Serous Tubal Intraepithelial Carcinoma Research Articles

Clinical and genetic findings of incidental serous tubal intraepithelial carcinoma (145)

<b>Objectives:</b> Serous tubal intraepithelial carcinoma (STIC) is thought to represent the precursor lesion to the high-grade serous fallopian tube or ovarian carcinoma. STIC lesions are found 0.6-6% of the time in women undergoing risk-reducing salpingo-oophorectomy (RRSO) in the setting of a known hereditary predisposition. = However, due to the rarity of incidentally identified STIC lesions, there is limited data to guide management. NCCN guidelines suggest consideration of surgical staging and referral for genetic evaluation. In the absence of a known pathogenic variant as the indication for surgery, there is no data on rates of genetic testing or long-term outcomes. The objective of this study was to describe both clinical outcomes as well as genetic information collected for patients with incidentally noted STIC lesions. <b>Methods:</b> Following IRB approval, pathology records were used to identify all patients diagnosed with a STIC lesion on final pathology from 2007-2021 at a single institution. STIC lesions were characterized utilizing immunohistochemistry. Only patients with STIC lesions undergoing surgery for benign indications were included. Demographic, clinical-pathologic, and genetic data were collected. <b>Results:</b> A total of 16 patients were identified. The median age at diagnosis was 65.5 years (39-80). Fifteen patients (93.8%) had unilateral STIC lesions with one patient having bilateral STIC lesions. Most lesions were positive for p53 (94.1%) and had increased Ki67 proliferation, defined as >10% (94.1%). Two patients (12.5%) had a personal history of malignancy prior to their STIC lesion diagnosis. Patients had a wide variety of presentations, including pelvic mass (37.5%), prolapse (31.3%), abnormal uterine bleeding (25%), and pelvic pain (6.3%). Nine patients had additional surgical procedures performed (56.3%), and no cancer diagnosis was identified for any patient. Additional procedures included contralateral salpingo-oophorectomy, omentectomy, pelvic and paraaortic lymph node dissection, and peritoneal biopsies. No patients received adjuvant treatment. Eleven patients were offered a genetic counseling referral (68.8%), with seven patients completing a counseling appointment (63.6%). Five of the seven patients who completed their visit met criteria for testing based on additional personal and/or family history (71.4%), with one patient testing positive for a PALB2 pathogenic variant (20% of tested patients). Three patients, none of whom underwent genetic testing, were subsequently diagnosed with breast cancer during the follow-up period. <b>Conclusions:</b> Incidental STIC lesions are rare. In this cohort, there were no ovarian, fallopian tube, or primary peritoneal cancer diagnoses after additional surgical staging or during follow-up. More data is needed to guide treatment recommendations. However, compared to STIC lesions in patients undergoing RRSO for a known predisposition, it is not clear whether additional surgical procedures are warranted in patients with incidentally noted STIC lesions. Our data support NCCN recommendations for referral for genetic evaluation as 71% qualified for testing. One patient (20% of those who qualified for testing) had a clinically actionable pathogenic variant. Notably, three patients later developed breast cancer; however, without genetic testing, we cannot determine if there may be a genetic link. Further studies of these lesions are warranted.

Retrospective study of histopathological and prognostic characteristics of primary fallopian tube carcinomas: twenty-year experience (SOCRATE)

ObjectivePrimary fallopian tube carcinoma represents a rare entity, accounting for about 0.75%–1.2% of all gynecological malignancies. The rationale of our study is to describe the prognosis of primary fallopian tube...

Risk reducing surgery with peritoneal staging in BRCA1-2 mutation carriers. A prospective study

