Fallopian tube lesions as potential precursors of early ovarian cancer: a comprehensive proteomic analysis.

Ovarian cancer is the leading cause of death from gynecologic cancer worldwide. High-grade serous carcinoma (HGSC) is the most common and deadliest subtype of ovarian cancer. While the origin of ovarian tumors is still debated, it has been suggested that HGSC originates from cells in the fallopian tube epithelium (FTE), specifically the epithelial cells in the region of the tubal-peritoneal junction. Three main lesions, p53 signatures, STILs, and STICs, have been defined based on the immunohistochemistry (IHC) pattern of p53 and Ki67 markers and the architectural alterations of the cells, using the Sectioning and Extensively Examining the Fimbriated End Protocol. In this study, we performed an in-depth proteomic analysis of these pre-neoplastic epithelial lesions guided by mass spectrometry imaging and IHC. We evaluated specific markers related to each preneoplastic lesion. The study identified specific lesion markers, such as CAVIN1, Emilin2, and FBLN5. We also used SpiderMass technology to perform a lipidomic analysis and identified the specific presence of specific lipids signature including dietary Fatty acids precursors in lesions. Our study provides new insights into the molecular mechanisms underlying the progression of ovarian cancer and confirms the fimbria origin of HGSC.

SOX6 Expression Is Sensitive for Peritoneal Epithelioid Malignant Mesothelioma, But Not Specific in the Differential Diagnosis With Tubo-ovarian Serous Neoplasia.

Primary peritoneal malignant mesothelioma (MM) can demonstrate morphologic overlap with low-grade and high-grade tubo-ovarian serous neoplasms; it is also biologically and prognostically distinct from benign mesothelial proliferations. Currently, there is no single biomarker that can definitively distinguish these neoplasms. Sex-determining region Y box 6 (SOX6) immunohistochemistry has been recently described to differentiate pleural epithelioid MM from lung adenocarcinoma, but it has not been evaluated in the peritoneum. SOX6 immunohistochemistry was performed on 43 peritoneal epithelioid MM, 7 peritoneal biphasic MM, 5 well-differentiated papillary mesotheliomas, 5 serous borderline tumors, 29 low-grade serous carcinomas (LGSCs), 20 high-grade serous carcinomas (HGSCs), and 25 cases of peritoneal reactive mesothelial hyperplasia. Quantitative SOX6 expression in epithelioid MM (median, 100% of tumor cells) was significantly greater than in LGSC/serous borderline tumor (median, 90%; P=0.004) and HGSC (median, 45%; P=0.0001). However, when SOX6 is expression is defined as ≥10% of tumor cells, there was no significant difference in the rate of SOX6 positivity between epithelioid MM (41/43, 95%), LGSC (28/29, 97%; P=1.0), and HGSC (17/20, 85%; P=0.16). Quantitative extent of SOX6 expression in epithelioid MM was significantly greater than in biphasic MM (median, 0%; P=0.0001), well-differentiated papillary mesothelioma (median, 20%; P=0.001), and reactive mesothelial hyperplasia (median, 20%; P=0.0001), but not significantly different from flat quiescent mesothelium (median, 90%; P=0.82). SOX6 immunohistochemistry is 95% sensitive for peritoneal epithelioid MM, but is also consistently expressed in LGSC and HGSC, negating its usefulness in this common differential diagnosis. SOX6 also shows variable expression across the spectrum of reactive, benign neoplastic, and malignant mesothelial lesions of the peritoneum, and does not appear to be diagnostically useful in distinguishing benign from malignant mesothelial proliferations.

Analysis of Telomere Lengths in p53 Signatures and Incidental Serous Tubal Intraepithelial Carcinomas Without Concurrent Ovarian Cancer.

