Pretreatment Nutritional Status in Combination with Inflammation Affects Chemotherapy Interruption in Women with Ovarian, Fallopian Tube, and Peritoneal Cancer.

BACKGROUND: Discontinuing chemotherapy worsens cancer prognosis. This study aimed to investigate the relationship between nutritional status at the start of chemotherapy and chemotherapy discontinuation in patients with ovarian, fallopian tube, and primary peritoneal cancer. METHODS: This was a retrospective cohort study. One hundred and forty-six patients to whom weekly paclitaxel and carboplatin were administered as postoperative chemotherapy were included. Six courses in 21-day cycles were defined as complete treatment. As nutritional indicators, body mass index, weight change rate, serum albumin, total lymphocyte count, prognostic nutritional index, and C-reactive protein-to-albumin ratio (CAR) were compared between complete and incomplete treatment groups. Patients were divided into two groups according to CAR. The number of chemotherapy cycles was compared between these two groups. A Cox proportional hazard model was used for covariate adjustment. RESULTS: Several indicators differed between complete and incomplete treatment groups, and among the indicators, CAR had the highest discriminatory ability. The number of chemotherapy cycles was shorter in the high CAR group than in the low CAR group. A high CAR was associated with chemotherapy interruption even after adjusting for covariates. CONCLUSION: Based on CAR, nutritional status before chemotherapy is suggested to be associated with the risk of chemotherapy discontinuation.

Mechanisms of High-Grade Serous Carcinogenesis in the Fallopian Tube and Ovary: Current Hypotheses, Etiologic Factors, and Molecular Alterations.

Ovarian high-grade serous carcinomas (HGSCs) are a heterogeneous group of diseases. They include fallopian-tube-epithelium (FTE)-derived and ovarian-surface-epithelium (OSE)-derived tumors. The risk/protective factors suggest that the etiology of HGSCs is multifactorial. Inflammation caused by ovulation and retrograde bleeding may play a major role. HGSCs are among the most genetically altered cancers, and TP53 mutations are ubiquitous. Key driving events other than TP53 mutations include homologous recombination (HR) deficiency, such as BRCA 1/2 dysfunction, and activation of the CCNE1 pathway. HR deficiency and the CCNE1 amplification appear to be mutually exclusive. Intratumor heterogeneity resulting from genomic instability can be observed at the early stage of tumorigenesis. In this review, I discuss current carcinogenic hypotheses, sites of origin, etiologic factors, and molecular alterations of HGSCs.

Clinicopathological and molecular analyses of linearly expanded epithelial cells with ß-catenin alterations, "ß-catenin signature", in the normal fallopian tube.

AIMS: Recent advances in next-generation sequencing have made it clear that clonal expansion of cells harbouring driver gene mutations occurs in physiologically normal epithelium. Molecular analysis of tubal epithelium has been almost exclusively confined to the TP53 pathway, which is involved in serous carcinogenesis. Other oncogenic events have not been explored in detail. Here, we report the linear expansion of fallopian tubal epithelial cells exhibiting an altered ß-catenin profile (ß-catenin signature). Through molecular analyses, we determined the incidence and clinicopathological significance of ß-catenin signatures. METHODS AND RESULTS: We evaluated 64 specimens of surgically removed bilateral fallopian tubes. Thirty-three ß-catenin signatures were identified in 13 cases (20.3%); these patients were significantly younger than those without ß-catenin signatures (median ages of 44 and 57 years, respectively, P = 0.0317). No correlation between ß-catenin signature and any clinical factor was observed. CTNNB1 mutations were detected in three of eight ß-catenin signatures when tissues were microdissected and subjected to Sanger sequencing in two representative cases. CONCLUSIONS: This is the first report of the CTNNB1 mutation in clusters of morphologically bland tubal epithelial cells. The results of this study indicate that ß-catenin signatures are common, and they may be a part of diverse molecular alterations occurring in normal tubal epithelium.