IntroductionInternational guidelines recommend risk-reducing salpingo-oophorectomy (RRSO) in BRCA1-2 mutations carriers to decrease ovarian cancer occurrence. In this prospective study, we describe the incidence of occult malignancies and the surgical outcomes in asymptomatic BRCA mutation carriers submitted to RRSO. MethodsData on BRCA1-2 carriers undergoing RRSO with peritoneal washing and peritoneal/omental biopsies (PeS), between January 2019 until March 2021, were prospectively collected. ResultsA total of 132 patients were enrolled: 74 BRCA1 and 58 BRCA2 mutation carriers. 31.1% women underwent RRSO and PeS (16.2% of BRCA1 and 50% of BRCA2 carriers), while 68.9% patients were submitted also to concomitant hysterectomy. Almost all the procedures (99.2%) were performed by minimally invasive surgery. Postoperative complications occurred in twelve patients (9.1%): 10 in the concomitant hysterectomy group and two complications in the RRSO group. At the final pathological examination, 6 (4.5%) occult carcinomas were diagnosed: 3 fallopian tube carcinomas, one ovarian carcinoma and two serous tubal intraepithelial carcinomas (STICs), with negative PeS. Median age of occult carcinomas patients at RRSO was 54 (range: 48–79) years. The mean follow up was 20 (range: 7–34) months. During the follow up, no primary peritoneal cancer has been diagnosed. ConclusionsOccult pathologic findings in RRSO occurred in 4.5% (3% invasive carcinomas, STIC 1.5%) among our patients. The routine use of peritoneal biopsies does not improve the detection of occult malignancies. Our data confirm the importance of timely performing RRSO in BRCA1-2 carriers.

Differential epithelial and stromal LGR5 expression in ovarian carcinogenesis

Lgr5 has been identified as a marker of the stem/progenitor cells in the murine ovary and oviduct by lineage tracing. However, little is known regarding LGR5 expression or its functional significance in human ovary tissues. Here, using RNA in situ hybridization and/or immunohistochemistry, we thoroughly investigated LGR5 expression in normal human ovaries, fallopian tubes and various ovarian tumors. We discovered that LGR5 expression is negligible in the human ovary surface epithelium, whereas ovarian stromal cells normally express low levels of LGR5. Remarkably, fallopian tube epithelium, inclusion cysts and serous cystadenomas with a Müllerian phenotype expressed high levels of LGR5, and LGR5 expression was restricted to PAX8+/FOXJ1− secretory cells of the tubal epithelium. Strong stromal LGR5 expression without epithelial LGR5 expression was consistently observed in the path from serous cystadenoma to serous borderline tumor to low grade serous carcinoma (LGSC). Unlike LGSC, high grade serous carcinoma (HGSC), clear cell carcinoma, endometrioid carcinomas displayed various epithelial-stromal LGR5 expression. Notably, high levels of LGR5 expression were observed in serous tubal intraepithelial carcinoma, which slightly declined in invasive HGSC. LGR5 expression was significantly associated with improved progression-free survival in HGSC patients. Moreover, in vitro assays demonstrated that LGR5 expression suppressed tumor proliferation and migratory capabilities. Taken together, these findings indicate a tumor-suppressive role for LGR5 in the progression of HGSC.

NRG-CC008: A nonrandomized prospective clinical trial comparing the non-inferiority of salpingectomy to salpingo-oophorectomy to reduce the risk of ovarian cancer among BRCA1 carriers [SOROCk

TPS10615 Background: Studies of ovarian cancer screening in the general population have not demonstrated a reduction in ovarian cancer mortality. High-grade pelvic serous carcinomas (HGSCs) have traditionally been thought to originate from the ovarian surface epithelium. However, more recent data strongly suggests that most HGSCs originate from precursor lesions found in the distal fallopian tube. Serous tubal intra-epithelial carcinoma (STIC) lesions are found in association with HGSCs in 50-60% of cases and other early serous precursor lesions can be identified in an additional 25% of cases. The Society of Gynecologic Oncology has recently issued recommendations that salpingectomy can be considered at the completion of childbearing in indiviuals at increased genetic risk of ovarian cancer who do not agree to salpingo-oophorectomy. They also indicated that approximately 30% of BRCA1 mutation carriers choose not to remove their ovaries, and the mean age at RRSO for those who do is in the late 40s, much later than recommended age per guidelines. The purpose of this study is to compare risk-reducing approaches in high-risk women with deleterious germline BRCA1mutations; specifically, to demonstrate the non-inferiority of bilateral salpingectomy compared to bilateral salpingo-oophorectomy to reduce the incidence of ovarian cancer among deleterious germline BRCA1mutation carriers. Methods: This is a non-randomized prospective trial to determine if bilateral salpingectomy is non-inferior to bilateral salpingo-oophorectomy in terms ovarian, primary peritoneal, and fallopian tube cancer risk among gBRCA1m carriers between 35 and 50 years old. Individuals choose the treatment they want to receive in collaboration with their physician(s). The primary endpoint is the time to development of incident HGSC, specifically ovarian, primary peritoneal, or fallopian tube cancers. Secondary endpoints include measurement of health-related quality of life, estrogen deprivation symptoms, sexual function, menopausal symptoms, cancer distress, Medical Decision Making, and adverse events. Results: As of 1/31/2022, 116 individuals have been enrolled into this trial. A recent amendment was put forward to allow the following individuals to also participate in this trial: 1) Individuals who are receiving hormonal therapy for maintenance therapy (eg, tamoxifen, AIs, etc), 2) Individuals with a history of any prior cancer and have completed chemotherapy, at least 30 days ago, and 3) Individuals who are considering Assisted Reproductive Technologies (eg, IVF). Furthermore, there is ongoing consideration of allowing general Ob/Gyn providers to recruit patients to this trial and perform procedures, with proper pathology training and sign off at their hospitals. NCI grant UG1CA189867. Clinical trial information: NCT04251052.

