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Can morphometric analysis of the fallopian tube fimbria predict the presence of uterine papillary serous carcinoma (UPSC)?

ABSTRACT: Uterine serous papillary carcinoma (UPSC) is an aggressive tumor, often diagnosed as a metastatic disease and characterized by a high recurrence rate and poor prognosis. UPSC represents a distinct subtype of endometrial cancer which is different in clinical and pathological behaviors from endometrioid endometrial carcinoma (EEC) and resembles more to serous ovarian carcinoma. Since tumors of serous papillary of the ovary are hypothesized to stem from cells of the fallopian tube's fimbria, we hypothesized that UPSC may also origin in the fallopian tubes. In our previous study, using a novel method of computerized morphometry of the fimbrial epithelium we have found significant differences between fimbriae of healthy women and serous ovarian cancer patients. In this study we showed the presence of morphologic differences between twenty-four fimbriae from healthy women, and twenty six fimbriae from uterus cancer (13 from UPSC patients and 13 from EEC patients). All fimbriae reported by the pathologist as "normal" were subjected to a computerized histomorphometric analysis. Two-step method of computerized histomorphometry, i.e. Fast Fourier transformation (FFT) followed by a co-occurrence matrix analysis and an additional analysis of the nuclear symmetry of the tubal fimbrial epithelium were applied. Using these novel methods, we were able to show differences in the morphometric characteristics of the fimbriae in UPSC patients compared to EEC and healthy patients. It is yet to be determined the clinical significance of this observation.

SUBMITTER: Amit A

PROVIDER: S-EPMC6394988 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveStage I-II uterine papillary serous carcinoma (UPSC) has aggressive biological behavior and leads to poor prognosis. However, clinicopathologic risk factors to predict cancer-specific survival of patients with stage I-II UPSC were still unclear. This study was undertaken to develop a prediction model of survival in patients with early-stage UPSC.MethodsUsing Surveillance, Epidemiology, and End Results (SEER) database, 964 patients were identified with International Federation of Gynecology and Obstetrics (FIGO) stage I-II UPSC who underwent at least hysterectomy between 2004 and 2015. By considering competing risk events for survival outcomes, we used proportional subdistribution hazards regression to compare cancer-specific death (CSD) for all patients. Based on the results of univariate and multivariate analysis, the variables were selected to construct a predictive model; and the prediction results of the model were visualized using a nomogram to predict the cancer-specific survival and the response to adjuvant chemotherapy and radiotherapy of stage I-II UPSC patients.ResultsThe median age of the cohort was 67 years. One hundred and sixty five patients (17.1%) died of UPSC (CSD), while 8.6% of the patients died from other causes (non-CSD). On multivariate analysis, age ≥ 67 (HR = 1.45, P = .021), tumor size ≥ 2 cm (HR = 1.81, P = .014) and >10 regional nodes removed (HR = 0.52, P = .002) were significantly associated with cumulative incidence of CSD. In the age ≥67 cohort, FIGO stage IB-II was a risk factor for CSD (HR = 1.83, P = .036), and >10 lymph nodes removed was a protective factor (HR = 0.50, P = .01). Both adjuvant chemotherapy combined with radiotherapy and adjuvant chemotherapy alone decreased CSD of patients with stage I-II UPSC older than 67 years (HR = 0.47, P = .022; HR = 0.52, P = .024, respectively). The prediction model had great risk stratification ability as the high-risk group had higher cumulative incidence of CSD than the low-risk group (P < .001). In the high-risk group, patients with post-operative adjuvant chemoradiotherapy had improved CSD compared with patients who did not receive radiotherapy nor chemotherapy (P = .037). However, there was no such benefit in the low-risk group.ConclusionOur prediction model of CSD based on proportional subdistribution hazards regression showed a good performance in predicting the cancer-specific survival of early-stage UPSC patients and contributed to guide clinical treatment decision, helping oncologists and patients with early-stage UPSC to decide whether to choose adjuvant therapy or not.

Project description:BackgroundThe fallopian tube fimbria is regarded as the main tissue of origin and incessant ovulation as the main risk factor of ovarian high-grade serous carcinoma. Previously, we discovered the tumorigenesis activity of human ovulatory follicular fluid (FF) upon injection to the mammary fat pad of Trp53-null mice. We also found a mutagenesis activity of FF-ROS and a apoptosis-rescuing activity of Hb from retrograde menstruation. However, neither of them can explain the tumorigenesis activities of FF.MethodsFrom two cohorts of ovulatory FF retrieved from IVF patients, the main growth factor responsible for the transformation of human fimbrial epithelial cells was identified. Mechanism of activation, ways of signal transduction of the growth factor, as well as the cellular and genetic phenotypes of the malignant transformation was characterized.FindingsIn this study, we showed that insulin-like growth factor (IGF)-axis proteins, including IGFBP-bound IGF2 as well as the IGFBP-lytic enzyme PAPP-A, are abundantly present in FF. Upon engaging with glycosaminoglycans on the membrane of fimbrial epithelial cells, PAPP-A cleaves IGFBPs and releases IGF2 to bind with IGF-1R. Through the IGF-1R/AKT/mTOR and IGF-1R/AKT/NANOG pathways, FF-IGF leads to stemness and survival, and in the case of TP53/Rb or TP53/CCNE1 loss, to clonal expansion and malignant transformation of fimbrial epithelial cells. By depleting each IGF axis component from FF, we proved that IGF2, IGFBP2/6, and PAPP-A are all essential and confer the majority of the transformation and regeneration activities.InterpretationThis study revealed that the FF-IGF axis functions to regenerate tissue damage after ovulation and promote the transformation of fimbrial epithelial cells that have been initiated by p53- and Rb-pathway disruptions. FUND: The study was supported by grants of the Ministry of Science and Technology, Taiwan (MOST 106-2314-B-303-001-MY2; MOST 105-2314-B-303-017-MY2; MOST 107-2314-B-303-013-MY3), and Buddhist Tzu Chi General Hospital, Taiwan (TCMMP104-04-01).

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Can morphometric analysis of the fallopian tube fimbria predict the presence of uterine papillary serous carcinoma (UPSC)?

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