Uterine Cervical Adenosarcoma Showing an Endophytic Growth Pattern.

Adenosarcomas are biphasic neoplasms that usually originate in the uterine corpus and comprise a benign epithelial component and a malignant stromal component. Uterine adenosarcomas typically present with abnormal genital bleeding, an enlarged uterus, and a tumor that protrudes into the endometrial cavity. These tumors rarely protrude through the cervical os and are often misdiagnosed as cervical polyps. We present the case of a patient with cervical adenosarcoma with characteristics different from those reported in previous cases. This tumor showed endophytic growth, which is rare in cervical adenosarcomas. No watery discharge or obvious genital bleeding was noted. Although the tumor measured 4 cm, vaginal bleeding was noted only once at 6 months before diagnosis and was in the form of faint brown discharge.

Renal Subcapsular Hematoma Formation Due to Hydronephrosis Caused by Recurrent Uterine Cervical Cancer.

Most non-traumatic renal subcapsular hematomas are found in the presence of primary or metastatic renal tumors, or in the presence of vascular disease of the renal blood vessels. We managed an asymptomatic renal subcapsular hematoma that formed due to uterine cervical cancer that metastasized to the left common iliac lymph nodes. A 48-year-old woman with stage IB1 cervical cancer underwent neoadjuvant chemotherapy and concurrent chemoradiation following a radical hysterectomy. Six months after the completion of her first treatment, she developed left-sided hydronephrosis, a left subcapsular hematoma and left common iliac lymph nodes enlargement as demonstrated with contrast-enhanced computed tomography. Although a renal subcapsular hematoma is rarely a symptom of cervical cancer recurrence, it should be considered if other neoplastic or vascular diseases are ruled out.

WAPL induces cervical intraepithelial neoplasia modulated with estrogen signaling without HPV E6/E7.

Since cervical cancer still afflicts women around the world, it is necessary to understand the underlying mechanism of cervical cancer development. Infection with HPV is essential for the development of cervical intraepithelial neoplasia (CIN). In addition, estrogen receptor signaling is implicated in the development of cervical cancer. Previously, we have isolated human wings apart-like (WAPL), which is expected to cause chromosomal instability in the process of HPV-infected precancerous lesions to cervical cancer. However, the role of WAPL in the development of CIN is still unknown. In this study, in order to elucidate the role of WAPL in the early lesion, we established WAPL overexpressing mice (WAPL Tg mice) and HPV E6/E7 knock-in (KI) mice. WAPL Tg mice developed CIN lesion without HPV E6/E7. Interestingly, in WAPL Tg mice estrogen receptor 1 (ESR1) showed reduction as compared with the wild type, but cell growth factors MYC and Cyclin D1 controlled by ESR1 expressed at high levels. These results suggested that WAPL facilitates sensitivity of ESR1 mediated by some kind of molecule, and as a result, affects the expression of MYC and Cyclin D1 in cervical cancer cells. To detect such molecules, we performed microarray analysis of the uterine cervix in WAPL Tg mice, and focused MACROD1, a co-activator of ESR1. MACROD1 expression was increased in WAPL Tg mice compared with the wild type. In addition, knockdown of WAPL induced the downregulation of MACROD1, MYC, and Cyclin D1 but not ESR1 expression. Furthermore, ESR1 sensitivity assay showed lower activity in WAPL or MACROD1 downregulated cells than control cells. These data suggested that WAPL increases ESR1 sensitivity by activating MACROD1, and induces the expression of MYC and Cyclin D1. Therefore, we concluded that WAPL not only induces chromosomal instability in cervical cancer tumorigenesis, but also plays a key role in activating estrogen receptor signaling in early tumorigenesis.

Biochemical properties of human full-length aryl hydrocarbon receptor (AhR).