Telomere alterations represent one of the major molecular changes in the development of human cancer. We have previously reported that telomere lengths in most serous tubal intraepithelial carcinomas (STIC) are shorter than they are in ovarian high-grade serous carcinomas (HGSC) or in normal-appearing fallopian tube epithelium from the same patients. However, it remains critical to determine if similar telomere alterations occur in TP53-mutated but histologically unremarkable "p53 signature" lesions, as well as incidental STICs without concurrent HGSC. In this study, we quantitatively measured telomere lengths by performing telomere-specific fluorescence in situ hybridization in conjunction with p53 immunolabeling in 15 p53 signatures and 30 incidental STICs without concurrent HGSC. We compared these new results with our previous data in paired STICs and concurrent HGSCs. We found that most p53 signatures (80%) and incidental STICs without HGSC (77%) exhibited significant telomere shortening compared with adjacent normal-appearing fallopian tube epithelium (P<0.01). Interestingly, however, p53 signatures and incidental STICs without HGSC displayed longer telomeres and less cell-to-cell telomere length heterogeneity than STICs associated with HGSC (P<0.001). These findings indicate that telomere shortening occurs in p53 signatures, the earliest precancer lesion. Moreover, incidental STICs without concurrent HGSC are indeed similar to p53 signatures as they have less telomere shortening and less cell-to-cell telomere length heterogeneity than STICs associated with HGSC.

Synchronous Cervical Minimal Deviation Adenocarcinoma, Gastric Type Adenocarcinoma and Lobular Endocervical Glandular Hyperplasia Along with STIL in Peutz-Jeghers Syndrome: Eliciting Oncogenesis Pathways.

We describe an unusual case of a Peutz-Jeghers syndrome associated with a composite synchronous cervical neoplasia comprising precursor "lobular endocervical glandular hyperplasia (LEGH)", "minimal deviation adenocarcinoma (MDA)" and "gastric-type adenocarcinoma (GTA)" along with a serous tubal intraepithelial lesion (STIL) in the right fallopian tube. A 24-year-old woman presented with a white mucoid discharge and bleeding per vaginum for one year. Histopathological evaluation showed MDA & GTA in FIGO grade III with pelvic lymph node metastasis despite a deceptively bland tumour morphology and low Ki-67 index, indicating an aggressive tumour course and poor prognosis. Diagnostic marker profile in the cervix showed gastric type mucin and positive expression of CK-7, CK-20 (patchy), CEA, and negative CDX-2, p16, ER and PR. Further an attempt at eliciting the oncogenesis pathway in view of the p16 and HPV negative nature of the gastric type cervical adenocarcinoma showed negativity for p53 but activation of cyclin D1. Growth factors including Her2 and EGFR were negative while VEGFR was over-expressed. She was treated by radical hysterectomy and pelvic radiation. She was free from recurrence at the 12-month follow-up. This is a first-time report of a STIL in the fallopian tube which was validated by a unilateral mutant type p53 expression and increased Ki67 index, associated with synchronous gastric type adenocarcinoma of the cervix in all stages of evolution.

MED12 is frequently mutated in ovarian and other adnexal leiomyomas.

In the female genital tract, extrauterine leiomyomas such as those that arise in the ovary and paraovarian/paratubal regions are rare. Currently, little is known about the background genetic changes in such adnexal leiomyomas. Recent studies have found that the MED12 mutation is common in uterine leiomyomas, which suggests that such mutations may play an oncogenic role in smooth muscle neoplasms in females. Herein, we examined a series of ovarian and other adnexal leiomyomas in terms of MED12 mutational status to investigate possible MED12 involvement in the pathogenesis of extrauterine smooth muscle tumors. We evaluated 10 cases of adnexal leiomyomas (5 ovarian, 3 paraovarian, and 2 paratubal) and 49 cases of ovarian sex cord-stromal tumors as controls. We performed polymerase chain reaction followed by direct sequencing of exon 2 of MED12, and immunohistochemical staining for smooth muscle actin and desmin. We identified somatic MED12 mutations in 90% (9/10) of the adnexal leiomyomas. None of the sex cord-stromal tumors in the control group harbored MED12 mutations. Diffuse immunoreactivity for both smooth muscle actin and desmin was characteristic of adnexal leiomyomas only. Thus, we conclude that ovarian leiomyomas are distinct from sex cord-stromal tumors. MED12 mutations are key molecular features of ovarian and other adnexal leiomyomas. We speculate that the pathogenesis of adnexal leiomyoma is similar to that of its uterine counterpart.

