Targeting progesterone signaling prevents metastatic ovarian cancer.

Effective cancer prevention requires the discovery and intervention of a factor critical to cancer development. Here we show that ovarian progesterone is a crucial endogenous factor inducing the development of primary tumors progressing to metastatic ovarian cancer in a mouse model of high-grade serous carcinoma (HGSC), the most common and deadliest ovarian cancer type. Blocking progesterone signaling by the pharmacologic inhibitor mifepristone or by genetic deletion of the progesterone receptor (PR) effectively suppressed HGSC development and its peritoneal metastases. Strikingly, mifepristone treatment profoundly improved mouse survival (∼18 human years). Hence, targeting progesterone/PR signaling could offer an effective chemopreventive strategy, particularly in high-risk populations of women carrying a deleterious mutation in the BRCA gene.

In vivo modeling of metastatic human high-grade serous ovarian cancer in mice.

Metastasis is responsible for 90% of human cancer mortality, yet it remains a challenge to model human cancer metastasis in vivo. Here we describe mouse models of high-grade serous ovarian cancer, also known as high-grade serous carcinoma (HGSC), the most common and deadliest human ovarian cancer type. Mice genetically engineered to harbor Dicer1 and Pten inactivation and mutant p53 robustly replicate the peritoneal metastases of human HGSC with complete penetrance. Arising from the fallopian tube, tumors spread to the ovary and metastasize throughout the pelvic and peritoneal cavities, invariably inducing hemorrhagic ascites. Widespread and abundant peritoneal metastases ultimately cause mouse deaths (100%). Besides the phenotypic and histopathological similarities, mouse HGSCs also display marked chromosomal instability, impaired DNA repair, and chemosensitivity. Faithfully recapitulating the clinical metastases as well as molecular and genomic features of human HGSC, this murine model will be valuable for elucidating the mechanisms underlying the development and progression of metastatic ovarian cancer and also for evaluating potential therapies.

Successful yolk-sac tumor treatment with fertility-sparing partial oophorectomy.

Yolk-sac tumors account for about 20% of ovarian germ cell tumors and occur predominantly in women below 35 years of age. Modern evidence-based treatment strategies have ensured long term post-treatment survival, but with increased survival, attention has been turned to an urgent need for developing fertility sparing treatment strategies. In this report we describe the successful treatment of a young woman who was able to conceive and deliver two children, in spite of the loss of one ovary two years prior to being diagnosed with an ovarian yolk-sac tumor on the remaining ovary.

Cell Origins of High-Grade Serous Ovarian Cancer.

High-grade serous ovarian cancer, also known as high-grade serous carcinoma (HGSC), is the most common and deadliest type of ovarian cancer. HGSC appears to arise from the ovary, fallopian tube, or peritoneum. As most HGSC cases present with widespread peritoneal metastases, it is often not clear where HGSC truly originates. Traditionally, the ovarian surface epithelium (OSE) was long believed to be the origin of HGSC. Since the late 1990s, the fallopian tube epithelium has emerged as a potential primary origin of HGSC. Particularly, serous tubal intraepithelial carcinoma (STIC), a noninvasive tumor lesion formed preferentially in the distal fallopian tube epithelium, was proposed as a precursor for HGSC. It was hypothesized that STIC lesions would progress, over time, to malignant and metastatic HGSC, arising from the fallopian tube or after implanting on the ovary or peritoneum. Many clinical studies and several mouse models support the fallopian tube STIC origin of HGSC. Current evidence indicates that STIC may serve as a precursor for HGSC in high-risk women carrying germline BRCA1 or 2 mutations. Yet not all STIC lesions appear to progress to clinical HGSCs, nor would all HGSCs arise from STIC lesions, even in high-risk women. Moreover, the clinical importance of STIC remains less clear in women in the general population, in which 85⁻90% of all HGSCs arise. Recently, increasing attention has been brought to the possibility that many potential precursor or premalignant lesions, though composed of microscopically-and genetically-cancerous cells, do not advance to malignant tumors or lethal malignancies. Hence, rigorous causal evidence would be crucial to establish that STIC is a bona fide premalignant lesion for metastatic HGSC. While not all STICs may transform into malignant tumors, these lesions are clearly associated with increased risk for HGSC. Identification of the molecular characteristics of STICs that predict their malignant potential and clinical behavior would bolster the clinical importance of STIC. Also, as STIC lesions alone cannot account for all HGSCs, other potential cellular origins of HGSC need to be investigated. The fallopian tube stroma in mice, for instance, has been shown to be capable of giving rise to metastatic HGSC, which faithfully recapitulates the clinical behavior and molecular aspect of human HGSC. Elucidating the precise cell(s) of origin of HGSC will be critical for improving the early detection and prevention of ovarian cancer, ultimately reducing ovarian cancer mortality.