Metabolic syndrome and risk of ovarian and fallopian tube cancer in the United States: An analysis of linked SEER-Medicare data.

OBJECTIVE: To clarify associations between metabolic syndrome, its components, and ovarian cancer risk. METHODS: Using a case-control study within the U.S.-based Surveillance, Epidemiology and End Results (SEER)-Medicare linked database, we examined metabolic syndrome, its components (obesity, impaired fasting glucose, hypertension, HDL cholesterol, triglycerides), and ovarian/fallopian tube cancer risk. Cases (n = 16,850) were diagnosed with cancer between age 68-89 from 1994 through 2013. Controls (n = 281,878) were Medicare enrollees without these cancers living in registry areas. We estimated adjusted odds ratios (OR) and 95% confidence intervals (CI) with logistic regression. RESULTS: Women with metabolic syndrome had reduced ovarian cancer risk compared to women not meeting the diagnostic criteria (OR 0.86, CI 0.82-0.89). Having one or two syndrome components was associated with increased risk, but having ≥3 was not, when compared to women without any components. Impaired fasting glucose, which was highly prevalent among those with metabolic syndrome, was associated with reduced risk (OR 0.90, CI 0.87-0.93). Hypertension and high triglycerides, the most prevalent components among women without metabolic syndrome, were associated with increased risks (OR 1.08, CI 1.04-1.12; OR 1.05, CI 1.01-1.08, respectively). CONCLUSIONS: Specific metabolic syndrome components may have modest associations with ovarian cancer. These associations varied in direction and the prevalence of the components influenced the overall association between metabolic syndrome and ovarian cancer. Evaluating metabolic syndrome as a composite exposure could be misleading in ovarian cancer research, but further study of the syndrome components is warranted.

Serous tubal intraepithelial carcinoma arising from the intrauterine portion of the fallopian tube after bilateral salpingo-oophorectomy.

Serous tubal intraepithelial carcinoma (STIC) is considered the precursor of pelvic serous carcinomas and the earliest malignant alteration in BRCA mutation-positive women. Recently, risk-reducing salpingo-oophorectomy (RRSO) is being performed in BRCA mutation-positive women and STIC is often discovered incidentally in the fallopian tubes. A 62-year-old woman underwent bilateral salpingo-oophorectomy (BSO) for ovarian cysts. Ten months later, cytological screening for the endometrium revealed adenocarcinoma. No atypical tissue was detected by the endometrial curettage. Imaging tests and hysteroscopy found no abnormal findings. She underwent hysterectomy and was diagnosed with STIC originating from the intrauterine portion of the residual fallopian tube. Here, the authors report the first case of STIC being detected during an endometrial cytological examination after BSO. Although STIC associated with the BRCA mutation usually involves the distal fallopian tube, the present case suggests that the intrauterine portion of the fallopian tube should be removed or cauterized during RRSO.

Tubal ligation and incidence of 26 site-specific cancers in the Million Women Study.

BACKGROUND: Tubal ligation is known to be associated with a reduction in ovarian cancer risk. Associations with breast, endometrial and cervical cancers have been suggested. We investigated associations for 26 site-specific cancers in a large UK cohort. METHODS: Study participants completed a questionnaire on reproductive and lifestyle factors in 1996-2001, and were followed for cancer and death via national registries. Using Cox regression models, we estimated adjusted relative risks (RRs) for 26 site-specific cancers among women with vs without tubal ligation. RESULTS: In 1 278 783 women without previous cancer, 167 430 incident cancers accrued during 13.8 years' follow-up. Significantly reduced risks were found in women with tubal ligation for cancers of the ovary (RR=0.80, 95% CI: 0.76-0.85; P<0.001; n=8035), peritoneum (RR=0.81, 0.66-0.98; P=0.03; n=730), and fallopian tube (RR=0.60, 0.37-0.96; P=0.04; n=168). No significant associations were found for endometrial, breast, or cervical cancers. CONCLUSIONS: The reduced risks of ovarian, peritoneal and fallopian tube cancers are consistent with hypotheses of a common origin for many tumours at these sites, and with the suggestion that tubal ligation blocks cells, carcinogens or other agents from reaching the ovary, fallopian tubes and peritoneal cavity.