Abstract PR005: TP53 field defects in uterine fluid are associated with ovarian cancer risk

Abstract Background: High grade serous ovarian cancer (HGSC), the most common and aggressive type of ovarian cancer, is nearly always driven by TP53 mutations, which can be detected in uterine lavages using ultra-deep duplex sequencing. While this finding supports the development of a uterine lavage assay for early HGSC detection, age-related TP53 mutations compromise specificity. The goal of this study was to thoroughly characterize the nature of TP53 mutations identified in uterine lavage of women with and without HGSC to better understand TP53 clonal evolution during aging and to determine its association to HGSC. Methods: Uterine lavages were collected preoperatively in 54 “average-risk” women undergoing gynecological surgery for suspicious masses (34 women ultimately had HGSC, 20 were cancer free) and in 98 “high-risk” women undergoing risk-reducing salpingo-oopherectomy (17 were found to have HGSC or serous tubal intraepithelial carcinomas (STICs), 81 were cancer-free). Ultra-deep (&amp;gt;10,000x), ultra-accurate sequencing of TP53 was performed on uterine lavage DNA using duplex sequencing. Tumors and STICs were also duplex sequenced to determine TP53 tumor-driving mutations. The frequency of TP53 mutations and large TP53 mutant clones (those found in &amp;gt;2 duplex reads) was compared between women with and without HGSC. Results: The tumor-specific TP53 mutation was detected in 53% of lavages from average-risk women with HGSC and in 22% of lavages from high-risk women with HGSC/STICs. As in prior studies, TP53 biological background mutations were identified in nearly all women and their frequency was age-related. TP53 background mutations, however, were more abundant in women with prior chemotherapy, regardless of their cancer status or age. In women without prior chemotherapy and without high-risk of HGSC, having HGSC was associated with a significantly higher frequency of large TP53 mutant clones (p=0.007) and large TP53 mutant clones containing pathogenic mutations (p=0.007) or TP53 mutations commonly found in cancer (p=0.001). Interestingly, women at high risk of HGSC also carried high frequency of large and pathogenic TP53 mutant clones in lavage, even in those cases in which cancer or STICs were not identified. Conclusions: Ultra-sensitive duplex sequencing enabled detection of a patient’s HGSC or STIC driver mutations, respectively, in about half and a quarter of uterine lavages. However, of even greater interest, we observed a significant excess of large and pathogenic TP53 mutant clones in lavages of women with HGSC that were not present in the tumor. These results indicate that TP53 somatic evolution is associated with HGSC development and suggest that the measurement of TP53 mutant clones in uterine lavages harbors value as a predictor of ovarian cancer risk. Citation Format: Rosana Risques, Thomas H. Smith, Zachary K. Norgaard, Roniz Katz, Fang Yin Lo, Elizabeth K. Schmidt, Jacob E. Higgins, Martin Filipits, Intidhar Labidi-Galy, David Cibula, Lukáš Dostálek, Gabriel Jelenek, Magdalena Plch, Jiří Bouda, Alexander Mustea, Mateja Condic, Sabine Grill, Noreen Gleeson, Peter Oppelt, Gunda Pristauz-Telsnigg, Adriaan Vanderstichele, Siel Obrecht, Adam Rosenthal, Paul Speiser, Jesse Salk. TP53 field defects in uterine fluid are associated with ovarian cancer risk [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr PR005.

Genomic catastrophe, the peritoneal cavity and ovarian cancer prevention.

