Case Report: A case of COL1A1-PDGFB fusion uterine sarcoma at cervix and insights into the clinical management of rare uterine sarcoma.

COL1A1-PDGFB gene fusion uterine sarcoma is an especially rare malignant mesenchymal tumor that was previously classified as an undifferentiated uterine sarcoma due to the lack of specific features of differentiation. Till now, only five cases have been reported, and here we presented another case recently diagnosed in a Chinese woman who had vaginal bleeding. She presented with a cervical mass at the anterior lip of the cervix invading the vagina and was treated with laparoscopic total hysterectomy plus bilateral salpingo-oophorectomy (TH+BSO) and partial vaginal wall resection with the final pathology of COL1A1-PDGFB fusion uterine sarcoma. Our aim is to emphasize the importance of differential diagnosis of this rare tumor, as early precise diagnosis may allow patients to benefit from the targeted therapy imatinib. This article also serves as further clinical evidence of this disease, serving to increase clinical awareness of this rare sarcoma to avoid misdiagnosis.

Joint detection of multiple HPV-testing technologies and evaluation of clinicopathological characteristics discriminate between HPV-independent and low-copy HPV-associated cervical squamous cell carcinoma (CSCC) -an analysis of 3869 cases.

OBJECTIVES: This study aimed to investigate the frequency and clinicopathological characteristics of HPV-independent cervical squamous cell carcinoma (CSCC). METHODS: A total of 3869 patients with CSCC from 2017 to 2021 were searched. p16INK4a immunochemistry (IHC), two HPV-DNA(L1) polymerase chain reactions and HPV mRNA in situ hybridization were performed. Viral copies were detected using the 21 HPV quantitative test. RESULTS: Six cases showed negative results in all four assays (group 1, 0.16%). Twenty-seven cases showed discordant results (group 2), and 3836 cases presented all-positive results (group 3). p16INK4a IHC showed similar sensitivity, specificity, and positive predictive value compared to the other three direct HPV assays. 21 HPV genotyping showed 100% of negative predictive value. HPV copies were extremely lower in Group 2 than in Group 3 (P < 0.01), but were not significantly different from those in Group 1. Older age, advanced FIGO stage (III-IV) and abnormal p53 (p53abn) IHC were independent predictors of HPV-negative status in univariate and multivariate logistic regression. Group 2 had similar proportions of age >60 years and p53abn IHC with Group 1, but had fewer cases with advanced FIGO stage (P < 0.05) and TILs (P < 0.05). Groups 1 and 2 had worse disease-free survival (DFS) and disease-specific survival (DSS) than Group 3 (P < 0.01), while no significant difference was found between these two groups. HPV-negative status was a risk factor for both DFS (P < 0.05) and DSS (P < 0.01) in univariate but not multivariate Cox regression. CONCLUSIONS: Joint detection of multiple technologies and evaluation of clinicopathological characteristics discriminate between HPV-independent and low-copy HPV-associated CSCC cases that present similar prognoses. Additional attention should be paid to these low-copy HPV-associated cases in clinical practice.

A 2-tier subdivision of papillary proliferations of the endometrium (PPE) only emphasizing the complexity of papillae precisely predicts the neoplastic risk and reflects the neoplasia-related molecular characteristics-a single-centered analysis of 207 cases.

