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Epithelial ovarian cancer (EOC) is one of the leading causes of death from gynecologic cancers and peritoneal dissemination is the major cause of death in patients with EOC. Although the loss of 4.1N is associated with increased risk of malignancy, its association with EOC remains unclear. To explore the underlying mechanism of the loss of 4.1N in constitutive activation of epithelial-mesenchymal transition (EMT) and matrix-detached cell death resistance, we investigated samples from 268 formalin-fixed EOC tissues and performed various in vitro and in vivo assays. We report that the loss of 4.1N correlated with progress in clinical stage, as well as poor survival in EOC patients. The loss of 4.1N induces EMT in adherent EOC cells and its expression inhibits anoikis resistance and EMT by directly binding and accelerating the degradation of 14-3-3 in suspension EOC cells. Furthermore, the loss of 4.1N could increase the rate of entosis, which aggravates cell death resistance in suspension EOC cells. Moreover, xenograft tumors in nude mice also show that the loss of 4.1N can aggravate peritoneal dissemination of EOC cells. Single-agent and combination therapy with a ROCK inhibitor and a 14-3-3 antagonist can reduce tumor spread to varying degrees. Our results not only define the vital role of 4.1N loss in inducing EMT, anoikis resistance, and entosis-induced cell death resistance in EOC, but also suggest that individual or combined application of 4.1N, 14-3-3 antagonists, and entosis inhibitors may be a promising therapeutic approach for the treatment of EOC.
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The development of female germ cells can be mainly divided into two stages: fetal germ cells and oocytes in folliculogenesis after puberty. Mitosis-meiosis transition, meiosis arrest and re-activation are the key phases of the development. Several phases may be characterized by their distinct molecular events, which involve precise regulation of gene expression and interaction with corresponding gonadal niche cells. In recent years, single-cell transcriptome studies have clarified phase-specific patterns of gene expression, signaling pathways and epigenetic modification during oogenesis and folliculogenesis. These works have provided important insights into the development of female germ cells and pathogenesis of germ-cell related diseases, which may promote clinical application of reproductive genetic research.
Subject(s)
Female , Humans , Germ Cells , Meiosis , Oocytes , Oogenesis/genetics , Signal TransductionABSTRACT
Objective@#To explore molecular characteristics of endometrial endometrioid cancer according to The Cancer Genome Atlas (TCGA) based molecular classification of endometrial carcinomas and to confirm simple and clinically applicable surrogate methodologies in pathological practice.@*Methods@#Two hundred and twenty-eight cases of endometrial endometroid adenocarcinomas (EnACs) collected from August 2001 to August 2017 from Peking University Health Science Center, Peking University Third Hospital were molecularly categorized by using Sanger sequencing for the exonuclease domain mutations (EDM) of POLE, and by immunohistochemistry for p53 and mismatch repair (MMR) proteins. The cohort was classified into polymerase-E exonuclease domain mutation (POLE EDM), mismatch repair deficiency (MMR-D), p53 abnormal (p53-abn) and p53 wild type (p53-wt) groups. The correlation between molecular subgroups and the clinical-pathological features including prognosis were analyzed.@*Results@#The cohort was distributed as follows: 11(4.8%) POLE EDM, 47(20.6%) MMR-D, 9(4.0%) p53-abn and 161(70.6%) p53-wt. p53-wt subgroup patients demonstrated significantly higher lymph node metastasis (P=0.011) and more advanced stage (P=0.036) than those of somatic hypermutation group cases (POLE EDM and MMR-D). In the FIGO grade 2-3 EnACs cohort, TCGA molecular subtyping was significantly correlated with progression-free survival and overall survival (P=0.043). POLE EDM subgroup had the best survival, while p53-abn subgroup had the worst.@*Conclusions@#Identification of POLE EDM and MMR-D subgroups provides independent and highly valuable prognostic information beyond established histological classification. Based on immunohistochemistry of MMR, p53 and POLE mutational analysis, this pragmatic molecular classification scheme can be served as a reliable surrogate for TCGA molecular classification, which has potential to be used routinely in Chinese pathological practice.