The ovary is an alternative site of origin for high-grade serous ovarian cancer in mice.

Although named "ovarian cancer," it has been unclear whether the cancer actually arises from the ovary, especially for high-grade serous carcinoma (HGSC), also known as high-grade serous ovarian cancer, the most common and deadliest ovarian cancer. In addition, the tumor suppressor p53 is the most frequently mutated gene in HGSC. However, whether mutated p53 can cause HGSC remains unknown. In this study, we bred a p53 mutation, p53(R172H), into conditional Dicer-Pten double-knockout (DKO) mice, a mouse model duplicating human HGSC, to generate triple-mutant (TKO) mice. Like DKO mice, these TKO mice develop metastatic HGSCs originating from the fallopian tube. Unlike DKO mice, however, even after fallopian tubes are removed in TKO mice, ovaries alone can develop metastatic HGSCs, indicating that a p53 mutation can drive HGSC arising from the ovary. To confirm this, we generated p53(R172H)-Pten double-mutant mice, one of the genetic control lines for TKO mice. As anticipated, these double-mutant mice also develop metastatic HGSCs from the ovary, verifying the HGSC-forming ability of ovaries with a p53 mutation. Our study therefore shows that ovaries harboring a p53 mutation, as well as fallopian tubes, can be a distinct tissue source of high-grade serous ovarian cancer in mice.

Genotype-specific prevalence and distribution of human papillomavirus genotypes in underserved Latino women with abnormal Papanicolaou tests.

INTRODUCTION: Knowledge about the prevalence and distribution of human papillomavirus (HPV) genotypes in cervical premalignant and malignant lesions is crucial to guide development of clinical management strategies and prophylactic vaccines. The aim of this study was to determine HPV genotype-specific prevalence and distribution in an underserved cohort of Latino women. MATERIALS AND METHODS: From December 2009 to April 2011, 808 SurePath cervicovaginal specimens were collected from women who were referred from charity clinics for abnormal Papanicolaou tests. The patients' average age was 36.5 years (range 19-85 years). The specimens were tested for HPV genotypes by DNA microarray and sequencing assays. RESULTS: The HPV infection rate was extremely high (93% for any HPV and 64% for high-risk [HR]-HPV), with frequent multiple-strain infection (39%). Younger age (<30 years) was associated with frequent HR-HPV infection, multiple strain infections, and cytologic abnormalities. When compared with previous reports, HPV 16 remained the most common genotype (44.6%) in women with high-grade squamous intraepithelial lesion; however, a significant increase in HPV 31 (17.9%) and 45 (10.7%) and a decrease in HPV 35, 52, 33, and 66 were observed. CONCLUSIONS: The HPV genotype-specific prevalence and distribution pattern in this cohort of underserved Latino women differed significantly from previously published data in the United States. Understanding the potentially changing trends in HPV distribution pattern will help guide the development of appropriate preventive and therapeutic strategies for both underserved and general populations.

Tumor-to-tumor metastasis with endometrial carcinoma metastatic to squamous cell carcinoma of vulva: the first reported case.