Pseudoxanthomatous salpingitis as an ex vivo model of fallopian tube serous carcinogenesis: a clinicopathologic study of 49 cases.

Iron is a well-documented carcinogen based on both animal models and observational studies in humans. There are limited published data on pseudoxanthomatous salpingitis, an uncommon condition characterized by the accumulation of histiocytes containing iron and iron-related compounds-lipofuscin and hemosiderin-in the lamina propria of the fallopian tube. The clinical and pathologic features of 49 consecutive cases were evaluated. The mean patient age was 53. A history of endometriosis was found in 20%, infertility in 17%, and tubal ligation in 7%. Thirteen (27%) had endometrial cancer and 2 patients had prior radiation therapy for cervical carcinoma. Histologic evidence of endometriosis other than tubal pigment deposition was identified in 65%, and in the fallopian tubes in 35%. Pigment deposition was unilateral in 65% and multifocal or diffuse in 80%. Plasma cells, eosinophils, and neutrophils were present in the tubal lamina propria in 57%, 18%, and 24%, respectively. Hydrosalpinx was present in 51%. An iron stain was positive in pseudoxanthoma cells lacking hemosiderin in 14 of 18 cases (78%). By immunohistochemistry, 2 of 22 cases displayed p53 signatures. The Ki67 proliferation index was elevated (>10%) in 11 of 22 cases, with a mean index of 32% in those cases. An elevated proliferation index did not correlate with inflammation. In summary, these findings characterize the clinical and pathologic features of pseudoxanthomatous salpingitis and confirm its close association with endometriosis, occasional association with radiation therapy, and the presence of iron in the histiocytes. In view of the evolving paradigm shift implicating the fallopian tubal epithelium as the site of origin of high-grade extrauterine serous carcinoma, the presence of iron and iron-related compounds in the fallopian tube provides an opportunity to study the early events in high-grade serous carcinogenesis in a setting characterized by a well-documented carcinogen in close anatomic proximity to the putative epithelium of origin.

Serous ovarian, fallopian tube and primary peritoneal cancers: a common disease or separate entities - a systematic review.

OBJECTIVE: The aim of this systematic review is to analyze data on risk factors, epidemiology, clinicopathology and molecular biology from studies comparing primary peritoneal cancer, fallopian tube cancer and ovarian cancer of serous histology, in order to achieve a greater understanding of whether or not these disorders should be considered as separate entities. METHODS: A systematic literature search was conducted in PubMed and MEDLINE. Case-control studies comparing primary serous peritoneal or fallopian tube carcinomas with primary serous ovarian carcinomas or a control group were included. RESULTS: Twenty-eight studies were found eligible. Primary peritoneal cancer patients were older, had higher parity, were more often obese and had poorer survival compared to ovarian cancer patients. Differences in protein expression patterns of Her2/neu, estrogen and progestin receptors and frequency of loss of heterozygosity differed between primary peritoneal cancer and primary ovarian cancer patients. No major differences were found between primary fallopian tube cancer and primary ovarian cancer. The proportion of serous tubal intraepithelial carcinomas (STIC) was lower in primary peritoneal cancer and primary ovarian cancer compared to primary fallopian tube cancer. CONCLUSION: Except from differences in the proportion of STIC only few differences between primary fallopian tube cancer and primary ovarian cancer have been found. In contrast, observed differences in risk factor profile, clinicopathologic and prognostic factors, as well as in the molecular patterns, indicate that peritoneal cancer and ovarian cancer may be linked to different carcinogenic pathways.

Precursors of ovarian cancer in the fallopian tube: serous tubal intraepithelial carcinoma--an update.