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Objective@#To investigate the clinicopathological characteristics and significance of solid, endometrioid and transitional (SET) ovarian high-grade serous carcinoma (HGSC).@*Methods@#A total of 408 cases of ovarian HGSC admitted to Peking University People's Hospital from January 2011 to September 2016 were collected. (1) According to the proportion of tumors with SET form in all tumors, they were divided into three groups: HGSC-classic group (<25%), HGSC-SET Ⅰ (25%-50%) and HGSC-SET Ⅱ (>50%) group. The clinical and pathological characteristics of three groups of ovarian HGSC patients were compared respectively. (2) According to the growth pattern, that was, the proportion of pushing/expanding invasive tumors in the whole pelvic disseminated tumors of pelvic disseminated tumors, the three groups were divided into four subgroups: group A (0-25%), group B (26%-50%), group C (51%-75%) and group D (>75%). Differences in progression-free survival (PFS) among the four subgroups in each group were compared respectively.@*Results@#The median age of 408 cases with ovarian HGSC was 63.3 years (47-78 years), including 152 cases premenopausal and 256 cases postmenopausal. Among 408 cases of ovarian HGSC, 290 cases were in HGSC-classic group, 91 cases in HGSC-SET Ⅰ and 27 cases in HGSC-SET Ⅱ group. (1) There were significant differences in age, proportion of menopausal patients, tumor necrosis (including map necrosis or acne necrosis), response rate to primary chemotherapy, 5-year mortality rate and PFS between HGSC-SET Ⅰ and HGSC-SET Ⅱ (P<0.05). There was no significant difference among the above indexes between HGSC-SET Ⅰ and HGSC-SET Ⅱ (P>0.05). In HGSC-classic group, HGSC-SET Ⅰ and HGSC-SET Ⅱ, the proportion of family members or patients with history of epithelial ovarian cancer or breast cancer increased in turn, and the detection rate of serous tutal intraepithelial carcinoma (STIC) in fallopian tube tissue decreased in turn. There were significant differences between the two groups (P<0.05). (2) In HGSC-classic group, there were 147 cases in group A, 124 cases in group B and 19 cases in group C (0 case in group D), with median PFS of 17.4, 17.7 and 16.5 months respectively (P<0.05); 10, 6, 29 and 46 cases in group A, B, C and D in HGSC-SET Ⅰ, with median PFS of 9.6, 12.7, 30.1 months and 39.0 months respectively, which there were significant difference among group A and C and D (all P<0.05); among group B, C and D group in HGSC-SET Ⅱ, there were respectively 3, 12 and 12 cases (0 case in group A), and the median PFS was 13.5, 34.2 and 47.8 months (P<0.05). PFS was positively correlated with the increase of push/expansive infiltration ratio.@*Conclusions@#The detection rate of STIC in ovarian HGSC patients with SET is higher, the effect of primary chemotherapy is better, and PFS is prolonged. PFS was significantly prolonged in patients with pelvic disseminated tumors of HGSC-SET, the infiltration of which were predominated by pushing or expanding boarder.
