Cervical Cancer, Papillomavirus, and miRNA Dysfunction

Cervical cancer is the leading cause of death by cancer in women from developing countries. Persistent infection with high-risk human papillomavirus (HPV) types 16 and 18 is a major risk factor for cervical carcinogenesis. Nevertheless, only a few women with morphologic expression of HPV infection progress into invasive disease suggesting the involvement of other factors in cervical carcinogenesis. MicroRNAs (miRNAs) are conserved small non-coding RNAs that negatively regulate gene expression including genes involved in fundamental biological processes and human cancer. Dysregulation of miRNAs has been widely reported in cervical cancer. This work focuses on reviewing the miRNAs affected during the HPV infection process, as well relevant miRNAs that contribute to the development and maintenance of malignant cervical tumor cells. Finally, we recapitulate on miRNAs that may be used to distinguish between healthy individuals from patients with precancerous lesions or cervical tumors.

A Cost-Effectiveness Analysis of Neoadjuvant Therapy for Neuroendocrine Cervical Tumors

Purpose. This study aimed to assess the cost-effectiveness of neoadjuvant therapy in combination with surgery and adjuvant therapy compared with either surgery alone or surgery plus adjuvant therapy for the treatment of neuroendocrine cervical tumors (NETs). Materials and methods. A single-institution retrospective analysis of 107 patients with NETs was performed based on the new International Federation of Gynecology and Obstetrics (FIGO 2018) staging system. We divided the patients who underwent radical surgery into two groups: neoadjuvant therapy (NACT) and non-neoadjuvant therapy (non-NACT) groups. We performed subgroup analysis of overall survival and cost-effectiveness by dividing the patients with stage I-IV disease into four subgroups. An assessment was constructed to reflect the costs and effectiveness of the treatment from the perspectives of both clinical practice and health economics.Results. The NACT group had -0.45 life-years (LYs) at an incremental cost of $15197.58, compared with the non-NACT group, which means that it is not cost-effective. However, subgroup analysis of patients with stage II disease showed that the NACT group had significantly better overall survival time than the non-NACT group (median overall survival had not been reached versus 29.23 months, p＜0.001). The NACT group had an incremental cost-effectiveness ratio (ICER) of $5921.43/LY compared with the non-NACT group for stage II disease. Probabilistic sensitivity analyses showed that when the willingness-to-pay (WTP) threshold reached $31118.29/LY, which is nearly three times China's per capita GDP 2020, the probability of NACT being cost-effective was 97% versus non-NACT group in the treatment of stage II neuroendocrine tumors of the uterine cervix. Conclusion. NACT is not a cost-effective treatment strategy compared with non-NACT in the treatment of NETs, but may be a cost-effective treatment option for stage II NETs.

Extrachromosomal Amplification of Human Papillomavirus Episomes as a Mechanism of Cervical Carcinogenesis

Integration of Human Papillomaviruses (HPV) is an important mechanism of carcinogenesis but is absent in a significant fraction of HPV16+ tumors. We applied long-read whole-genome sequencing (WGS) to cervical cancer cell lines and tumors. In two HPV16+ cell lines, we identified large tandem arrays of full-length and truncated viral genomes integrated into multiple locations indicating formation as extrachromosomal DNA (HPV superspreading). An HPV16+ cell line with episomal DNA has tandem arrays of full-length, truncated, and rearranged HPV16 genomes (multimer episomes). WGS of HPV16+ cervical tumors revealed that 11/20 with only episomal HPV (EP) have intact monomer episomes. The remaining nine EP tumors have multimer and rearranged HPV genomes. Most HPV rearrangements disrupt the E1 and E2 genes, and EP tumors overexpress the E6 and E7 viral oncogenes. Tumors with both episomal and integrated HPV16 display multimer episomes and concatemers of human and viral sequences. One tumor has a recurrent deletion of an inhibitory site regulating E6 and E7 expression, and another has a recurrent duplication consistent with HPV superspreading. Therefore, HPV16 can cause cancer without integration through aberrant episomal replication, forming rearranged and multimer episomes.

Antibody-Antineoplastic Conjugates in Gynecological Malignancies: Current Status and Future Perspectives

In the last decade, antibody-drug conjugates (ADCs), normally formed by a humanized antibody and a small drug via a chemical cleavable or non-cleavable linker, have emerged as a potential treatment strategy in cancer disease. They allow to get a selective delivery of the chemotherapeutic agents at the tumor level, and, consequently, to improve the antitumor efficacy and, especially to decrease chemotherapy-related toxicity. Currently, nine antibody-drug conjugate-based formulations have been already approved and more than 80 are under clinical trials for the treatment of several tumors, especially breast cancer, lymphomas, and multiple myeloma. To date, no ADCs have been approved for the treatment of gynecological formulations, but many formulations have been developed and have reached the clinical stage, especially for the treatment of ovarian cancer, an aggressive disease with a low five-year survival rate. This manuscript analyzes the ADCs formulations that are under clinical research in the treatment of gynecological carcinomas, specifically ovarian, endometrial, and cervical tumors.