The current theory of carcinogenesis for the deadliest of 'ovarian' cancers-high-grade serous carcinoma (HGSC)-holds that the malignancy develops first in the fallopian tube and spreads to the ovaries, peritoneum, and/or regional lymph nodes. This is based primarily on the observation of early forms of serous neoplasia (serous tubal intraepithelial lesions [STILs], and serous tubal intraepithelial carcinomas [STICS]) in the fimbria of women undergoing risk reduction surgery. However, these lesions are uncommon in the general population, confer a low risk (5%) of HGSC following their removal in at-risk women with germ-line BRCA1/2 mutations, and require 4 or more years to recur as intraperitoneal HGSC. These features suggest that isolated STILs and STICs behave as precursors, with uncertain cancer risk rather than carcinomas. Their evolution to HGSC within, or after, escape from the tube could proceed stepwise with multiple biologic events; however, it is unclear whether tubal or ovarian HGSCs encountered in the setting of advanced disease evolved in the same fashion. The latter scenario could also be explained by a 'catastrophic' model in which STICs suddenly develop with invasive and metastatic potential, overwhelming or obscuring the site of origin. Moreover, a similar model might explain the sudden emergence of HGSC in the peritoneal cavity following escape of precursor cells years before. Long-term follow-up data from opportunistic or prophylactic salpingectomy should shed light on where malignant transformation occurs, as well as the timeline from precursor to metastatic HGSC. © 2022 The Pathological Society of Great Britain and Ireland.

Precursors in the ovarian stroma: another pathway to explain the origin of ovarian serous neoplasms

Ovarian serous neoplasms are thought to arise from the fallopian tube or from the ovarian surface epithelium. The possibility of a third pathway-involving the mesenchymal-epithelial transition and mimicking the formation of the Müllerian duct-arose from observations gathered from our routine cases. The purpose of this study is to determine the association of precursors in the ovarian stroma with different types of ovarian serous neoplasms. Three hundred neoplasms, benign (25), borderline (63), and malignant ovarian serous neoplasms (40 low-grade serous carcinomas [LGSCas] and 172 high-grade serous carcinomas [HGSCas]), were reviewed. Clinicopathologic features analyzed includedpatient's age, tumor size, stage, histologic pattern, and possible precursors in the ovarian parenchyma (endosalpingiosis, inverted macropapillae, polyploid giant cancer cells, and simple cysts). All benign and borderline cases showed continuity with benign serous cysts or endosalpingiosis. In LGSCas, continuity with serous cysts was found in 29 (72%) of 40 cases, and inverted macropapillae were found in 12 (30%) of 40 cases. In untreated HGSCas, there was continuity with simple cysts in 42% of cases. In addition, these HGSCas contained polyploid giant cancer cells in 20% of cases. There were no different features in the ovaries in cases with or without serous tubal intraepithelial carcinoma. Our study shows that in a subset of cases, ovarian serous neoplasms and the Müllerian duct develop in similar fashion, originating from epithelial cells derived from the mesothelium, or occur de novo from structures derived from mesenchymal-epithelial transition.

Focal Serous Tubal Intra-Epithelial Carcinoma Lesions Are Associated With Global Changes in the Fallopian Tube Epithelia and Stroma.

ObjectiveSerous tubal intra-epithelial carcinoma (STIC) lesions are thought to be precursors to high-grade serous ovarian cancer (HGSOC), but HGSOC is not always accompanied by STIC. Our study was designed to determine if there are global visual and subvisual microenvironmental differences between fallopian tubes with and without STIC lesions.MethodsComputational image analyses were used to identify potential morphometric and topologic differences in stromal and epithelial cells in samples from three age-matched groups of fallopian tubes. The Benign group comprised normal fallopian tubes from women with benign conditions while the STIC and NoSTIC groups consisted of fallopian tubes from women with HGSOC, with and without STIC lesions, respectively. For the morphometric feature extraction and analysis of the stromal architecture, the image tiles in the STIC group were further divided into the stroma away from the STIC (AwaySTIC) and the stroma near the STIC (NearSTIC). QuPath software was used to identify and quantitate secretory and ciliated epithelial cells. A secretory cell expansion (SCE) or a ciliated cell expansion (CCE) was defined as a monolayered contiguous run of >10 secretory or ciliated cells uninterrupted by the other cell type.ResultsImage analyses of the tubal stroma revealed gradual architectural differences from the Benign to NoSTIC to AwaySTIC to NearSTIC groups. In the epithelial topology analysis, the relative number of SCE and the average number of cells within SCE were higher in the STIC group than in the Benign and NoSTIC groups. In addition, aging was associated with an increased relative number of SCE and a decreased relative number of CCE. ROC analysis determined that an average of 15 cells within SCE was the optimal cutoff value indicating the presence of a STIC lesion in the tubal epithelium.ConclusionsOur findings suggest that global stromal alterations and age-associated reorganization of tubal secretory and ciliated cells are associated with STIC lesions. Further studies will need to determine if these alterations precede STIC lesions and provide permissible conditions for the formation of STIC.

