA-hMDMA2-3, the cell apoptosis was increased and the cell invasive capacity was reduced as compared with those transfected with negative control siRNA (P<0.05). Furthermore, the tumor inhibition rate of nude mice treated with siRNA-hMDMA2-3 was increased significantly as compared with those treated with negative control siRNA (P<0.05). Conclusions: Hp-LPS can induce malignant transformation of gastric epithelial cells by up-regulating MDM2 expression. Inhibiting MDM2 expression might suppress the malignant transformation and tumor growth by inducing cell apoptosis and reducing cell invasiveness.

Dedifferentiated liposarcoma of extremities: a clinicopathologic analysis / 中华病理学杂志

Objective@#To study the clinicopathologic features of dedifferentiated liposarcoma of extremities.@*Methods@#Nine cases of dedifferentiated liposarcoma of extremities diagnosed at Beijing Jishuitan Hospital from 2009 to 2017 were selected. The histological features of cases of dedifferentiated liposarcoma of extremities were evaluated by HE and immunohistochemistry, together with the clinical and radiological features. Flourescence in situ hybridization(FISH) was used to detect MDM2 amplification.@*Results@#They were located in the thigh (6 cases), calf (2 cases) and buttock (1 case). There were six females and three males. Patients′ age ranged from 61 to 79 years (mean 68 years). Histologically, there were two components, well-differentiated liposarcoma and dedifferentiated sarcoma with or without transitional lesions between them. The histology of dedifferentiated liposarcoma included undifferentiated sarcoma and fibrosarcoma. Heterologous elements such as bone and cartilage were present in two cases. Immunohistochemical study showed the tumor cells expressed vimentin, CDK4 and p16. MDM2 were positive in 6 cases (6/9) and p53 was positive in one case(1/9). CKpan was positive in the epithelioid differentiation area. S-100 protein was positive in the well-differentiated liposarcoma component. FISH showed the amplification of MDM2(6/9).@*Conclusions@#Dedifferentiated liposarcoma of extremities is very rare. The diagnosis should be combined with the histological characteristics and immunohistochemical results and differentiated from the other tumors and tumor-like lesions.

ASSOCIATION BETWEEN MURINE DOUBLE MINUTE 2 - T309G polymorphism and recurrence of hepatocellular carcinoma after surgical treatment

Background - Discovery and incorporation of biomarker panels to cancer studies enabled the understanding of genetic variation and its interference in carcinogenesis at molecular level. The potential association between single nucleotide polymorphism (SNP) 309 and increased development of tumors, such as hepatocellular carcinoma, has been subject to several studies. This is the first study on this association conducted in Brazil. Methods - 62 cases of cirrhotic patients with hepatocellular carcinoma surgically treated by partial hepatectomy (HPT) or by liver transplantation (LTX) from 2000 to 2009 at Santa Casa Hospital Complex, in the city of Porto Alegre, were retrospectively analyzed. Tumor samples from surgical specimen were collected and prepared for study in paraffin blocks. Results - Overall survival was 26.7 months in the HPT group and 62.4 months in the LTX group (P <0.01). Overall tumor recurrence was 66.7% in the HPT group (10/15) and 17% in the LTX group (8/47) (X²=13.602, P <0.01). Alpha-fetoprotein levels >200ng/mL, microvascular invasion and histological grade were associated with tumor recurrence (P <0.01). Recurrence rates in each surgical group and analysis of factors associated with tumor recurrence, when stratified for each genotypic pattern, were both not statistically significant. Conclusion - G/G genotype was not associated with tumor recurrence after surgical treatment and it did not show any correlation with other prognostic factors.