Endometrial carcinoma metastasizing to the vulva is a rare occurrence, with only 15 reported cases in the literature. To our knowledge, no cases of tumor-to-tumor metastasis involving endometrial carcinoma as a donor tumor have ever been published. We report the first case of an endometrial carcinoma as a donor tumor metastasizing to a squamous cell carcinoma of the vulva, a recipient tumor. A 79-year-old woman with a history of endometrioid adenocarcinoma of the uterus presented with a vulvar lesion. Pathologic examination of the excised lesion confirmed the presence of metastatic endometrioid adenocarcinoma; however, it was found within a well-differentiated squamous cell carcinoma of the vulva. Surrounding the squamous cell carcinoma was a background of a high-grade vulvar intraepithelial lesion (vulvar intraepithelial neoplasia 3), and immunohistochemistry confirmed the presence of 2 separate tumors involved in a tumor-to-tumor metastasis. This unique case highlights the importance of awareness of the phenomenon, and expands the current spectrum of tumor-to-tumor metastases.

Digital slide imaging in cervicovaginal cytology: a pilot study.

CONTEXT: Digital whole slide imaging is the anticipated future of anatomic pathology, where sign-out of glass slides will be replaced by scanned images. Whole slide imaging has been successfully used in surgical pathology, but its usefulness and clinical application have been limited in cytology for several reasons, including lack of availability of z-axis depth focusing and large file size. Recently, several systems have become available in the United States for whole slide imaging with z-axis technology. OBJECTIVE: To determine the accuracy and efficiency of whole slide imaging, as compared with traditional glass slides, for use in cervicovaginal diagnostic cytology. DESIGN: Eleven cervicovaginal cytology cases (ThinPrep and SurePath) scanned at ×20, ×40, and ×40 z-stack magnifications using the BioImagene iScan Coreo Au 3.0 scanner were evaluated by 4 cytotechnologists and 3 pathologists in a blinded study. Different magnification scans were recorded as separate cases and presented in a randomized sequence. Corresponding glass slides were also reviewed. For each case, the diagnoses and total time to reach each diagnosis were recorded. RESULTS: Diagnostic accuracy was higher and average time per case was lower with glass slides as compared with all digital images. Among the digital images, the ×40 or ×40 z-stack had the highest diagnostic accuracy and lowest interpretation time. CONCLUSIONS: Whole slide imaging is a viable option for the purposes of teaching and consultations, and as a means of archiving cases. However, considering the large file size and total time to reach diagnosis on digital images, whole slide imaging is not yet ready for daily cervicovaginal diagnostic cytology screening use.

High-grade serous ovarian cancer arises from fallopian tube in a mouse model.

Although ovarian cancer is the most lethal gynecologic malignancy in women, little is known about how the cancer initiates and metastasizes. In the last decade, new evidence has challenged the dogma that the ovary is the main source of this cancer. The fallopian tube has been proposed instead as the primary origin of high-grade serous ovarian cancer, the subtype causing 70% of ovarian cancer deaths. By conditionally deleting Dicer, an essential gene for microRNA synthesis, and Pten, a key negative regulator of the PI3K pathway, we show that high-grade serous carcinomas arise from the fallopian tube in mice. In these Dicer-Pten double-knockout mice, primary fallopian tube tumors spread to engulf the ovary and then aggressively metastasize throughout the abdominal cavity, causing ascites and killing 100% of the mice by 13 mo. Besides the clinical resemblance to human serous cancers, these fallopian tube cancers highly express genes that are known to be up-regulated in human serous ovarian cancers, also demonstrating molecular similarities. Although ovariectomized mice continue to develop high-grade serous cancers, removal of the fallopian tube at an early age prevents cancer formation--confirming the fallopian tube origin of the cancer. Intriguingly, the primary carcinomas are first observed in the stroma of the fallopian tube, suggesting that these epithelial cancers have a mesenchymal origin. Thus, this mouse model demonstrates a paradigm for the origin and initiation of high-grade serous ovarian carcinomas, the most common and deadliest ovarian cancer.