Ovarian tumors comprise a wide variety of entities. The largest group, epithelial ovarian carcinoma, can be classified into two main groups, type I and type II tumors. Recent advances in the understanding of ovarian cancer development have resulted in the finding of 'serous tubal intraepithelial carcinoma', which is believed to represent the precursor lesion in high-grade serous ovarian carcinoma. In this review, lines of evidence for this are discussed and possible future implications for clinical and research settings are outlined.

Tu-be or not tu-be: that is the question about serous ovarian carcinogenesis.

Our understanding of the early natural history of epithelial ovarian carcinoma is limited by the access to early lesions as the disease is very often diagnosed at advanced stages. The incessant ovulation theory from the last century that indicated the ovary as the site for the initiation of high-grade serous cancers is contrary to the newly emerging idea that ovarian cancer could arise from the distal fallopian tube. In view of the recent pathological and molecular studies, we propose to discuss the genesis of high-grade serous ovarian cancer.

Ovarian cancer risk factors by tumor dominance, a surrogate for cell of origin.

Differentiating ovarian tumors based on developmental pathway may further enhance our understanding of the disease. Traditionally, ovarian cancers were thought to arise from the ovarian surface epithelium; however, recent evidence suggests that some tumors originate in the fallopian tube. We classified cases in a population-based case-control study (New England Case-Control [NECC] Study) and two cohort studies (Nurses' Health Study [NHS]/Nurses' Health Study II [NHSII]) by tumor dominance, a proxy for tissue of origin. Dominant tumors (likely ovarian origin) are restricted to one ovary or are at least twice as large on one ovary compared to the other. Ovarian cancer risk factors were evaluated in relation to dominant and nondominant tumors (likely tubal origin) using polytomous logistic regression (NECC) or competing risks Cox models (NHS/NHSII). Results were combined using random-effects meta-analyses. Among 1,771 invasive epithelial ovarian cancer cases, we observed 1,089 tumors with a dominant mass and 682 with no dominant mass. Dominant tumors were more likely to be mucinous, endometrioid or clear cell, whereas nondominant tumors were more likely to be serous. Tubal ligation, two or more births, endometriosis and age were more strongly associated with dominant tumors (rate ratio [RR] = 0.60, 0.83, 1.58 and 1.37, respectively) than nondominant tumors (RR = 1.03, 0.93, 0.84 and 1.14, respectively; p-difference = 0.0001, 0.01, 0.0003 and 0.01, respectively). These data suggest that risk factors for tumors putatively arising from ovarian versus fallopian tube sites may differ; in particular, reproductive factors may be more important for ovarian-derived tumors. As this is the first study to evaluate ovarian cancer risk factors by tumor dominance, these results need to be validated by other studies.

The role of the fallopian tube in ovarian cancer.

High-grade serous carcinoma (HGSC) is the most common and lethal subtype of ovarian cancer. Research over the past decade has strongly suggested that "ovarian" HGSC arises in the epithelium of the distal fallopian tube, with serous tubal intraepithelial carcinomas (STICs) being detected in 5-10% of BRCA1/2 mutation carriers undergoing risk-reducing surgery and up to 60% of unselected women with pelvic HGSC. The natural history, clinical significance, and prevalence of STICs in the general population (ie, women without cancer and not at an increased genetic risk) are incompletely understood, but anecdotal evidence suggests that these lesions have the ability to shed cells with metastatic potential into the peritoneal cavity very early on. Removal of the fallopian tube (salpingectomy) in both the average and high-risk populations could therefore prevent HGSC, by eliminating the site of initiation and interrupting spread of potentially cancerous cells to the ovarian/peritoneal surfaces. Salpingectomy may also reduce the incidence of the 2 next most common subtypes, endometrioid and clear cell carcinoma, by blocking the passageway linking the lower genital tract to the peritoneal cavity that enables ascension of endometrium and factors that induce local inflammation. The implementation of salpingectomy therefore promises to significantly impact ovarian cancer incidence and outcomes.