Contexto - A descoberta e incorporação de painéis de biomarcadores aos estudos do câncer permitiram o conhecimento de variações genéticas e sua interferência no processo de carcinogênese. A possibilidade de associação do polimorfismo de nucleotídeo simples T309G do gene MDM2 com o aumento da formação de tumores, dentre eles o hepatocarcinoma, tem sido alvo de diversos estudos. Objetivo - Analisar a influência do polimorfismo T309G do gene MDM2 na recidiva tumoral de pacientes cirróticos com hepatocarcinoma submetidos a tratamento cirúrgico. Métodos - Foram analisados retrospectivamente pacientes cirróticos com carcinoma hepatocelular submetidos a tratamento cirúrgico (hepatectomia parcial ou transplante hepático) no período de 2000 a 2009, na Santa Casa Hospital Complex in Porto Alegre, South Brazil. Foram coletadas amostras de fragmentos tumorais da peça operatória (fígado explantado ou segmento hepático), as quais foram preparadas para estudo em bloco parafinado. Resultados - A sobrevida global foi de 26,7 meses para o grupo hepatectomias e 62,4 meses para o grupo transplante hepático (P <0,01), havendo 66,7% de recidiva global no grupo hepatectomias (10/15), e 17% no grupo transplante hepático (8/47) (X²=13,602, P <0.01). Níveis de AFP>200ng/mL correlacionaram-se com a recidiva tumoral em ambos os subgrupos cirúrgicos. Observou-se que 83,3% dos pacientes com recidiva também apresentaram invasão microvascular ao exame anátomo-patológico (P <0,01). Não houve significância estatística quando a recidiva neoplásica foi avaliada para os diferentes genótipos e analisada para cada subgrupo cirúrgico. A análise dos fatores prognósticos relacionados à recidiva do hepatocarcinoma, quando estratificada para cada padrão genotípico, também não se mostrou significante. Conclusão - O nosso estudo revelou que o genótipo G/G não esteve associado à recidiva tumoral após o tratamento cirúrgico, seja nas hepatectomias parciais ou transplante hepático. Além disso, a presença desse genótipo não mostrou correlação com os fatores prognósticos estudados.

Association between single nucleotide polymorphism of 309 T/G in murine doubleminute 2 gene and the susceptibility of non-small cell lung cancer: A Meta-analysis / 肿瘤

Objective: To evaluate the association between a single nucleotide polymorphism (SNP) of 309 T/G in the promoter of murine doubleminute 2 (MDM2) gene and the susceptibility of non-small cell lung cancer (NSCLC). Methods: A computer-based online search was performed by using Cochrane Library, PubMed, EMBase, China National Knowledge Infrasrtucture (CNKI), Wanfang database and VIP database. The case-control studies were selected according to defined inclusion and exclusion criteria. After quality evaluation and data abstraction, a meta-analysis was performed by using STATA 12.0 software. The odds ratio (OR) of the association between MDM2 SNP 309T/G and NSCLC susceptibility was calculated. Then the subgroup analysis, sensitivity analysis and publication bias test were performed. Results: A total of 8 case-control studies were eligible for this analysis, including 5 343 NSCLC patients and 6 652 healthy controls. Meta-analysis showed that MDM2 SNP 309GG could significantly increase the risk of NSCLC [TT vs GG, OR = 0.77, 95% confidence interval (CD = 0.62-0.96; GT vs GG, OR = 0.83, 95% CI = 0.75-0.92; TT+GT vs GG, OR = 0.82, 95% CI = 0.75-0.91]. In the subgroup analysis of ethnicity, MDM2 SNP 309GG could significantly increase the risk of NSCLC for Asian people [TT vs GG, OR = 0.62, 95% CI = 0.52-0.73; GT vs GG, OR = 0.78, 95% CI = 0.67-0.90; TT vs GG+GT, OR = 0.71, 95% CI = 0.59-0.86; TT+GT vs GG, OR = 0.73, 95% CI = 0.63-0.84]. In the subgroup analysis of gender, MDM2 SNP 309GG could significantly increase the risk of NSCLC for female population [TT vs GG, OR = 0.70, 95% CI = 0.54-0.91; GT vs GG, OR = 0.69, 95% CI = 0.54-0.90; TT+GT vs GG, OR = 0.70, 95% CI = 0.55-0.89]. Conclusion: MDM2 SNP 309GG may be a potential biomarker for NSCLC risk, particularly for Asian people and women. Copyright© 2014 by Tumor.