Fallopian Tube Mucosal Involvement in Cervical Gastric-type Adenocarcinomas: Report of a Series With Discussion of the Distinction From Synchronous In Situ Tubal Lesions.

Cervical gastric-type adenocarcinomas are aggressive non-human papillomavirus-related carcinomas with a propensity for extracervical spread, including unusual sites such as the omentum, peritoneum, and ovary. We report 7 cases of cervical gastric-type adenocarcinoma with fallopian tube involvement predominantly in the form of mucosal colonization without underlying invasion. As far as we are aware, this has not been previously described and this report adds to the literature regarding metastatic neoplasms, which may exhibit tubal mucosal involvement and mimic an in situ lesion at this site. In all cases, there was associated ovarian involvement and in 6 of 7 cases, there was endometrial colonization. We speculate that the fallopian tube (and ovarian) involvement is secondary to transuterine spread. Given the occasional occurrence of multifocal gastric-type glandular lesions (benign or malignant) involving different sites in the female genital tract, we discuss the distinction between synchronous independent and metastatic lesions.

[Morphologic features of fallopian tubal epithelium in pelvic high-grade serous carcinoma].

Objective: To study the pathologic features of fallopian tubal epithelium in patients with pelvic high-grade serous carcinoma (HGSC), to investigate its role in pelvic serous carcinogenesis and to reclassify the primary site of HGSC based on recently proposed criteria. Methods: The fallopian tubes in 58 cases of pelvic HGSC (54 cases of ovarian primary, 3 cases of tubal primary, 1 case of peritoneum) and 25 cases of pelvic non-HGSC (5 cases of ovarian low-grade serous cancer, 9 cases of endometrioid cancer, and 11 cases of clear cell ovary carcinoma) were collected from June 2015 to December 2016, and serially examined under light microscope (SEE-FIM protocol). Immunostaining for p53 and Ki-67 was performed to evaluate the presence of p53 signature, serous tubal intraepithelial lesion (STIL), serous tubal intraepithelial carcinoma (STIC) and invasive carcinoma in these fallopian tubes. Meanwhile, primary site of HGSC based on the recently proposed diagnostic criteria were also reclassified. Results: Among the study group, the frequencies of p53 signature, STIL, STIC and invasive HGSC were 27.6% (16/58), 43.1% (25/58), 36.2% (21/58) and 67.2% (39/58), respectively, while in control group, the proportions were 24.0% (6/25), 0, 0 and 8.0% (2/25), respectively. The continuum of epithelial changes in the process of serous neoplasia including p53 signature, STIL, STIC and invasive carcinoma was identified in 8 cases of pelvic HGSC. The proportions of STIL, STIC and invasive carcinomas in HGSC group were higher than that in non-HGSC group (P<0.01). About 80.0% (20/25) of STIL and 85.7% (18/21) of STIC were present unilaterally. Diagnostically, the study group contained the 17 cases of ovarian HGSC, 40 cases of tubal HGSC, and 1 case of peritoneal HGSC after reclassification of the cancer primary. Conclusions: Continuous changes of tubal epithelium including p53 signature, STIL, STIC and invasive carcinomas are identified in patients with HGSC, supporting the current understanding that the fallopian tube is likely the cellular source of the majority HGSC. STIL and STIC may be specific to pelvic HGSC and may act as a target for future research on the early detection and prevention of this disease. The newly proposed diagnostic criteria for pelvic HGSC will lead us to more accurate classification of cancer primary sites. Correct classification of HGSC may have potential impacts for cancer prevention and improve our understanding of ovarian serous carcinogenesis.

LEF1 is preferentially expressed in the tubal-peritoneal junctions and is a reliable marker of tubal intraepithelial lesions.