Fallopian tube origin of supposed ovarian high-grade serous carcinomas.

INTRODUCTION: Serous carcinomas are the most frequent histologic type of ovarian and peritoneal cancers, and can also be detected in the endometrium and fallopian tubes. Serous carcinomas are usually high-grade neoplasms when diagnosed, yet the identification of an associated precursor lesion remains challenging. Pathological examination of specimens obtained from prophylactic bilateral salpingo-oophorectomies that were performed for patients harboring BRCA1/2 mutations suggests that high-grade serous carcinomas may arise in the fallopian tubes rather than in the ovaries. OBJECTIVE: To investigate the presence and extent of fallopian tube involvement in cases of serous pelvic carcinomas. METHODS: Thirty-four cases of serous pelvic carcinoma with clinical presentations suggesting an ovarian origin were analyzed retrospectively. Histologic samples of fallopian tube tissues were available for these cases and were analyzed. Probable primary site, type of tubal involvement, tissues involved in the neoplasia and vascular involvement were evaluated. RESULTS: Fallopian tube involvement was observed in 24/34 (70.6%) cases. In 4 (11.8%) of these cases, an intraepithelial neoplasia was present, and therefore these cases were hypothesized to be primary from fallopian tubes. For an additional 7/34 (20.6%) cases, a fallopian tube origin was considered a possible primary. CONCLUSIONS: Fallopian tubes can be the primary site for a subset of pelvic high-grade serous carcinomas.

Multidrug resistance gene (MDR-1) and risk of brain metastasis in epithelial ovarian, fallopian tube, and peritoneal cancer.

BACKGROUND: To evaluate risk factors that predict brain metastasis in epithelial ovarian, fallopian tube, and peritoneal cancer. METHODS: All patients with FIGO stage I to IV who underwent initial cytoreductive surgery between January 1995 and January 2009 were evaluated. The tumor samples were evaluated for 7 markers including multidrug resistance gene (MDR-1), DNA aneuploidity and S-phase fraction, human epidermal growth factor receptor 2, estrogen receptor, progesterone receptor, p53 mutation, epidermal growth factor receptor, and CD31. Biomarker expression was evaluated as a predictor of hematogenous metastasis to the following locations: (i) liver and spleen, (ii) lung, and (iii) brain. RESULTS: There were 309 cases identified during the period. Of those, 5 (1.6%, 95% CI: 0.2%-3.0%) women developed brain metastasis. Time to onset of brain metastasis was significantly longer than that for other recurrent sites (median time to recurrence after initial cytoreduction, brain vs. lung vs. liver, 21.4 vs. 12.6 vs. 11.0 months, P< 0.05). Significantly increased expression of MDR-1 was seen in tumors from women who developed brain metastasis (brain vs. nonbrain sites, 80% vs. 4.2%-24.3%, P= 0.004). In multivariate analysis, MDR-1 was the only significant variable associated with the risk of brain metastasis. MDR-1 expression predicted brain metastasis (receiver-operator-characteristic curve analysis, AUC 0.808, P= 0.018), and with a 10% positive expression of MDR-1 as the cutoff value, sensitivity, specificity, positive predictive value, negative predictive value, accuracy of prediction of brain metastasis were 80%, 86.1%, 15.4%, 99.3%, and 85.9%, respectively (odds ratio: 24.7, 95% CI: 2.64-232, P= 0.002). CONCLUSIONS: Increased expression of MDR-1 in the tumor tissue obtained at initial cytoreduction is associated with increased risk of developing brain metastases in women with epithelial ovarian, fallopian tube, or peritoneal cancer.