Carcinosarcoma del cuello uterino: reporte de un caso y revisión de la literatura

Cervical carcinosarcomas are extremely rare, accounting for less than 0.5% of cervical tumors. Due to its low incidence there is no specific protocol of action, which is associated with a poor prognosis. It is frequently diagnosed in postmenopausal women and in advanced stage, with large tumors with vaginal and parametrial metastases. Surgery is considered the treatment of choice, requiring in some cases adjuvant radio-chemotherapy. The prognosis will depend fundamentally on the stage at the time of diagnosis. Since there is little published evidence on this type of tumors we see the need for the publication of cases and reviews of the literature in this regard, to develop unified protocols for the management of this rare pathology. We present the case of a 51-yearold woman who consulted for postmenopausal metrorrhagia, observing a cervical mass with vaginal involvement, corresponding to a carcinosarcoma of the cervix; receiving treatment with radio-chemotherapy, with few side effects and good response. Keywords: Carcinosarcoma, uterine cervix, chemotherapy, radiotherapy, surgery.

Lack of Conserved miRNA Deregulation in HPV-Induced Squamous Cell Carcinomas

Squamous cell carcinomas (SCCs) in the anogenital and head and neck regions are associated with high-risk types of human papillomaviruses (HR-HPV). Deregulation of miRNA expression is an important contributor to carcinogenesis. This study aimed to pinpoint commonly and uniquely deregulated miRNAs in cervical, anal, vulvar, and tonsillar tumors of viral or non-viral etiology, searching for a common set of deregulated miRNAs linked to HPV-induced carcinogenesis. RNA was extracted from tumors and nonmalignant tissues from the same locations. The miRNA expression level was determined by next-generation sequencing. Differential expression of miRNAs was calculated, and the patterns of miRNA deregulation were compared between tumors. The total of deregulated miRNAs varied between tumors of different locations by two orders of magnitude, ranging from 1 to 282. The deregulated miRNA pool was largely tumor-specific. In tumors of the same location, a low proportion of miRNAs were exclusively deregulated and no deregulated miRNA was shared by all four types of HPV-positive tumors. The most significant overlap of deregulated miRNAs was found between tumors which differed in location and HPV status (HPV-positive cervical tumors vs. HPV-negative vulvar tumors). Our results imply that HPV infection does not elicit a conserved miRNA deregulation in SCCs.

ARHGEF10L Promotes Cervical Tumorigenesis via RhoA-Mediated Signaling

Background. Rho guanine nucleotide exchange factor 10-like protein (ARHGEF10L) is a member of the guanine nucleotide exchange factor family, which regulates Rho GTPase activities, thus contributing to tumorigenesis. Our previous study demonstrated a strong association between the ARHGEF10L gene and the risk of cervical carcinoma. This study investigated the pathogenic role and mechanism of ARHGEF10L in cervical tumors. Methods. The HeLa cell line, which was derived from cervical carcinoma, was transfected with ARHGEF10L-overexpressing plasmids or anti-ARHGEF10L siRNA. Cell counting kit-8 assays, wound-healing assays, and cell apoptosis assays were performed to investigate the effects of ARHGEF10L on cell activities. A Rho pull-down assay and RNA-sequencing analysis were performed to investigate the pathogenic pathway of ARHGEF10L involvement in cervical tumors. Results. ARHGEF10L overexpression promoted cell proliferation and migration, reduced cell apoptosis, and induced epithelial-to-mesenchymal transition (EMT) via downregulation of E-cadherin and upregulation of N-cadherin and Slug in transfected HeLa cells. The overexpression of ARHGEF10L also upregulated GTP-RhoA, ROCK1, and phospho-ezrin/radixin/moesin (ERM) expression in HeLa cells. RNA-sequencing analysis detected altered transcription of 31 genes in HeLa cells with ARHGEF10L overexpression. Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) pathway analyses identified significant differences in cyclin-dependent protein serine/threonine kinase activity, cell responses to vitamin A, and Toll-like receptor signaling pathways. Both real-time PCR and Western blotting verified the increased expression of heat shock 70 kDa protein 6 (HSPA6) in ARHGEF10L-overexpressing HeLa cells. Since we reported that ARHGEF10L played a role through RhoA-ROCK1-ERM signaling, an important pathway in tumorigenesis, and stimulated EMT and HSPA6 expression in liver tumors and gastric tumor cells, we suggest that ARHGEF10L is a novel oncogene in many tumors.

Malacoplakia of the Uterine Cervix: A Case Report

Malacoplakia is an uncommon chronic granulomatous inflammation that rarely affects the female genital tract. A case of a 78-year-old woman with malacoplakia involving the uterine cervix and the vagina is described. The patient complained of vaginal bleeding. Clinically, a 13-mm mass was detected in the cervix, which was confirmed by ultrasound scan and magnetic resonance imaging. Histological examination showed a dense histiocytic infiltrate with abundant Michaelis–Gutmann bodies involving the uterine cervix and the upper vagina. The presence of Escherichia coli was confirmed in the lesion by immunohistochemistry and polymerase chain reaction. Only 12 cases of cervical malacoplakia have been reported to date. This condition should be included in the differential diagnosis of cervical tumors.

Small Cell Neuroendocrine Cervical Carcinoma: A Case Report

Objective: Small cell neuroendocrine cervical carcinoma is a neuroendocrine tumor with the great aggravation that comprises 0.5 to 3 percent of cervical tumors and progresses rapidly with early lymphogenous and hematogenous metastases. Case report: We reported a 40 years old woman with cervical cancer in stage IB2 that had radical hysterectomy with mistaken diagnosis of squamous cervical cancer. The disease has progressed after 50 days of surgery with a 6 cm tumor in vaginal cuff; review of pathology demonstrated small cell neuroendocrine cervical carcinoma. Conclusion: Recognition of this separate histopathological entity with IHC analysis is important. Chemoradiotherapy and multimodality therapeutic approaches could improve the survival rates.