Recently it has been reported that serous tubal intraepithelial carcinoma (STIC), the likely precursor of ovarian/extra-uterine high-grade serous carcinoma, are frequently located in the vicinity of tubal-peritoneal junctions, consistent with the cancer-prone features of many epithelial transitional regions. To test if p53 (aka TP53)-signatures and secretory cell outgrowths (SCOUTs) also localize to tubal-peritoneal junctions, we examined these lesions in the fallopian tubes of patients undergoing salpingo-oophorectomy for sporadic high-grade serous carcinomas or as a prophylactic procedure for carriers of familial BRCA1 or 2 mutations. STICs were located closest to the tubal-peritoneal junctions with an average distance of 1.31 mm, while SCOUTs were not detected in the fimbriated end of the fallopian tube. As many epithelial transitional regions contain stem cells, we also determined the expression of stem cell markers in the normal fallopian tube, tubal intraepithelial lesions and high-grade serous carcinomas. Of those, LEF1 was consistently expressed in the tubal-peritoneal junctions and all lesions, independent of p53 status. All SCOUTs demonstrated strong nuclear expression of ß-catenin consistent with the LEF1 participation in the canonical WNT pathway. However, ß-catenin was preferentially located in the cytoplasm of cells comprising STICs and p53 signatures, suggesting WNT-independent function of LEF1 in those lesions. Both frequency of LEF1 expression and ß-catenin nuclear expression correlated with the worst 5-year patient survival, supporting important role of both proteins in high-grade serous carcinoma. Taken together, our findings suggest the existence of stem cell niche within the tubal-peritoneal junctions. Furthermore, they support the notion that the pathogenesis of SCOUTs is distinct from that of STICs and p53 signatures. The location and discrete patterns of LEF1 and ß-catenin expression may serve as highly sensitive and reliable ancillary markers for the detection and differential diagnosis of tubal intraepithelial lesions.

A randomised, open-label, phase 2 study of the IDO1 inhibitor epacadostat (INCB024360) versus tamoxifen as therapy for biochemically recurrent (CA-125 relapse)-only epithelial ovarian cancer, primary peritoneal carcinoma, or fallopian tube cancer.

OBJECTIVE: Indoleamine 2,3-dioxygenase-1 (IDO1) is a key regulator of immune tolerance in ovarian cancer. This study investigated efficacy and safety of the IDO1 enzyme inhibitor epacadostat versus tamoxifen in patients with biochemical-only recurrence (CA-125 elevation) following complete remission after first-line chemotherapy for advanced epithelial ovarian, primary peritoneal, or fallopian tube cancer. METHODS: In this open-label, phase 2 study (NCT01685255), patients were randomised 1:1 to epacadostat 600mg or tamoxifen 20mg twice daily for successive 28-day cycles and stratified by time since completion of first-line chemotherapy to first CA-125 elevation (3 to <12 or ≥12months). The primary endpoint was investigator-assessed progression-free survival (PFS; RECIST v1.1). Secondary endpoints included CA-125 response (Gynecologic Cancer InterGroup criteria), overall survival, safety, and tolerability. RESULTS: The study was terminated primarily due to slow accrual and lack of evidence of superiority. Median PFS was 3.75months for epacadostat (n=22) versus 5.56months for tamoxifen (n=20; HR, 1.34 [95% CI, 0.58-3.14]; P=0.54). Of evaluable patients, 1 (5.0%) epacadostat and 3 (15.8%) tamoxifen patients had confirmed CA-125 responses. The most common treatment-emergent adverse event was fatigue (epacadostat, 36.4%; tamoxifen, 40.0%). Immune-related adverse events, observed with epacadostat only, were primarily rash (18.2%) and pruritus (9.1%). Epacadostat pharmacokinetics/pharmacodynamics were consistent with its known mechanism of action. IDO1 expression was observed in 94% of archival tumour samples. CONCLUSIONS: This first report of immunotherapy evaluation in biochemical-only relapse ovarian cancer and of IDO1 inhibitor monotherapy in ovarian cancer found no significant difference in efficacy between epacadostat and tamoxifen. Epacadostat was generally well tolerated.

Safety and Activity of Mirvetuximab Soravtansine (IMGN853), a Folate Receptor Alpha-Targeting Antibody-Drug Conjugate, in Platinum-Resistant Ovarian, Fallopian Tube, or Primary Peritoneal Cancer: A Phase I Expansion Study.