The aryl hydrocarbon receptor (AhR) is a very unstable protein. AhR binds to the molecular chaperone complex (HSP90-p23-XAP2) to maintain a stable structure in the cytoplasm. After binding to ligands, such as dioxin, AhR translocates from the cytoplasm to the nucleus with a molecular chaperone complex. The protein forms a heterodimer with Arnt after nuclear transfer, functions as a transcription factor by binding to a xenobiotic responsive element (XRE), and induces the cytochrome P450 1A1 (CYP1A1). Because of the unstable protein, expression of the full-length AhR in the E. coli expression system is very difficult. Many studies investigated AhR using AhR domains in vitro. We expressed and purified the human full-length AhR in E. coli expression system. Furthermore, specific antibodies were prepared. Purified full-length AhR could bind to ligand. In the presence of ligand, α-helix and random coil of AhR increased and ß-sheet decreased on CD spectrum. Full-length AhR could bind to HSP90, XAP2 and p23 in the presence or absence of ligand. We now show the biochemical properties of full-length AhR.

Villoglandular Papillary Adenocarcinoma With Cervical Intraepithelial Neoplasia 3 of the Cervix in a Woman With a Misdiagnosis of a Cervical Polyp.

We report a case in which a polypoid lesion with a diameter of 5 mm was diagnosed as a cervical polyp due to a negative Papanicolaou (Pap) smear in the cervix, and polypectomy revealed a diagnosis of villoglandular papillary adenocarcinoma (VGA) on histopathological examination. A 63-year-old woman with a cervical polyp, who had no abnormal symptoms and a negative Pap smear was referred to our hospital. We performed cervical polypectomy, and the pathological result was VGA with cervical intraepithelial neoplasia (CIN) 3. Even if an asymptomatic cervical polyp with a negative Pap smear is diagnosed, in some patients VGA of the uterine cervix may coexist with CIN. Therefore, asymptomatic cervical polyps with negative Pap smears should not be followed up without removal.

Vaginal Intraepithelial Neoplasia 3 in a Woman Without Simultaneous Cervical Intraepithelial Neoplasm.

In the presence of the uterus, it is rare that vaginal intraepithelial neoplasia (VAIN) alone exists. We described our experience with a case in which VAIN3 was found in the vaginal fornix without lesions in the uterine cervix. She had cervical intraepithelial neoplasm (CIN) 1 several years ago. After that, it disappeared. However, high-grade squamous intraepithelial lesion persisted cytologically. After hysterectomy was performed, VAIN3 was found in the vaginal fornix. CIN was not found in the cervix. We are apt to suspect endocervical lesions when Papanicolau (Pap) smear shows abnormalities and colposcopy fails to identify columnar epithelium. However, we need to keep in mind that the vaginal fornix may have a lesion. It may be difficult to assess the vaginal fornix in young women because of a large cervix. The presence of VAIN should also be considered when cytological abnormalities persist on Pap smears.

Identifying selection criteria for non-radical hysterectomy in FIGO stage IB cervical cancer.

AIM: This retrospective study sought to identify the selection criteria required for a non-radical hysterectomy with minimal parametrectomy in patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB invasive cervical cancer. METHODS: Overall, 461 patients with FIGO stage IB cervical cancer who underwent a radical hysterectomy were reviewed clinicopathologically according to pathological tumor size (≤2 cm, >2 - ≤4 cm, and > 4 cm). RESULTS: The pathological parametrial involvement rate in the less than equal to 2 cm group (2%) was significantly lower than in greater than 2-less than equal to 4 cm (13%) or greater than 4 cm (29%) groups (both P < 0.001). The 5-year overall survival rate was significantly higher in the less than equal to 2 cm group (97%, 95% confidence interval [CI] 94-99%) compared with greater than 2-less than equal to 4 cm (90%, 95% CI 94-86%) and greater than 4 cm (70%, 95% CI 79-60%) groups (both P < 0.001). Cox model analysis identified tumor size to be an independent prognostic factor for survival (95% CI 1.33-5.78) and recurrence (95% CI 1.31-5.66) compared to other pathological factors. However, a significant difference between the three groups was not found in rates of Grade 3 or 4 adverse events following radical hysterectomy (P = 0.19). CONCLUSIONS: Tumor size is an independent prognostic factor for survival in patients with FIGO stage IB invasive cervical cancer. This retrospective study suggests that FIGO stage IB patients with a less than equal to 2 cm tumor size are optimal candidates for non-radical hysterectomy with minimal parametrectomy, and without resulting bladder dysfunction.

Knowledge, fatigue, and cognitive factors as predictors of lymphoedema risk-reduction behaviours in women with cancer.