Risk of Peritoneal Carcinomatosis After Risk-Reducing Salpingo-Oophorectomy: A Systematic Review and Individual Patient Data Meta-Analysis.

After risk-reducing salpingo-oophorectomy (RRSO), BRCA1/2 pathogenic variant (PV) carriers have a residual risk to develop peritoneal carcinomatosis (PC). The etiology of PC is not yet clarified, but may be related to serous tubal intraepithelial carcinoma (STIC), the postulated origin for high-grade serous cancer. In this systematic review and individual patient data meta-analysis, we investigate the risk of PC in women with and without STIC at RRSO. Unpublished data from three centers were supplemented by studies identified in a systematic review of EMBASE, MEDLINE, and the Cochrane library describing women with a BRCA-PV with and without STIC at RRSO until September 2020. Primary outcome was the hazard ratio for the risk of PC between BRCA-PV carriers with and without STIC at RRSO, and the corresponding 5- and 10-year risks. Primary analysis was based on a one-stage Cox proportional-hazards regression with a frailty term for study. From 17 studies, individual patient data were available for 3,121 women, of whom 115 had a STIC at RRSO. The estimated hazard ratio to develop PC during follow-up in women with STIC was 33.9 (95% CI, 15.6 to 73.9), P < .001) compared with women without STIC. For women with STIC, the five- and ten-year risks to develop PC were 10.5% (95% CI, 6.2 to 17.2) and 27.5% (95% CI, 15.6 to 43.9), respectively, whereas the corresponding risks were 0.3% (95% CI, 0.2 to 0.6) and 0.9% (95% CI, 0.6 to 1.4) for women without STIC at RRSO. BRCA-PV carriers with STIC at RRSO have a strongly increased risk to develop PC which increases over time, although current data are limited by small numbers of events.

Signal transduction pathway activity in high-grade serous carcinoma, its precursors and Fallopian tube epithelium

ObjectiveTo determine the activity of key signal transduction pathways in serous tubal intraepithelial carcinoma (STIC) and concurrent high-grade serous carcinoma (HGSC) and compare this to pathway activity in normal Fallopian tube epithelium (FTE). MethodsWe assessed mRNA expression levels of pathway-specific target genes with RT-qPCR in STIC and concurrent HGSC (n = 8) and normal FTE (n = 8). Subsequently, signal transduction pathway assays were used to assess functional activity of the androgen (AR) and estrogen receptor (ER), phosphoinositide-3-kinase (PI3K), Hedgehog (HH), transforming growth factor beta (TGF-β) and canonical wingless-type MMTV integration site (Wnt) pathways. ResultsThere were no statistically significant differences in pathway activity between STIC and HGSC, but STIC and HGSC demonstrated significantly lower ER and higher PI3K and HH pathway activity in comparison to normal FTE, suggesting these pathways as putative early drivers. In addition, we determined FOXO3a protein expression by immunohistochemistry and found loss of FOXO3a protein expression in STIC and HGSC compared to normal FTE. This observation confirmed that activation of PI3K signaling by loss of FOXO is an early hallmark of serous carcinogenesis. Furthermore, HGSC demonstrated significant loss of AR and Wnt pathway activity in relation to FTE, suggesting these pathways contribute to disease progression. ConclusionOur observations, together with the previously described associations between p53 signaling and both PI3K and HH pathway activity, provide evidence that increased PI3K and HH pathway activity and loss of ER pathway activity may be underlying events contributing to neoplastic transformation of FTE into STIC.

Prevalence of precursor lesions (P53 signature, SCOUT, STIL, STIC) in fallopian tubes resected for non-neoplastic causes.