Purpose This phase I expansion cohort study evaluated the safety and clinical activity of mirvetuximab soravtansine (IMGN853), an antibody-drug conjugate consisting of a humanized anti-folate receptor alpha (FRα) monoclonal antibody linked to the tubulin-disrupting maytansinoid DM4, in a population of patients with FRα-positive and platinum-resistant ovarian cancer. Patients and Methods Patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer received IMGN853 at 6.0 mg/kg (adjusted ideal body weight) once every 3 weeks. Eligibility included a minimum requirement of FRα positivity by immunohistochemistry (≥ 25% of tumor cells with at least 2+ staining intensity). Adverse events, tumor response (via Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1), and progression-free survival (PFS) were determined. Results Forty-six patients were enrolled. Adverse events were generally mild (≤ grade 2), with diarrhea (44%), blurred vision (41%), nausea (37%), and fatigue (30%) being the most commonly observed treatment-related toxicities. Grade 3 fatigue and hypotension were reported in two patients each (4%). For all evaluable patients, the confirmed objective response rate was 26%, including one complete and 11 partial responses, and the median PFS was 4.8 months. The median duration of response was 19.1 weeks. Notably, in the subset of patients who had received three or fewer prior lines of therapy (n = 23), an objective response rate of 39%, PFS of 6.7 months, and duration of response of 19.6 weeks were observed. Conclusion IMGN853 exhibited a manageable safety profile and was active in platinum-resistant ovarian cancer, with the strongest signals of efficacy observed in less heavily pretreated individuals. On the basis of these findings, the dose, schedule, and target population were identified for a phase III trial of IMGN853 monotherapy in patients with platinum-resistant disease.

Expression of Stem Cell Markers in Preinvasive Tubal Lesions of Ovarian Carcinoma.

In order to better understand the ovarian serous carcinogenic process with tubal origin, we investigated the expression of stem cell markers in premalignant tubal lesions (serous tubal intraepithelial carcinoma or STIC). We found an increased stem cell marker density in the normal fallopian tube followed by a high CD117 and a low ALDH and CD44 expression in STICs raising the question of the role of the stem cell markers in the serous carcinogenic process.

Data set for reporting of ovary, fallopian tube and primary peritoneal carcinoma: recommendations from the International Collaboration on Cancer Reporting (ICCR).

A comprehensive pathological report is essential for optimal patient management, cancer staging and prognostication. In many countries, proforma reports are used but these vary in their content. The International Collaboration on Cancer Reporting (ICCR) is an alliance formed by the Royal College of Pathologists of Australasia, the Royal College of Pathologists of the United Kingdom, the College of American Pathologists, the Canadian Partnership Against Cancer and the European Society of Pathology, with the aim of developing an evidence-based reporting data set for each cancer site. This will reduce the global burden of cancer data set development and reduplication of effort by different international institutions that commission, publish and maintain standardised cancer reporting data sets. The resultant standardisation of cancer reporting will benefit not only those countries directly involved in the collaboration but also others not in a position to develop their own data sets. We describe the development of a cancer data set by the ICCR expert panel for the reporting of primary ovarian, fallopian tube and peritoneal carcinoma and present the 'required' and 'recommended' elements to be included in the report with an explanatory commentary. This data set encompasses the recent International Federation of Obstetricians and Gynaecologists staging system for these neoplasms and the updated World Health Organisation Classification of Tumours of the Female Reproductive Organs. The data set also addresses issues about site assignment of the primary tumour in high-grade serous carcinomas and proposes a scoring system for the assessment of tumour response to neoadjuvant chemotherapy. The widespread implementation of this data set will facilitate consistent and accurate data collection, comparison of epidemiological and pathological parameters between different populations, facilitate research and hopefully will result in improved patient management.

Nongynecologic metastases to fallopian tube mucosa: a potential mimic of tubal high-grade serous carcinoma and benign tubal mucinous metaplasia or nonmucinous hyperplasia.