Overexpression and clinical implication of MDM2 oncogene in acute leukemia / 白血病·淋巴瘤

Objective To study the over-expression and clinical implications of the oncogene MDM2 in acute leukemia (AL). Methods The expression of MDM2 gene in 100 patients with newly diagnosed and relapse or refractory AL and 20 healthy as control was measured by relative quantitative reverse transcriptase polymerase chain reaction (RT-PCR),then the results was measured by χ2-test,t-test and one-way ANOVA to compare expession positive rate and intensity of MDM2. Results Among 100 patients,fifty-eight had the high expression of MDM2 gene (58 %). The expression level of MDM2 gene in patients was higher than that of health controls(P ＜0.05). The expression positive rate of MDM2 is higher in poor outcome group (67.9 %,19/28)than that in general outcome group (33.9%,19/56) (P＜0.05). Conclusion Our results suggest that the expression of MDM2 gene plays an important role in the pathogenesis and poor outcome of AL.

Functional characterization of human oncoprotein gankyrin in Zebrafish

Gankyrin is an oncoprotein containing seven ankyrin repeats that is overexpressed in hepatocellular carcinoma (HCC). Gankyrin binds to Mdm2, which results in accelerated ubiquitylation via degradation of p53, and it also plays an important role in cell proliferation. However, little is known about the relationships between p53 levels, cell proliferation, and gankyrin over-expression. In order to investigate the influence of gankyrin protein on p53 and Mdm2 in a zebrafish model, we injected human gankyrin (hgankyrin) containing expression vectors (pCS2-hgankyrin, pCS2-hgankyrin-EGFP) into zebrafish embryos. To measure p53 and Mdm2 expression in hgankyrin-injected embryos, RT-PCR, Northern blot and in-situ hybridization and BrdU immunostaining were used. In addition, to know the effect of hgankyrin on cell proliferation in vitro, cell viability assays such as MTT, trypan blue staining and RT-PCR following transfection of hgankyrin-containing vector into HEK 293 cell line were performed. In vivo results indicated that p53 mRNA levels decreased but those of Mdm2 were not decreased in the presence of hgankyrin. These results suggest that gankyrin downregulates p53 expression and not Mdm2 expression. In the study of cell proliferation, BrdU-positive cells were predominantly increased in the head and tail regions in hgankyrin-injected zebrafish. Additional in vitro studies using trypan blue staining and MTT assay showed that gankyrin-expressing HEK 293 cells proliferated at a faster rate, indicating that gankyrin promotes cell proliferation. Our results demonstrate that hgankyrin overexpression downregulates p53 expression and promotes cell proliferation in zebrafish. Gankyrin may play an important role in tumorigenesis via its effects on p53 and cell proliferation.

Proliferating cell nuclear antigen (PCNA), p53 and MDM2 expression in Hodgkins disease

CONTEXT AND OBJECTIVE: Tumor cells in Hodgkins disease (HD) express cell proliferation markers that are evaluated according to the oncogenes involved or the expression of their proteins. Correlations between the protein expression grade and clinical data are now important for disease prognosis. DESIGN AND SETTING: This was a retrospective analysis on proliferating cell nuclear antigen (PCNA), p53 and MDM2 (murine double minute-2) expression using immunohistochemistry, on formalin-fixed, paraffin-embedded tissues from diagnostic biopsies on 51 patients with HD. The study was conducted at the Division of Hematology and Transfusion Medicine, Hospital São Paulo, Universidade Federal de São Paulo. METHODS: Antigen expression was evaluated as the proportions of positive Hodgkin and Reed-Sternberg (HRS) cells and reactive lymphocytes (L), which were compared using Spearman correlation coefficients. The Friedman test was used for comparisons between the markers. The Pearson test was used to investigate associations between marker expression and clinical and laboratory parameters, marrow involvement, complete remission (CR) and overall survival (OS) rates. RESULTS: There was overexpression of antigen proteins in HRS, in relation to L (p < 0.001). In HRS, MDM2 was higher than p53 and PCNA (p < 0.003), while the latter two were equivalent. In L, p53 was lower than MDM2 and PCNA (p < 0.001), while the latter two were equivalent. There was no relationship between protein expression and clinical and laboratory variables or outcome. CONCLUSIONS: PCNA, p53 and MDM2 are tumor markers for HD, but showed no clinical or prognostic significance in our analysis.