High-grade pelvic serous carcinoma is a common cause of death in women worldwide and India. Recent evidence has clearly implicated the changes in the mucosa of the fimbrial end of the fallopian tube in its pathogenesis. 1) To study histopathology features of surgically resected specimens of fallopian tubes received with non-neoplastic lesions of the uterus and ovary for the presence of any precursor lesions [secretory cell outgrowth (SCOUT), serous tubal intraepithelial lesion (STIL), p53 signatures, and serous tubal intraepithelial carcinoma (STIC)]. 2) To confirm the findings with immunohistochemistry. 3) To correlate the prevalence of precursor lesions with clinical parameters and benign lesions of the uterus and ovaries. Assessment of histopathological changes in 100 specimens of distal fallopian tubes was done using the sectioning and extensive examination of the fimbrial end (SEE-FIM) protocol. H and E stain followed by immunohistochemistry for Bcl-2, p53, and Ki-67. The statistical significance of the difference in the mean values of precursor areas was evaluated by an unpaired t-test. Among 100 specimens taken on H and E, precursor lesions were suspected in 49% of the cases. SCOUT, suspicious for STIC, suspicious for STIC with areas of SCOUT, and unequivocal for STIC with areas of SCOUT were seen in 8%, 4%, 33%, and 4% of the cases, respectively. However, on IHC, SCOUTS were confirmed in 45% of the cases, p53 signature in 2%, STIL in 9%, and STIC in 4% of the cases. Sectioning and extensive examination of the fimbrial end (SEE-FIM) should be routinely done as it provides the opportunity to detect the early malignant changes. It may help in evolving the strategies for early detection, management, and reducing mortality.

Progestin Significantly Inhibits Carcinogenesis in the Mogp-TAg Transgenic Mouse Model of Fallopian Tube Cancer.

Recent studies suggest that the fallopian tube epithelium (FTE) harbors the precursor for high-grade ovarian cancer, creating opportunities for targeting the FTE for ovarian cancer prevention. Preclinical evidence supports progestins as ovarian cancer preventives, but the effect of progestins on the FTE is not well characterized. The murine oviduct-specific glycoprotein promotor-driven simian virus 40 large T-Antigen (mogp-TAg) transgenic mouse model develops neoplastic lesions in the fallopian tube in a manner similar to that described in human fallopian tube and ovarian cancers. In this study, we investigated the inhibitory effects of the progestin depo-medroxyprogesterone acetate (DMPA) on fallopian tube carcinogenesis following treatment for 3 and 7 weeks in 5-week-old mogp-TAg mice. Overall, compared with vehicle-treated mice, the fallopian tube of DMPA-treated mice was significantly smaller (P < 0.0005), accumulated fewer p53-positive cells, had normal distribution of ciliated cells, less nuclear pleomorphism and epithelial tufting, and had a significantly lower proliferative index (P = 0.001). Accumulation of p53 signatures and serous tubal intraepithelial carcinomas (STIC) in the fallopian tube was significantly reduced in the DMPA (P < 0.0005) treatment group. Moreover, the fallopian tube of the DMPA-treated mice developed significantly less adenocarcinoma compared with vehicle (P < 0.005) at both treatment time points. DMPA treatment significantly induced cleaved caspase-3 (P < 0.0005) in the FTE compared with vehicle suggesting that apoptosis is involved in DMPA-related clearance of abnormal cells from the fallopian tube. These data demonstrate that DMPA targets early events in fallopian tube carcinogenesis by clearing genetically damaged cells, leading to marked reduction in adenocarcinoma, supporting progestins as chemopreventive agents for fallopian tube and ovarian cancers. PREVENTION RELEVANCE: The fallopian tube is thought to harbor the cell of origin for most ovarian cancers. We show in a mouse model of fallopian tube cancer that progestin eradicates the earliest known precancerous lesions and markedly inhibits fallopian tube carcinogenesis, adding to growing preclinical evidence supporting progestins as potent ovarian cancer chemopreventive agents.

Are histomorphologic changes in the fimbrial ends more to blame for primary epithelial ovarian carcinomas than initially thought?