Mucosal alterations of the fallopian tube are generally thought to represent alterations of the native tubal mucosal epithelium, whether benign or malignant. The current paradigm implicating the fallopian tube fimbriae as the origin of most pelvic high-grade serous carcinomas (HGSCs) is based on the premise that HGSC growing within the tubal mucosa originated there. This has fueled proposals to redefine classification rules for assigning the primary site of origin on the basis of the presence or absence of HGSC in the tubal mucosa. The corollary is that it is unlikely for metastatic carcinoma to grow within fallopian tube mucosa. Evidence to support or refute this corollary is minimal, in part because the fallopian tubes historically have been ignored. This study reports the pattern and topography of 100 nongynecologic cancers that metastasized to the fallopian tubes. Most tumors were adenocarcinoma (87%), and the remainder included lymphomas, neuroendocrine tumors, and mesotheliomas. The most common primary origins of tumor were the colon (35%) and breast (15%). Gross evidence of a tubal nodule or mass was only seen in 35% of cases. Ovarian metastases were present in 95% of cases, although 23% did not exhibit gross evidence of metastasis. Tumor involved the fimbriae in 49% of cases, including 10% of cases in which the tumor was restricted to the fimbriae without involving the nonfimbriated portion of the tube. The anatomic distribution of metastases included the tubal mucosa (29%), submucosa (43%), muscularis (54%), serosa (76%), lymphovascular spaces (38%), intraluminal space (16%), and mesonephric remnants (39%). The most common architectural pattern of mucosal growth was a flat layer (22/29 cases), followed by varying degrees of stratification, tufting, and papillary growth. High-grade atypia was present in 18/29 cases of mucosal growth, resulting in patterns that resembled primary tubal HGSC. Accompanying growth in the tubal submucosa frequently produced a pseudoinvasive pattern mimicking invasive tubal HGSC. Immunohistochemical expression of p53 by 8/18 high-grade mucosal metastases further contributed to the resemblance to primary tubal HGSC. Bland cytology was present in 11/29 cases of mucosal growth, some of which also exhibited mucinous features, resulting in patterns that resembled either tubal mucinous metaplasia or nonmucinous tubal hyperplasia. Although uncommon, it is possible for metastases of nongynecologic cancers to grow within the mucosa of the fallopian tube and create a potential diagnostic pitfall. Intramucosal growth of a tumor in the fallopian tube is not pathognomonic of a primary tubal origin of the tumor. These findings may carry implications for proposed criteria using the status of the fallopian tube mucosa to assign primary origin of a gynecologic cancer.

Incidental serous tubal intraepithelial carcinoma and early invasive serous carcinoma in the nonprophylactic setting: analysis of a case series.

A precursor for invasive ovarian/pelvic high-grade serous carcinoma, termed serous tubal intraepithelial carcinoma (STIC), has been identified and characterized through careful analysis of the fallopian tubes in both prophylactic salpingo-oophorectomy specimens obtained from women with either a family history of breast and/or ovarian cancer or germline mutations of BRCA1 and BRCA2 and in cases of pelvic high-grade serous carcinoma. Data on incidental STICs and clinically occult microscopic invasive high-grade serous carcinomas are limited. We analyzed the clinicopathologic features of 22 cases, including 15 pure STICs and 7 STICs associated with microscopic invasive high-grade serous carcinomas, identified incidentally in fallopian tubes removed for nonprophylactic indications. Patient age ranged from 39 to 79 years (mean: 62.7; median: 61), with only 1 patient under the age of 50. No patients were known to carry BRCA1 or BRCA2 mutations. Of the 12 pure STICs for which the location in the fallopian tube could be established, 9 were in the fimbriated portion, 1 was at the junction of the fimbria and infundibulum, and 2 were in the nonfimbriated tube. Of the 7 STICs with associated invasive high-grade serous carcinoma, 3 were located in the fimbriated portion, 2 were at the junction of the fimbria and infundibulum, and 2 were in the nonfimbriated tube. The invasive components were in the fallopian tube in 6 cases, 4 in subepithelial stroma of tubal mucosa, and 2 as an intramucosal (exophytic) luminal lesion without invasion of underlying subepithelial stroma (size range: 1 to 4 mm). The remaining case had a microscopic focus of high-grade serous carcinoma within the ipsilateral ovary (1.3 mm cortical focus) identified only on deeper sections, without an associated invasive component in the fallopian tube. The preferential finding of atypical epithelium with the cytologic features of high-grade serous carcinoma, namely STIC, in the fallopian tubes rather than the ovaries as an incidental (clinically occult) microscopic lesion in the absence of widespread pelvic carcinoma provides further evidence that STIC is the earliest form of pelvic high-grade serous carcinoma and that the fallopian tube is the site of origin. This study demonstrates the potential for complete examination of the fallopian tubes and ovaries to identify STICs and early invasive serous carcinomas that might be more amenable to the earliest intervention and potential cure.