OBJECTIVE: To identify social-cognitive factors predicting lymphoedema risk-reduction behaviours (hereafter, self-care) after discharge among patients in Japan with breast or gynaecological cancers, using the extended model of the theory of planned behaviour. METHODS: A cross-sectional questionnaire study was conducted in an oncology hospital. Items measured were (1) knowledge about self-care; (2) the Cancer Fatigue Scale; (3) social-cognitive factors in the theory of planned behaviour (attitudes, subjective norms, and perceived behavioural control); (4) self-care (limb hygiene, observation, articular movement, recommended risk-reduction behaviours in daily life, and diet and weight control); and (5) demographics. Of 202 respondents, 147 who had not been diagnosed with lymphoedema were eligible for statistical analysis (65.3% with gynaecological cancer, 34.7% with breast cancer). RESULTS: Structural equation modelling was used to examine a hypothesised model based on the theory of planned behaviour. The results revealed that a longer time since surgery, higher levels of fatigue, less knowledge, higher expected efficacy of self-care, and lower perceived behavioural control directly and significantly predicted less self-care behaviour. CONCLUSIONS: Besides education about self-care behaviour, levels of fatigue and perceived behavioural control should be taken into account to encourage female patients with cancer to perform self-care after discharge. Continuous psycho-educational programmes after discharge may help to facilitate self-care behaviours among long-term female cancer survivors.

Integrated extracellular microRNA profiling for ovarian cancer screening.

A major obstacle to improving prognoses in ovarian cancer is the lack of effective screening methods for early detection. Circulating microRNAs (miRNAs) have been recognized as promising biomarkers that could lead to clinical applications. Here, to develop an optimal detection method, we use microarrays to obtain comprehensive miRNA profiles from 4046 serum samples, including 428 patients with ovarian tumors. A diagnostic model based on expression levels of ten miRNAs is constructed in the discovery set. Validation in an independent cohort reveals that the model is very accurate (sensitivity, 0.99; specificity, 1.00), and the diagnostic accuracy is maintained even in early-stage ovarian cancers. Furthermore, we construct two additional models, each using 9-10 serum miRNAs, aimed at discriminating ovarian cancers from the other types of solid tumors or benign ovarian tumors. Our findings provide robust evidence that the serum miRNA profile represents a promising diagnostic biomarker for ovarian cancer.

Information-seeking, information sources and ongoing support needs after discharge to prevent cancer-related lymphoedema.

OBJECTIVES: To compare gynaecological and breast cancer patients in their information-seeking behaviours, usefulness of information sources and ongoing care needs after discharge to prevent the onset of lymphoedema. METHODS: We conducted a consecutive cross-sectional survey in an oncology hospital. Adult patients with stage I, II or III gynaecological or breast cancer who had undergone lymph node dissection and had not been diagnosed with lymphoedema were eligible for inclusion. The survey explored physical health status, knowledge of self-care, information-seeking behaviours, information sources and need for ongoing care from an oncology hospital and/or community health centre. RESULTS: Among 254 patients recruited, 202 responded (79.5% response rate). In total, 147 patients were eligible for statistical analysis. Irrespective of cancer type, the most commonly sought information was lymph drainage. Information on preventing weight gain was sought more often by breast cancer patients than gynaecological cancer patients. Regardless of cancer type, the most common information sources were nurses at an oncology hospital. Gynaecological cancer patients perceived nurses at the oncology hospital as useful for understanding risks, symptoms and prevention of lymphoedema. Irrespective of cancer type, ongoing need for help with lymphoedema prevention was reported both from the oncology hospital and the community centre. Limb symptoms, poor health status and poor knowledge affected the ongoing needs of gynaecological cancer patients at the oncology hospital, whereas poor health status affected ongoing needs in community health centres among both types of cancer patients. CONCLUSIONS: Both gynaecological and breast cancer patients reported ongoing care needs, but that details of information-seeking behaviours differed.

Prognostic factors for patients with early-stage uterine serous carcinoma without adjuvant therapy.