Papillary proliferation of the endometrium (PPE) is subdivided based on the complexity of the papillae and the proliferation of lesions, and the complex group is considered to have an increased risk of concurrent/subsequent endometrial neoplasia. However, the current subdivision criteria fail to prove the equivalence of the quantity of simple papillae and structural complexity. In this study, we divided PPE of 207 cases from 2014 to 2022 into 3 groups according to structural complexity and proliferation degrees: Group 1 equaled to the simple PPE with a simple papillary structure and typical localized proliferation; group 2 had the simple structure similar to group 1 but occupy over 50% of the endometrial polyp or > 2 lesions in the surface of nonpolypoid endometrium; group 3 had the truly complex branching papillae despite of its proportion. Group 3 was implicated with significantly more concurrent endometrial neoplasia (EAH and carcinoma) compared with groups 1 and 2 (P < 0.01), while no difference was found between groups 1 and 2. In 128 cases with no concurrent endometrial abnormalities in the initial biopsy or curettage specimens, 4 cases presented endometrial neoplasia (3 carcinoma and 1 atypical hyperplasia) in the subsequent specimens, all of which presented PPE of group 3 but not group 1 or 2 in the prior tissues (P < 0.01). The immunochemistry of 83 cases showed similar expressions of ER, PTEN, ARID1A, PTEN, p16, ß-catenin, and p53 between PPE and the surrounding normal endometrium. Nearly 100% of PPE cases lost expressions of PR. A total of 2/83 cases showing PAX2 expression were all in the group 3 and correlated with endometrial neoplasia (2/17, 11.76%, P < 0.05). 76/83 (91.57%) of PPE lesions had KRAS mutations, and the distributions of which were similar among 3 groups. The frequency of mucinous metaplasia was significantly higher in the PPE lesions with KRAS mutations (72/74, 97.30%, P < 0.01). Group 3 showed higher frequency of single KRAS mutations compared with the combination of groups 1 and 2 (P < 0.01). Finally, the concordance of KRAS mutation profiles between PPE and endometrial neoplasia was significantly higher in group 3 than either group 1 or 2 (P < 0.01), while no difference was found between group 1 and 2. Thus, a new 2-tier subdivision system only emphasizing the complexity of papillae is recommended, which might precisely predict the risk of endometrial neoplasia and neoplasia-related molecular characteristics.

Extensive HPV Genotyping Reveals High Association between Multiple Infections and Cervical Lesions in Chinese Women.

Objective: The relationship between human papillomavirus (HPV) and cervical lesions has been extensively elucidated, but infection with multiple genotypes is less investigated due to methodology limitations. In the current study, with a method of genotyping 21 HPVs in a routine cervical screening population, we aimed to investigate the prevalence and diversity of HPV infections in Chinese women and further evaluate the impact of multiple infections of HPV on cervical lesion progression. Methods: Totally, 73,596 patients who underwent 21-genotype HPV testing from January 2018 to April 2019 were retrieved from the database of the Department of Pathology, Obstetrics and Gynecology Hospital of Fudan University. HPV testing was performed by real-time PCR assay, including 13 high-risk HPVs (hrHPV), 5 potential hrHPVs, and 3 low-risk HPVs. Results: Of the 17,079 (infection rate, 23.2%) hrHPV- or potential hrHPV- (hr/phrHPV-) positive cases, 26.3% had multiple infections. Women younger than 25 and older than 65 were more prone to multiple infections. Of the hr/phrHPV-positive cases involving cervical intraepithelial neoplasia (CIN) 2 or worse (CIN2+), HPV73, 53, and 66 (=59) were the top three genotypes most likely to be included in multiple infections, while HPV16, 18, and 58 were the 3 least. Patients with single infection of HPV16 had higher incidences of CIN2+ than those with multiple-infection pattern (P < 0.001), indicating that mixing with other genotypes alleviated pathogenicity. The infection of HPV52, 53, 56, 51, 39, 66, 59, 68, and 35 showed an opposite pattern, indicating that they were less likely to be pathogens individually. All other types showed no significant differences, indicating the capability of pathogenesis independently. HPV26 showed a higher OR for CIN2+ than most traditional hrHPV genotypes. The vial load and the percentage of HPV16 showed positive correlation with the severity of cervical lesions. Conclusion: Extensive genotyping identified 3 most frequent genotypes, HPV16, 52, and 58, in CIN2+ of Chinese population. HPV16 mixing with other genotypes alleviated its pathogenicity. The vial load and the percentage of HPV16 were positively correlated with the severity of cervical lesions. HPV26 may be considered as a hrHPV, which needs to be evaluated and confirmed by more cases.