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Objective To investigate the clinicopathological characteristics and significance of solid, endometrioid and transitional (SET) ovarian high-grade serous carcinoma (HGSC). Methods A total of 408 cases of ovarian HGSC admitted to Peking University People's Hospital from January 2011 to September 2016 were collected. (1) According to the proportion of tumors with SET form in all tumors, they were divided into three groups: HGSC-classic group (<25%), HGSC-SET Ⅰ (25%-50%) and HGSC-SETⅡ (>50%) group. The clinical and pathological characteristics of three groups of ovarian HGSC patients were compared respectively. (2) According to the growth pattern, that was, the proportion of pushing/expanding invasive tumors in the whole pelvic disseminated tumors of pelvic disseminated tumors, the three groups were divided into four subgroups: group A (0-25%), group B (26%-50%), group C (51%-75%) and group D (>75%). Differences in progression-free survival (PFS) among the four subgroups in each group were compared respectively. Results The median age of 408 cases with ovarian HGSC was 63.3 years (47-78 years), including 152 cases premenopausal and 256 cases postmenopausal. Among 408 cases of ovarian HGSC, 290 cases were in HGSC-classic group, 91 cases in HGSC-SETⅠand 27 cases in HGSC-SET Ⅱ group. (1) There were significant differences in age, proportion of menopausal patients, tumor necrosis (including map necrosis or acne necrosis), response rate to primary chemotherapy, 5-year mortality rate and PFS between HGSC-SET Ⅰ and HGSC-SET Ⅱ (P<0.05). There was no significant difference among the above indexes between HGSC-SETⅠand HGSC-SETⅡ(P>0.05). In HGSC-classic group, HGSC-SET Ⅰ and HGSC-SET Ⅱ, the proportion of family members or patients with history of epithelial ovarian cancer or breast cancer increased in turn, and the detection rate of serous tutal intraepithelial carcinoma (STIC) in fallopian tube tissue decreased in turn. There were significant differences between the two groups (P<0.05). (2) In HGSC-classic group, there were 147 cases in group A, 124 cases in group B and 19 cases in group C (0 case in group D), with median PFS of 17.4, 17.7 and 16.5 months respectively (P<0.05); 10, 6, 29 and 46 cases in group A, B, C and D in HGSC-SETⅠ, with median PFS of 9.6, 12.7, 30.1 months and 39.0 months respectively, which there were significant difference among group A and C and D (all P＜0.05); among group B, C and D group in HGSC-SET Ⅱ, there were respectively 3, 12 and 12 cases (0 case in group A), and the median PFS was 13.5, 34.2 and 47.8 months (P＜0.05). PFS was positively correlated with the increase of push/expansive infiltration ratio. Conclusions The detection rate of STIC in ovarian HGSC patients with SET is higher, the effect of primary chemotherapy is better, and PFS is prolonged. PFS was significantly prolonged in patients with pelvic disseminated tumors of HGSC-SET, the infiltration of which were predominated by pushing or expanding boarder.
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Objective To investigate the significance of Silva pattern system about clinical application in invasive endocervical adenocarcinoma. Methods Data obtained from the Maternity Affiliated Hospital of Dalian Medical University was analyzed, 78 endocervical adenocarcinoma cases were included from December, 2006 to August, 2017. The average age of patients was (45.1 ± 9.1) years old (ranged 27-71 years old). Clinical stage: stageⅠa 26 cases and Ⅰb 49 cases and stage Ⅱa 3 cases. All pathological slides were reviewed, stratified cases into pattern A, B and C according to Silva system criteria.Clinicopathological parameters of three Silva subgroups were analyzed, χ2 test was used to investigate the correlation of Silva system and clinicopathological parameters. Follow-up data were collected until Jan. 3rd, 2018. The median follow-up time was 41 months (ranged 5-90 months). Kruskal-Wallis H test and Fisher test were used to analyze prognoses among different Silva subgroups. Results (1) Silva A cases accounted for 38％(30/78) of all patients, 24 cases were stageⅠa, 6 cases were stageⅠb. The median tumor thickness was 2.1 mm (ranged 1.0-10.0 mm). No lymph vascular space invasion (LVSI) and perineural invasion (PNI) was detected, and all lymph node (LN) were negative for metastatic carcinoma. All patients were alive and had no evidence of recurrence. About 21％(16/78) cases were classified as Silva B, including 2 stageⅠa and 14 stage Ⅰb. The median tumor thickness was 5.2 mm (ranged 2.0-11.0 mm). Several patients had LVSI (4/16), LN metastasis (1/10) or PNI (1/16), but there was no recurrence or death. Thirty two (41％,32/78) cases were Silva C, including 29 stageⅠb and 3 stageⅡa. The median tumor thickness was 11.5 mm (ranged 4.0-21.0 mm). The incidence of LVSI (53％, 17/32), LN metastasis (31％, 8/26) or PNI (16％, 5/32) was significantly increased. There were two recurrent cases and one death cases. (2) Statistical data demonstrated that Silva pattern system was closely correlated with clinicopathological parameters , such as clinical stage (r=0.754, P=0.000), tumor depth (P=0.000) and LVSI (r=0.534, P=0.000). But there was no correlation between Silva system and LN metastasis or PNI (all P>0.05). (3) Silva subgroups demonstrated no significant difference in recurrence and death (P>0.05). Conclusions The application of Silva pattern system could effectively predict the prognosis of patients. It may be helpful to select reasonable operation before surgery and to realize individualized treatment of cervical adenocarcinoma.