OBJECTIVE: Uterine serous carcinoma (USC) is an aggressive type 2 endometrial cancer. Data on prognostic factors for patients with early-stage USC without adjuvant therapy are limited. This study aims to assess the baseline recurrence risk of early-stage USC patients without adjuvant treatment and to identify prognostic factors and patients who need adjuvant therapy. METHODS: Sixty-eight patients with International Federation of Gynecology and Obstetrics (FIGO) stage I-II USC between 1997 and 2016 were included. All the cases did not undergo adjuvant treatment as institutional practice. Clinicopathological features, recurrence patterns, and survival outcomes were analyzed to determine prognostic factors. RESULTS: FIGO stages IA, IB, and II were observed in 42, 7, and 19 cases, respectively. Median follow-up time was 60 months. Five-year disease-free survival (DFS) and overall survival (OS) rates for all cases were 73.9% and 78.0%, respectively. On multivariate analysis, cervical stromal involvement and positive pelvic cytology were significant predictors of DFS and OS, and ≥1/2 myometrial invasion was also a significant predictor of OS. Of 68 patients, 38 patients had no cervical stromal invasion or positive pelvic cytology and showed 88.8% 5-year DFS and 93.6% 5-year OS. CONCLUSION: Cervical stromal invasion and positive pelvic cytology are prognostic factors for stage I-II USC. Patients with stage IA or IB USC showing negative pelvic cytology may have an extremely favorable prognosis and need not receive any adjuvant therapies.

Uterine adenosarcoma in Japan: Clinicopathologic features, diagnosis and management.

AIM: Uterine adenosarcoma is a rare malignancy with limited cohort data in Asian countries. This study evaluated the clinicopathologic features of Japanese patients with uterine adenosarcoma and their potential treatment challenges. METHODS: A retrospective chart review was performed at the National Cancer Center Hospital, Japan from 2000 to 2016. A literature search for Japanese cases of uterine adenosarcoma was conducted using PubMed, Japanese Central Review of Medicine, and the Annual of Pathological Autopsy Cases in Japan. Only histologically confirmed cases of uterine adenosarcoma were included. All collected data were analyzed. RESULTS: A total of 110 cases was identified (6 from our hospital and 104 from the literature review). Most baseline characteristics were similar to those reported in western countries. Death due to the disease was observed in 34% (29/86) of patients, whereas patients with stage IA disease showed a 13% (4/30) recurrence rate and a 3.3% (1/30) mortality rate. Preoperative radiological and pathological examinations occasionally failed to help reach the correct diagnosis. In cases of sarcomatous overgrowth, the recurrence and mortality rates were 45% (9/20) and 35% (7/20), respectively. Distant recurrence occurred in 44% (12/27) of cases, 75% of which included lung metastasis. CONCLUSIONS: This study showed the clinicopathologic features of Japanese patients with uterine adenosarcoma and suggested potential solutions for improving prognosis including early treatment based on a timely diagnosis, the development of effective adjuvant therapy for patients at high risk of recurrence, and optimal follow-up focusing on late recurrence and lung metastasis.

A combination of circulating miRNAs for the early detection of ovarian cancer.

Ovarian cancer is the leading cause of gynecologic cancer mortality, due to the difficulty of early detection. Current screening methods lack sufficient accuracy, and it is still challenging to propose a new early detection method that improves patient outcomes with less-invasiveness. Although many studies have suggested the utility of circulating microRNAs in cancer detection, their potential for early detection remains elusive. Here, we develop novel predictive models using a combination of 8 circulating serum miRNAs. This method was able to successfully distinguish ovarian cancer patients from healthy controls (area under the curve, 0.97; sensitivity, 0.92; and specificity, 0.91) and early-stage ovarian cancer from patients with benign tumors (0.91, 0.86 and 0.83, respectively). This method also enables subtype classification in 4 types of epithelial ovarian cancer. Furthermore, it is found that most of the 8 miRNAs were packaged in extracellular vesicles, including exosomes, derived from ovarian cancer cells, and they were circulating in murine blood stream. The circulating miRNAs described in this study may serve as biomarkers for ovarian cancer patients. Early detection and subtype determination prior to surgery are crucial for clinicians to design an effective treatment strategy for each patient, as is the goal of precision medicine.

Malignant extracellular vesicles carrying MMP1 mRNA facilitate peritoneal dissemination in ovarian cancer.