Prevalence and carcinogenic risk of high-risk human papillomavirus subtypes in different cervical cytology: a study of 124,251 cases from the largest academic center in China.

INTRODUCTION: We investigated the prevalence and carcinogenic risks of individual high-risk human papillomavirus (HR-HPV) in all types of cervical cytology specimens in the Shanghai population. METHODS: A total of 124,251 cases with cotesting of cytology and HPV genotyping between October 2017 and February 2020 were included. RESULTS: The overall HPV positive rate was 24.3%, with 22.9% for HR-HPV and 6.1% for low-risk HPV. The top five most common HR-HPV subtypes were HPV 52/16/58/53/39 in the entire studied population, and HPV 16/53/56/51/39 in women with abnormal cytology. The most prevalent subtypes in negative/LSIL, HSIL, and glandular lesions were HPV 52, 16, and 18, respectively. HPV 16, 33, 26, 18, 58, and 82 were the most common subtypes significantly associated with an increased risk for HSIL + cytology. HPV 16/18 were present in 53.6% and 66.7%, and HPV 16/18/31/33/45/52/58 were identified in 90.3% and 80.1% of HSIL and squamous cell carcinoma cytology, respectively. HPV 16/18 and HPV 16/18/31/33/45/52/58 were detected in 37.0% and 44.4% of women with cytologic interpretation of in situ and invasive adenocarcinoma. CONCLUSIONS: This large-scale study identified the most common HPV subtypes in each cytology category, and the carcinogenic risks of individual HR-HPV in the studied Shanghai population. The results would provide valuable information for the development of next-generation HPV vaccines and cervical cancer screening programs for the Chinese population, and, more specifically, the Shanghai metropolitan population.

LINC00152 Promotes Tumor Progression and Predicts Poor Prognosis by Stabilizing BCL6 From Degradation in the Epithelial Ovarian Cancer.

Long non-coding RNA 00152 (LINC00152) is tumorigenic in multiple somatic malignancies. However, its prognostic significance and molecular mechanisms in the epithelial ovarian cancer (EOC) remain elusive. Here our study reveals that dysregulation of LINC00152 is a predictor of poor prognosis in patients with EOC and facilitates ovarian tumor growth and metastasis both in vitro and in vivo; the expression of LINC00152 positively correlates with the protein levels of BCL6 in EOC tissues and ovarian tumor cells; LINC00152 binds to Ser333 and Ser343 of BCL6 protein and stabilizes BCL6 from poly-ubiquitination thus facilitating the oncogenic functions in EOC. Moreover, overexpression of the mutant BCL6S333A/S343A fails to rescue the reduced proliferation and invasion caused by the knockdown of endogenous BCL6 in LINC00152-overexpressing cells. Our study might not only offer clues to the network of lncRNA-protein interactions but also provide potential therapeutic targets for the tumor pharmacology.

High-risk HPV E6/E7 mRNA in situ hybridization in endocervical glandular neoplasia: performance compared with p16INK4a and Ki67 immunochemistry.