Objective: To investigate the relationship between primary epithelial ovarian tumors and histomorphologic changes in the fimbrial ends (FEs) of the fallopian tubes. Materials and Methods: Twenty-eight serous carcinomas (SCs) and 12 non-serous carcinomas (NSC) were studied. Ovarian and concomitant invasive tumors in FEs were labeled with PAX8, WT-1 and Calretinin. Results: Eighty-six percent of SCs were high grade (HG), 14% of were low grade (LG). 71% of SCs (85% HG, 15% LG) had concomitant invasive tumors in FEs. Serous tubal intraepithelial carcinoma (STIC) was seen in 29% (75% HG, 25% LG), all had concomitant invasive tumors in FEs. The presence of tumors in FEs was statistically significant in SCs (p=0.03). 33% of NSCs had concomitantly invasive tumors in FEs. 67% of endometrioid tumors, 33% of clear cell carcinomas had endometriosis. 50% of mucinous tumors, 67% of endometrioid tumors, 50% of benign Brenner tumors had Walthard nest. Except for mucinous carcinomas, ovarian and concomitant invasive tumors in FEs displayed tubal phenotype (Calretinin-/PAX8+). Conclusion: The results of our study suggest that, invasive tumors and STIC in FEs are not only limited to HGSCs, but can also be seen in LGs. FEs could also be a site of origin for NSCs, however, future studies with more cases are needed.

TP53 variants in p53 signatures and the clonality of STICs in RRSO samples.

ObjectivePrecursor lesions may be identified in fallopian tube tissue after risk-reducing salpingo-oophorectomy (RRSO) in patients with pathogenic variants of BRCA1/2. Serous tubal intraepithelial carcinoma (STIC) is considered a precursor of high-grade serous carcinoma, whereas the significance of the p53 signature remains unclear. In this study, we investigated the relationship between the p53 signature and the risk of ovarian cancer.MethodsWe analyzed the clinicopathological findings and conducted DNA sequencing for TP53 variants of p53 signatures and STIC lesions isolated using laser capture microdissection in 13 patients with pathogenic variants of BRCA1/2 who underwent RRSO and 17 control patients with the benign gynecologic disease.Results TP53 pathogenic variants were detected significantly higher in RRSO group than control (p<0.001). No difference in the frequency of p53 signatures were observed between groups (53.8% vs 29.4%; p=0.17). TP53 sequencing and next-generation sequencing analysis in a patient with STIC and occult cancer revealed 2 TP53 mutations causing different p53 staining for STICs and another TP53 mutation shared between STIC and occult cancer.ConclusionThe sequence analysis for TP53 revealed 2 types of p53 signatures, one with a risk of progression to STIC and ovarian cancer with pathological variants in TP53 and the other with a low risk of progression without pathological variants in TP53 as seen in control.

Protocol for the Detection of Organoid-Initiating Cell Activity in Patient-Derived Single Fallopian Tube Epithelial Cells.

Identification of serous tubal intraepithelial carcinomas (STIC) in the fallopian tubes of women who are carriers of germ line pathogenic variants in tubo-ovarian cancer predisposition genes (i.e., BRCA1 and BRCA2) has led to the hypothesis that many high-grade serous carcinomas (HGSC) arise from the fimbria of the fallopian tube. However, the primitive (stem and progenitor) tubal epithelial cells that give rise to STIC and HGSC have not been defined. Further, as putative HGSC precursors are discovered at salpingectomy, the natural history of such lesions is truncated at diagnosis. Thus, living cultures of human fallopian tubes suitable for experimental studies are needed to define and characterize the cellular origin of HGSCs and thereby advance the discovery of improved methods to assess risk, develop effective early detection tests and identify novel prevention approaches. Accordingly, patient-derived tissue-organoids and isolated epithelial stem cell derived-organoids generated from average and high-risk patients are vital resources to understand the developmental biology of aging fallopian tubes and pathogenesis of HGSCs. With a vision to boost HGSC prevention research, we have established state-of-the-art protocols for the collection, processing, storage, distribution, and management of fallopian tube tissues. Here we describe the protocol for preparing these organoids, with emphasis on the key steps that require meticulous attention to achieve success.

A prospective multicentric study of risk-reducing salpingo-oophorectomy in BRCA mutation patients.