CONTEXTO E OBJETIVO: As células tumorais da doença de Hodgkin (HD) são positivas para marcadores de proliferação celular que são analisados por seus genes e respectivas proteínas. A correlação entre a expressão destas proteínas e os parâmetros clínico-laboratoriais são, no momento, de importância para o prognóstico da doença. TIPO DE ESTUDO E LOCAL: Estudo retrospectivo da expressão do antígeno de proliferação celular (PCNA) e da p53 e MDM2 em tecidos obtidos ao diagnóstico, fixados por formol, embebidos em parafina de 51 pacientes com HD. O trabalho foi realizado na Divisão de Hematologia e Transfusão, Hospital São Paulo, Universidade Federal de São Paulo. MÉTODOS: As expressões antigênicas foram analisadas através da proporção de células de Hodgkin e células de Reed Sternberg (HRS) e linfócitos reacionais (L) positivos. A intensidade de expressão de cada proteína foi comparada entre L e HRS através do coeficiente de Spearman. A comparação da PCNA, p53 e MDM2 em L e HRS se fez pelo teste de Fiedman. As correlações entre variáveis clínico-laboratoriais, comprometimento da medula óssea, taxas de sobrevida geral e remissão clínica com as proteínas em HRS se fizeram pelo coeficiente de Pearson. RESULTADOS: Houve superexpressão das três proteínas em células HRS comparadas aos L (p < 0,001). Nas células HRS, a MDM2 foi maior que a p53 e a PCNA (p < 0,003), que foram equivalentes. Nos L, a p53 foi menor que a MDM2 e a PCNA (p < 0,001), que foram equivalentes Não houve relação entre as expressões das proteínas com as variáveis clínico-laboratoriais e sobrevida. CONCLUSÕES: PCNA, p53 e MDM2 são marcadores tumorais na HD, porém não mostraram significado clínico-prognóstico em nossa análise.

Association of the MDM2 polymorphisms with susceptibility of esophageal squamous cell carcinoma and that of gastric cardiac adenocarcinoma / 肿瘤

Objective: To investigate the correlation between the SNP309 and Del1518 polymorphisms in the promoter region of murine double minute 2 (MDM2) and genetic susceptibilities of esophageal squamous cell carcinoma (ESCC) and gastric cardiac adenocarcinoma (GCA). Methods: Genotypes of the MDM2 polymorphisms of 563 cancer patients (351 ESCC and 212 GCA) and 642 healthy controls were detected by a primer-introduced restriction analysis-polymerase chain reaction (PIRA-PCR). The combined effects of MDM2 polymorphisms were analyzed by EH and 2LD softwares. Results: Distributions of the MDM2 genotypes in both ESCC patients and healthy controls were not significantly different (P > 0.05), however, a significant different distribution between GCA patients and healthy controls was observed (P < 0.05). The MDM2 haplotype distributions were not significantly different between ESCC patients and healthy controls (P = 0.198). MDM2 haplotype distribution in the GCA patients was also significantly different from that in the healthy controls (P 0. 000). Compared with SNP309G/Del1518 + haplotype, SNP309T/Del1518 - haplotype significantly decreased the risk of developing GCA (adjusted OR = 0.51, 95% CI = 0.38-0.70). Conclusions: MDM2 polymorphisms may not be associated with susceptibility to ESCC. Individuals with MDM2 SNP309T allelotype (G/T and T/T genotype) and with Del1518 - allelotype (+/- and -/- genotype) have significantly lower risk of developing GCA, respectively. Individuals T/Del1518 - haplotype have significantly lower risk of developing GCA.