OBJECTIVE: HR-HPV E6/E7 mRNA in situ hybridization (HR-HPV RISH) can detect HPV-driven endocervical glandular neoplasia. Our aim was to compare its diagnostic performance with the conventional p16INK4a and Ki67 immunochemistry (IHC). METHODS: HR-HPV RISH and IHC were performed in normal cervix (n = 70), reactive cervix (n = 60), adenocarcinoma in situ (AIS) (n = 92), endocervical adenocarcinoma (ECA) and adenosquamous carcinoma (n = 21) samples (n = 163). The sensitivities and specificities of the three markers were compared in the benign, AIS, HPV-associated adenocarcinoma (HPVA) and non HPV-associated adenocarcinoma (NHPVA) samples, and in 39 endocervical curettage specimens containing endometrial and HPV-associated neoplastic glands. Finally, the inter-observer agreement rate for the three markers were calculated. RESULTS: The sensitivities of HR-HPV RISH, P16INK4a and Ki67 were 100% for the HPV-related glandular neoplasia and HPVAs in ECAs, while the specificity of HR-HPV RISH (100%) were higher than the other two (88.89% and 17.77% for P16INK4a and Ki67 respectively) in the HPVAs. Furthermore, HR-HPV RISH was more specific than either p16INK4a block+ or Ki67 in the endocervical curettage specimens and in HPVAs with poor differentiation. Finally, the inter-observer agreement for HR-HPV RISH was higher than that for the morphological, p16INK4a block+ and Ki67 markers (99.67% vs. 95.10%, 99.35% and 90.85% respectively). CONCLUSIONS: HR-HPV RISH is highly sensitive and specific for HPV-driven endocervical glandular neoplasia compared to p16INK4a and Ki67, and should be incorporated for ECA diagnosis.

The non-coding RNA OTUB1-isoform2 promotes ovarian tumour progression and predicts poor prognosis.

Ovarian cancer is the leading malignancy of the female reproductive system and is associated with inconspicuous early invasion and metastasis. We have previously reported that the oncogene OTUB1 plays a crucial role in ovarian cancer progression, but the role of its isoform, the non-coding RNA OTUB1-isoform2, in ovarian cancer is still elusive. Here, we reported that OTUB1-isoform2 expression in ovarian cancer tissues was significantly higher than that in the paired paratumorous tissues (P < .01). The patients with high expression of OTUB1-isoform2 had larger tumours than those with low expression (P < .05). The high expression of OTUB1-isoform2 was correlated with the involvement of bilateral ovaries (P < .05), lymph node metastasis (P < .05), vascular invasion (P < .05), greater omentum involvement (P < .01), fallopian tube involvement (P < .05), advanced FIGO stages (P < .01) and recurrence (P < .01). Moreover, OTUB1-isoform2 served as an independent negative prognostic predictor for disease-free survival (DFS) and disease-specific survival (DSS). Overexpression of OTUB1-isoform2 in the ovarian cancer cells stimulated cell proliferation, migration and invasion both in vitro and in vivo. In summary, our study suggested that OTUB1-isoform2 is a novel prognostic biomarker with independent oncogenic functions for ovarian cancer.

The expression of IMP3 in 366 cases with ovarian carcinoma of high grade serous, endometrioid and clear cell subtypes.

The clear cell (CCC), high grade serous (HGSC) and endometrioid (EC) ovarian carcinomas share overlapping histological features. The oncogene IMP3 is implicated in CCC with an elusive utility in differential diagnosis. We collected 366 cases with ovarian primary carcinomas to detect IMP3, Napsin-A and HNF-1ß by immunochemistry. In 351 cases, the positive expression rate of IMP3 in CCC was significantly higher than that either in EC or HGSC (p < 0.01). The sensitivity of IMP3 in CCC was higher than Napsin-A but lower than HNF-1ß (p < 0.01). The specificity of IMP3 in CCC was lower than Napsin-A but higher than HNF-1ß (p < 0.01). The composite markers Napsin-A+/IMP3+ and the IMP3+/HNF-1ß+/Napsin-A+ offered the highest odds ratio (p < 0.001), the highest specificity, the highest positive predictive value and the highest positive likelihood ratio. The ROC analysis showed that the combination of Napsin-A, HNF-1ß and IMP3 offered the biggest AUC compared with either the singular marker performances or the other binary combinations (p < 0.001). In 15 cases of EC mixed with CCC, IMP3 showed a better discrimination value than the other two markers. Consequently, adding IMP3 to the diagnostic panel might provide some help with the pathological diagnosis of ovarian CCC.