[Fallopian tube carcinoma: clinical and morphological features, analysis of 69 cases].

Primary fallopian tube carcinoma (PFTC) is a rare gynecological malignancy accounting 0.14-1.8% cases. The purpose of the study was to assess clinical, morphological and immunohistochemical features of PFTC. All the cases of PFTC were detected during 1980-2005. 31 cases of PFTC were analyzed as to Ki-67, HER-2 expression, estrogen receptors (ER), progesterone receptors (PR), grade and stage. 69 cases of PFTC were detected with an average age of 55, 6 years (range 21-73 years). Stage I detected in 34.2% cases, Stages II and III--32.8%, Ca in situ--10%. Among 31 patients ER were positive in 75% (n = 23), PR were positive in 46% (n = 14): ER+PR+ in 12 (38%) cases, ER+PR- in 11 (36%) cases, ER-PR+ in 2 (6%) cases, ER-PR- in 6 (19.4%) cases. Only 2 cases were HER-2 positive with ER+PR+ and ER-PR- status. Ki-67 labeling index (LI, %) values ranged from 15 to 95% (median 60) with average rate 58.03% +/- 4.08. Ki-67 LI values > or = 60% were graded as high and < 60% as low. We did not find any significant differences in Ki-67 LI values among tumors of various Receptor Status. However Ki-67 L1 > 60% was associated with poor 5-year survival (14%), vs 75% in Ki-67 L1 < 60%. Primary fallopian tube carcinoma is mainly HER-2 negative, receptor positive in 79.6%. Ki-67 rate is irrespective of ER PR status. However the level of Ki-67 (> 60%) was a significant survival prognostic factor.

Early detection of high-grade tubal serous carcinoma in women at low risk for hereditary breast and ovarian cancer syndrome by systematic examination of fallopian tubes incidentally removed during benign surgery.

Early detection of sporadic pelvic serous carcinoma remains an elusive goal. In women at high risk for hereditary breast and ovarian cancer syndrome who undergo prophylactic salpingectomy, systematic pathologic examination of the fallopian tubes will detect occult tubal cancer, mostly in the fimbriae, of a minority of women. Such tubal cancers are the putative precursor to advanced-stage pelvic cancer. We hypothesized that early tubal cancer detection can also be accomplished in women at low risk using a similar approach. In this study, we performed complete and systematic examination of the fallopian tubes removed during surgery performed for benign indications. Among 522 women, 4 cases of serous tubal intraepithelial carcinoma (STIC) were identified. Three of these cases would have gone undetected using the current standard of care of sampling only a single random section of the tube. The fourth case was accompanied by occult ovarian carcinoma. The fimbriae contained STIC in 3 of the 4 cases and atypical mucosa in 1 case in which the STIC was in the nonfimbriated portion of the tube. The morphologic and immunohistochemical features (aberrant p53 and MIB-1) of these STICs were similar to those expected in high-risk women. All 4 patients with STIC underwent BRCA1 and BRCA2 gene testing; no germline mutations were identified in any patient. An additional 11 specimens contained atypical mucosal proliferations that fell short of morphologic and immunohistochemical criteria for STIC. Two of these 11 fulfilled criteria for a serous tubal intraepithelial lesion, and the remaining atypical proliferations exhibited normal p53 and MIB-1. For most specimens, the fimbriae could be completely submitted in 1 or 2 cassettes per tube. These results demonstrate that systematic examination of the tubal fimbriae can serve as a form of early detection of sporadic tubal cancer without incurring significant labor or cost. We propose that the tubal fimbriae should be completely examined in all patients undergoing benign surgery even if there are no clinical features to suggest risk for hereditary breast and ovarian cancer syndrome.

Fallopian tube intraluminal tumor spread from noninvasive precursor lesions: a novel metastatic route in early pelvic carcinogenesis.