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Objective To study the clinicopathological features of sarcomatoid hepatocellular carcinoma (SHC).Methods The clinical data of 42 patients with SHC who underwent surgical resection in the Peking University People's Hospital (n =33) and the Department of Pathology of the Peking University Health Science Center (n=9) from January 2008 to May 2017 were retrospectively analyzed.Results The average age was 58.3 (aged 32～84) years;the ratio of male to female was 2.2 ∶ 1;the average diameter of the lesions was 8.2 cm;the median AFP value was 45.2 ng/ml.The median survival time was 10.5 months,the average progression-free survival time was 2.9 months,and the 5-year survival rate was 25.0％.On histopathology,the tumor consisted of various degrees of different differentiated carcinomas with aligned sarcomatoid spindle cells.Immunohistochemical results in the sarcomatoid region expressed both mesenchymal markers and epithelial-derived markers.Conclusions SHC tumors were highly aggressive,with high rates of lymph node metastasis and poor prognosis.The diagnosis of SHC mainly depended on histopathology.Immunohistochemistry was very important for its diagnosis and differential diagnosis.Surgical resection was the treatment modality of choice to achieve prolonged survival time.
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Objective To evaluate the diagnostic performance of the histogram analysis of mono-exponential and intravoxel incoherent motion(IVIM) models to the dualistic model of epithelial ovarian cancer(EOC). Methods Forty female patients with histopathologically proven epithelial ovarian cancer underwent preoperative MR examination. Scanning sequences included conventional imaging, diffusion-weighted magnetic resonance imaging with 11 b values (0, 30, 50, 100, 150, 200, 400, 600, 800, 1 000, 1 500 s/mm2) and dynamic contrast enhanced MRI (DCE-MRI). Based on the dualistic model of EOC, all patients were divided into two groups:typeⅠ(low grade, n=16) and typeⅡ(high grade, n=24). ADC, D, D*and f maps and their corresponding histograms were generated by post-processing software. Based on an entire-tumour measurement, the following histogram parameters were recorded, respectively: (a) Mean; (b) the 10th percentile (10th);(c) the mean of the top 10 percent (MeanL);(d) the 90th percentile (90th);(e) the mean of the bottom 10 percent (MeanR). Two types were compared using independent sample t test or Mann-Whitney U test. And areas under ROC curve between two groups were assessed. Results For ADC , D, and f, all indices(Mean,10th,MeanL,90th,MeanR) of the histogram were significantly lower in typeⅡthan in type Ⅰ(P0.05). D demonstrated a comparable accuracy with ADC in differentiating the grade of EOC (area under curve: Mean, 0.898 vs. 0.893; 10th, 0.880 vs. 0.846; MeanL, 0.878 vs. 0.858; 90th, 0.895 vs. 0.839; MeanR, 0.872 vs. 0.814), and both ADC and D have better performance than f. Conclusion It is feasible to stratify the grade of EOC by mono-exponential and IVIM models with histogram metrics,diagnositic efficiency of ADC and D values are higher.