Fallopian tube origin of supposed ovarian high-grade serous carcinomas

INTRODUCTION: Serous carcinomas are the most frequent histologic type of ovarian and peritoneal cancers, and can also be detected in the endometrium and fallopian tubes. Serous carcinomas are usually high-grade neoplasms when diagnosed, yet the identification of an associated precursor lesion remains challenging. Pathological examination of specimens obtained from prophylactic bilateral salpingo-oophorectomies that were performed for patients harboring BRCA1/2 mutations suggests that high-grade serous carcinomas may arise in the fallopian tubes rather than in the ovaries. OBJECTIVE: To investigate the presence and extent of fallopian tube involvement in cases of serous pelvic carcinomas. METHODS: Thirty-four cases of serous pelvic carcinoma with clinical presentations suggesting an ovarian origin were analyzed retrospectively. Histologic samples of fallopian tube tissues were available for these cases and were analyzed. Probable primary site, type of tubal involvement, tissues involved in the neoplasia and vascular involvement were evaluated. RESULTS: Fallopian tube involvement was observed in 24/34 (70.6 percent) cases. In 4 (11.8 percent) of these cases, an intraepithelial neoplasia was present, and therefore these cases were hypothesized to be primary from fallopian tubes. For an additional 7/34 (20.6 percent) cases, a fallopian tube origin was considered a possible primary. CONCLUSIONS: Fallopian tubes can be the primary site for a subset of pelvic high-grade serous carcinomas.

Bilateral papillary cystadenoma of the mesosalpinx: a rare manifestation of Von Hippel-Lindau disease.

We report a rare case of a woman with bilateral papillary cystadenomata of the broad ligament with von Hippel-Lindau disease (VHL) (other manifestations: capillary hemangioblastomas of the spinal cord). Patient surveillance is important, because in the course of VHL-associated tumors malignant lesions may arise that are relevant for the prognosis.

[Primary fallopian tube carcinoma].

INTRODUCTION: Primary fallopian tube carcinoma is extremely rare, making 0.3-1.6% of all female genital tract malignancies. Although the etymology of this tumor is unknown, it is suggested to be associated with chronic tubal inflammation, infertility, tuberculous salpingitis and tubal endometriosis. High parity is considered to be protective. Cytogenetic studies show the disease to be associated with over expression of p53, HER2/neu and c-myb. There is also some evidence that BRCA1 and BRCA2 mutations have a role in umorogeneis. CLINICAL FEATURES: The most prevailing symptoms with fallopian tube carcinoma are abdominal pain, abnormal vaginal discharge/bleeding and the most common finding is an adnexal mass. In many patients, fallopian tube carcinoma is asymptomatic. DIAGNOSIS: Due to its rarity, preoperative diagnosis of primary fallopian tube carcinoma is rarely made. It is usually misdiagnosed as ovarian carcinoma, tuboovarian abscess or ectopic pregnancy. Sonographic features of the tumor are non-specific and include the presence of a fluid-filled adnexal structure with a significant solid component, a sausage-shaped mass, a cystic mass with papillary projections within, a cystic mass with cog wheel appearance and an ovoid-shaped structure containing an incomplete separation and a highly vascular solid nodule. More than 80% of patients have elevated pretreatment serum CA-125 levels, which is useful in follow-up after the definite treatment. TREATMENT: The treatment approach is similar to that of ovarian carcinoma, and includes total abdominal hysterectomy and bilateral salpingo-oophorectomy. Staging is followed with chemotherapy.

Case report: Occurrence of fallopian tube cancer in a patient with previous history of estrogen receptor positive breast cancer.

Fallopian tube cancer is very rare, it accounts less than 1% of all genital tract cancer in women. The annual incidence is 3.6 per million women per year. The vast majority of fallopian tube cancers are papillary serous adenocarcinomas. Most women with fallopian tube cancer are usually diagnosed at age 50s to 60s. Vaginal bleeding or discharge is the most common presentation. We would like to present a case in which fallopian tube cancer was diagnosed in a patient with post menopausal bleeding, abnormal ultrasound finding and history of estrogen receptor (ER) positive breast cancer.