Pelvic serous carcinoma is usually advanced stage at diagnosis, indicating that abdominal spread occurs early in carcinogenesis. Recent discovery of a precursor sequence in the fallopian tube, culminating in serous tubal intraepithelial carcinoma (STIC), provides an opportunity to study early disease events. This study aims to explore novel metastatic routes in STICs. A BRCA1 mutation carrier (patient A) who presented with a STIC and tubal intraluminal shedding of tumor cells upon prophylactic bilateral salpingo-oophorectomy (PBSO) instigated scrutiny of an additional 23 women who underwent a PBSO and 40 patients with pelvic serous carcinoma involving the tubes. Complete serial sectioning of tubes and ovaries of patient A did not reveal invasive carcinoma, but subsequent staging surgery showed disseminated abdominal disease. STIC, intraluminal tumor cells, and abdominal metastases displayed an identical immunohistochemical profile (p53/WT1/PAX8/PAX2) and TP53 mutation. In 16 serous carcinoma patients (40%) tubal intraluminal tumor cells were found, compared with none in the PBSO group. This is the first description of a STIC, which plausibly metastasized without the presence of invasion through intraluminal shedding of malignant surface epithelial cells in the tube and subsequently spread throughout the peritoneal cavity. These findings warrant a reconsideration of the malignant potential of STICs and indicate that intraluminal shedding could be a risk factor for early intraperitoneal metastasis. Although rare in the absence of invasive cancer, we show that intraluminal shedding of tumor cells in the fallopian tubes from serous carcinoma cases are common and a likely route of abdominal spread.

Immunohistochemical localization of HE4 in benign, borderline, and malignant lesions of the ovary.

Despite advances in the development of novel methods to improve treatment, ovarian carcinoma is still the leading cause of gynecologic cancer death in the United States and other industrialized nations. Improvements in the clinical outcome of ovarian cancer will be achieved if methods can be developed to enable the detection of these tumors at the earliest possible stage. Thus, it is critically important to identify and validate new biomarkers of ovarian cancer. HE4 expression was defined by immunohistochemical analysis of a wide range of benign, borderline, and malignant ovarian lesions, including serous, endometrioid, mucinous, and clear cell lesions of the ovary and in primary tubal carcinomas and the normal fallopian tube. At the cellular level, HE4 was highly expressed in malignant ovarian tumors and in a wide range of benign and borderline ovarian lesions. In addition, HE4 was highly expressed in primary fallopian tube carcinomas and benign fallopian tubal epithelial cells. These results support the conclusion that HE4 is widely expressed in most benign, borderline, and malignant lesions of the ovary and the fallopian tube. The detection of HE4 expression at high levels in some benign lesions and normal tissues suggests that HE4 could have limited specificity as a marker of ovarian or tubal carcinoma. Furthermore, the relatively weak expression that was observed in many ovarian carcinomas indicates that HE4 could fail to detect some cases of primary or recurrent disease.

[Fallopian tube: the dark face of pelvic carcinogenesis]. / Trompe de Fallope : le côté obscur de la carcinogenèse pelvienne.

Ovarian carcinomas are a heterogeneous group of lesions, among which serous histologic subtype is the most frequent. Ovarian and peritoneal serous carcinomas are subdivided into low- and high-grade tumors. Low-grade carcinomas derive from serous tumors of low malignant potentiel, while high-grade carcinomas were thought to derive de novo from ovarian surface epithelium. Studies from prophylactic salpingo-oophorectomy in women with BRCA mutations revealed a precursor to pelvic serous carcinomas that originates in the distal fallopian tube, called STIC (serous tubal intraepithelial carcinoma). This review reports new findings on serous carcinogenesis in the tube (SCAT). It brings an explanation in French on different terminologies used in the English literature these last years such as SCOUT (secretory cell outgrowth), p53 signature, TILT (tubal intraepithelial lesion in transition), STIC and SCAT and on the macroscopic protocol of Brigham and Women's Hospital of annexectomies specially in the setting of BRCA mutation, the SEE-FIM (sectioning and extensively examining the fimbriated end of the fallopian tube).