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Objective To investigate the value of intravoxel incoherent motion (IVIM) model of diffusion weighted MRI in assessing grades and enhancement patten of uterine cervical cancer. Methods Thirty one patients with pathologically proven cervical cancer, who underwent MRI scan preoperatively, were analyzed retrospectively and were divided into 3 groups according to their pathological grading of cacer, including 6 with G1 cancer, 17 with G2 and 8 with G3. The diameter of each lesion was≥1 cm. 10 b values (0, 30, 50, 100, 150, 200, 400, 800, 1 000, 1 500 s/mm2) were used in DWI, and DCE-MRI was performed with a time resolution of 9.8 s. Parameters of DWI (ADC, D, f, D*) and semiquantitative parameters of DCE-MRI (Slop, Maxslop, CER, Washout, AUC90) were measured. One-way ANOVA analysis of variance and Pearson correlation were used to analyze normally distributed continuous data. Kruskal-Wallis H test and Spearman correlation were used to analyze abnormally distributed continuous data. Tumor volume and all of the MRI parameters were compared as well as correlated with pathological grading.The perfusion parameters derived from IVIM were correlated with those derived from dynamic enhanced MR imaging. The sensitivity and specificity of f value to to diagnose G3 cervical cancer and the best cutoff were calculated from areas under the ROC curves.Results Tumor volume of G1,G2 and G3 cancers were(33.8±31.1),(19.6±16.9)and(31.2±29.1)cm3(F=1.147,P=0.332), respectively.ADC values of the three groups were(1.03 ± 0.11)× 10-3,(1.00 ± 0.10)× 10-3 and(0.90 ± 0.05)× 10-3mm2/s,respectively(F=4.619,P=0.018).D values of the three groups were (0.80 ± 0.11) × 10-3, (0.77 ± 0.06) × 10-3and (0.69 ± 0.06) × 10-3mm2/s ,respectively(F=5.272, P=0.011).f values of the three groups were 0.20±0.02, 0.22±0.03 and 0.24± 0.03, respectively (F=3.524, P=0.043).All of the others were of no significant difference (P>0.05).Both ADC and D correlated negatively with tumor grading (r=-0.464 and-0.493, P=0.009 and 0.005, respectively). f value correlated positively with tumor grading (r=0.436, P=0.014).Areas of ADC, D and f value under ROC curves to diagnose G3 cancers were 0.179, 0.147 and 0.690, respectively. While the cut-off value of f was 0.22, the diagnostic performance for G3 cancer was with a sensitivity of 75.0% (6/8) and a specificity of 60.9% (14/23). The value of f had weak positive correlations with Slop, Maxslop, CER and AUC90 of semiquantitative analysis of DCE-MRI (r=0.319, 0.337, 0.293 and 0.344, respectively, P<0.01). Conclusion IVIM model of multi-b value DWI may provide information in the assessment of differentiation and en hancement pattern of cervical cancer.
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Objective:To detect the clinical features of vulvar and vaginal intraepithelial neoplasias(VIN and VAIN,respectively).Methods:Total 148 women were performed vulvar or vaginal coloposcopy-directed biopsy pathology tests,from Sep.2004 to Dec.2007.Results:Among 148 women,vulvar or vaginal histologic results were vulvar cancer for 1,VIN or VAIN 2,3 for 23,VIN or VAIN for 16,condyloma for 61,vulvitis and vaginitis for 47.Eighty-five percent(33/39) women with VIN or VAIN 2,3 were more than 30 years old.Compared to women with cervical intraepithelial neoplasia(CIN),women with VIN or VAIN were older.The rate of high-risk HPV DNA in women with vulvar or vaginal lesions was 84%(84/100).VAIN occurred mainly in the upper vagina(90%,69/75).VIN or VAIN often accompanied or followed CIN or cervical cancer(79%,31/39),and VIN or VAIN 2,3 often accompanied or followed CIN 2,3 or cervical cancer(70%,16/23).Conclusion:Our data suggest that women with high-risk HPV infection are at risk of developing VIN or VAIN 2,3.The vulva and vagina should be carefully inspected by colposcopic examination at the time of colposcopy for any abnormal findings.