Advanced ovarian cancers are highly metastatic due to frequent peritoneal dissemination, resulting in dismal prognosis. Here we report the functions of cancer-derived extracellular vesicles (EVs), which are emerging as important mediators of tumour metastasis. The EVs from highly metastatic cells strongly induce metastatic behaviour in moderately metastatic tumours. Notably, the cancer EVs efficiently induce apoptotic cell death in human mesothelial cells in vitro and in vivo, thus resulting in the destruction of the peritoneal mesothelium barrier. Whole transcriptome analysis shows that MMP1 is significantly elevated in mesothelial cells treated with highly metastatic cancer EVs and intact MMP1 mRNAs are selectively packaged in the EVs. Importantly, MMP1 expression in ovarian cancer is tightly correlated with a poor prognosis. Moreover, MMP1 mRNA-carrying EVs exist in the ascites of cancer patients and these EVs also induce apoptosis in mesothelial cells. Our findings elucidate a previously unknown mechanism of peritoneal dissemination via EVs.

Spontaneous ureteral rupture during concurrent chemoradiotherapy in a woman with uterine cervical cancer.

Spontaneous rupture of the renal pelvis and ureter is associated with obstruction of the urinary collecting system, but is rarely caused by tumors. We describe our experience with a patient who had uterine cervical cancer with mild hydroureter in whom spontaneous ureteral rupture occurred during concurrent chemoradiotherapy. The patient was a 66-year-old woman with stage IIIB uterine cervical cancer and mild hydroureter who received concurrent chemoradiotherapy. The patient felt uncontrolled right-side abdominal pain caused by ureteral rupture after she was given hydration and an intravenous bolus injection of furosemide during the first week of chemoradiotherapy. Contrast-enhanced computed tomography was more useful than ultrasonography for diagnosis of the ureteral rupture. The ureteral rupture in our patient was attributed to a rapid rise in the pressure of the urinary collecting system caused by hydration and the bolus injection of furosemide. Placement of a double-J stent before starting concurrent chemoradiotherapy may help to prevent ureteral rupture in patients who have uterine cervical cancer with mild hydroureter.

Immunophenotype and human papillomavirus status of serous adenocarcinoma of the uterine cervix.

Serous adenocarcinoma of the cervix (SACC) is a very rare tumor. Our study aimed to characterize the immune profile and human papillomavirus (HPV) status of SACC, in comparison with other serous adenocarcinomas arising in the female genital tract. The pathological specimens obtained from 81 patients with serous carcinoma of the uterine cervix (n = 12), 29 endometrium, 20 ovary and 20 patients with mucinous carcinoma of the uterine cervix were reviewed. We assessed the expression of WT-1, p53, p16, HER2, CEA, and CA125 by immunohistochemistry and HPV DNA by PCR in 12 SACC samples. Their immune profile was compared with that of uterine papillary serous carcinoma (UPSC), ovarian serous adenocarcinoma (OSA), and mucinous endocervical adenocarcinoma (MEA). WT-1 and HER2 were expressed in very few SACC samples (0 and 0%, respectively), but p16, CA125, CEA and p53 were present in 100, 92, 58 and 50%, respectively. The difference in WT-1 expression between SACC and UPSC, MEA is not significant, but SACC differ significantly from OSA (p < 0.01). HPV DNA (type 16 or 18) was detected in 4 of the 12 SACC. The immunophenotype of SACC was similar to UPSC, whereas the frequency of expression of WT-1 was significantly lower in SACC than OSA. It appeared that p53 expression was associated with worse clinical outcome in patients with SACC, and that HPV infection was related to its occurrence.

Combination of squamous cell carcinoma-antigen, carcinoembryonic antigen, and carbohydrate antigen 19-9 predicts positive pelvic lymph nodes and parametrial involvement in early stage squamous cell carcinoma of the uterine cervix.

AIM: We examined the correlations between the pretreatment values of four tumor markers (squamous cell carcinoma [SCC]-antigen, carcinoembryonic antigen [CEA], carbohydrate antigen [CA]19-9, and CA125) and postsurgical high-risk factors (parametrial involvement and positive pelvic lymph nodes) in women with SCC of the uterine cervix who had International Federation of Gynecology and Obstetrics clinical stage IB and IIA disease and underwent radical hysterectomy. MATERIAL AND METHODS: In this retrospective study, we reviewed 291 patients between April 1989 and December 2008. The first 200 subjects, studied between 1989 and 2001, served as the training set, and another 91 subjects, studied between 2002 and 2008, comprised the test set. To evaluate the correlations between pretreatment tumor markers and postsurgical high-risk factors, the χ²-test and logistic regression analysis were used for univariate and multivariate analysis, respectively. RESULTS: Multivariate analysis with receiver-operator curves showed that the combination of SCC-antigen, CEA, and CA19-9 strongly predicted postsurgical high-risk factors. Analysis of the training set showed that 66.7% (95% confidence interval, 52.6-84.8%) of patients who tested positive for at least two of these three tumor markers had postsurgical high-risk factors. Similar results were obtained with the test set. CONCLUSIONS: Preoperative levels of SCC-antigen, CEA, and CA19-9 are useful for predicting the status of postsurgical high-risk factors in women with SCC of the uterine cervix who undergo radical hysterectomy.

Clinicopathological and prognostic impact of human epidermal growth factor receptor type 2 (HER2) and hormone receptor expression in uterine papillary serous carcinoma.

Uterine papillary serous carcinoma (UPSC) is a rare and aggressive variant of endometrial carcinoma. Little is known about the pathological and biological features of this tumor. Human epidermal growth factor receptor 2 (HER2) and hormone receptor (HR) expression have an important role in tumor behavior and clinical outcome, but their relevance in UPSC is not clear. In the present study, the immunohistochemical expression of HER2 and HR was assessed in 27 patients with Stage I disease, 13 with Stage II disease, 25 with Stage III disease, and 6 with Stage IV disease. Correlations between HER2 and HR expression and the clinicopathological parameters of UPSC were evaluated using Cox's univariate and multivariate analyses. For all patients, the 5-year recurrence-free survival (RFS) and overall survival (OS) rates were 51% and 66%, respectively; in patients with Stage I, II, III and IV disease, the RFS and OS were 67%/81%, 59%/77%, 43%/54% and 0%/0%, respectively. Of all 71 patients, 14% (10/71) were positive for HER2 and 52% (37/71) were positive for HR. Overexpression of HER2 was correlated with lower OS (P = 0.01), whereas HR overexpression was correlated with higher OS (P = 0.008). In multivariate models, HER2, HR, and histologic subtype were identified as independent prognostic indicators for RFS (P = 0.022, P = 0.018, and P = 0.01, respectively), but HR was the only independent factor associated with OS (P = 0.044). Thus, HER2 and HR are prognostic variables in UPSC, with HR an independent prognostic factor for OS.

Prognostic impact of the history of breast cancer and of hormone therapy in uterine carcinosarcoma.

OBJECTIVE: Recent studies reveal an association between hormone therapy for breast cancer (BC), such as tamoxifen (TAM) and toremifene (TOR), and uterine carcinosarcoma (UCS). The aim of this study was to investigate the characteristics and prognosis of patients with UCS after BC and hormone therapy. METHODS: Between January 1997 and December 2007, we treated 51 patients with UCS. The medical records of these patients were reviewed, and factors that influenced their survival were retrospectively analyzed using univariate and multivariate analyses. RESULTS: Ten (19.6%) of the 51 patients had a history of BC; 6 (11.8%) had received hormone therapy with TAM or TOR. The characteristics of the patients with UCS were similar regardless of whether they had a history of BC or hormone therapy. On univariate analysis, age greater than 56 years, elevated serum lactate dehydrogenase levels, residual tumors, FIGO (International Federation of Gynecology and Obstetrics) stage higher than stage IIIa, and non-endometrioid carcinomatous components were identified as prognostic factors. On multivariate analysis, in addition to residual tumors, FIGO stage higher than stage IIIa, and non-endometrioid carcinomatous components, a history of BC (relative risk, 0.14), a history of TAM use (relative risk, 15.9), and a history of TOR use (relative risk, 16.9) were also identified as independently significant prognostic factors. CONCLUSIONS: Our data suggest that a history of BC and hormone therapy for BC is a risk factor for developing UCS without obvious impacts on the characteristics of UCS. Both of these factors had statistically significant impacts on the prognosis of patients with UCS. Further studies are necessary to clarify and validate these associations.