Background and aim of the work:BRCA1/2 are tumour-suppressor genes involved in DNA homologous recombination and ovarian cancer development. The study evaluated the risk of tumor cancer in women presenting the BRCA mutations.Methods:Risk-reducing surgery (RRS) was performed in 100 patients carrying BRCA1 (aged between 30-73 years, median age was 51 years) and BRCA 2 mutation (aged between 36-70 years, median age was 53 years). Fifty-eight patients had previous history of breast cancer.Results:Between the 100 patients, 82 women underwent risk-reducing salpingo-oophorectomy (RRSO) through a laparoscopic minimally invasive approach, 7 (7%) underwent laparoscopic RRSO and contextual hysterectomy, 1 woman (1%) underwent RRSO through a laparotomic approach and 10 women (10%) laparotomic RRSO and hysterectomy. During 5 (5%) laparoscopic RRSO, prophylactic bilateral mastectomy was also performed. Early and late complication occurred in 3 patients (3%). Two patients (2%) were found to have occult Serous Tubal Intraepithelial Carcinoma (STIC) and three patients (3%) occult cancer.Conclusions:RRSO is safe and feasible in BRCA mutation carriers. The procedure is effective for genetic prevention of ovarian cancer. (www.actabiomedica.it)

Multi-modal Profiling of the Extracellular Matrix of Human Fallopian Tubes and Serous Tubal Intraepithelial Carcinomas.

Recent evidence supports the fimbriae of the fallopian tube as one origin site for high-grade serous ovarian cancer (HGSOC). The progression of many solid tumors is accompanied by changes in the microenvironment, including alterations of the extracellular matrix (ECM). Therefore, we sought to determine the ECM composition of the benign fallopian tube and changes associated with serous tubal intraepithelial carcinomas (STICs), precursors of HGSOC. The ECM composition of benign human fallopian tube was first defined from a meta-analysis of published proteomic datasets that identified 190 ECM proteins. We then conducted de novo proteomics using ECM enrichment and identified 88 proteins, 7 of which were not identified in prior studies (COL2A1, COL4A5, COL16A1, elastin, LAMA5, annexin A2, and PAI1). To enable future in vitro studies, we investigated the levels and localization of ECM components included in tissue-engineered models (type I, III, and IV collagens, fibronectin, laminin, versican, perlecan, and hyaluronic acid) using multispectral immunohistochemical staining of fimbriae from patients with benign conditions or STICs. Quantification revealed an increase in stromal fibronectin and a decrease in epithelial versican in STICs. Our results provide an in-depth picture of the ECM in the benign fallopian tube and identified ECM changes that accompany STIC formation. (J Histochem Cytochem XX: XXX-XXX, XXXX).

Tubal histopathological abnormalities in BRCA1/2 mutation carriers undergoing prophylactic salpingo-oophorectomy: a case–control study

ObjectiveTo describe tubal histopathological abnormalities in women with germline BRCA1/2 mutations and in controls.MethodsConsecutive women with BRCA1/2 mutations undergoing bilateral salpingo-oophorectomy between 2010 and 2020 in two centers (San Gerardo...

TGFBI Production by Macrophages Contributes to an Immunosuppressive Microenvironment in Ovarian Cancer.

The tumor microenvironment evolves during malignant progression, with major changes in nonmalignant cells, cytokine networks, and the extracellular matrix (ECM). In this study, we aimed to understand how the ECM changes during neoplastic transformation of serous tubal intraepithelial carcinoma lesions (STIC) into high-grade serous ovarian cancers (HGSOC). Analysis of the mechanical properties of human fallopian tubes (FT) and ovaries revealed that normal FT and fimbria had a lower tissue modulus, a measure of stiffness, than normal or diseased ovaries. Proteomic analysis of the matrisome fraction between FT, fimbria, and ovaries showed significant differences in the ECM protein TGF beta induced (TGFBI, also known as βig-h3). STIC lesions in the fimbria expressed high levels of TGFBI, which was predominantly produced by CD163-positive macrophages proximal to STIC epithelial cells. In vitro stimulation of macrophages with TGFβ and IL4 induced secretion of TGFBI, whereas IFNγ/LPS downregulated macrophage TGFBI expression. Immortalized FT secretory epithelial cells carrying clinically relevant TP53 mutations stimulated macrophages to secrete TGFBI and upregulated integrin αvβ3, a putative TGFBI receptor. Transcriptomic HGSOC datasets showed a significant correlation between TGFBI expression and alternatively activated macrophage signatures. Fibroblasts in HGSOC metastases expressed TGFBI and stimulated macrophage TGFBI production in vitro. Treatment of orthotopic mouse HGSOC tumors with an anti-TGFBI antibody reduced peritoneal tumor size, increased tumor monocytes, and activated β3-expressing unconventional T cells. In conclusion, TGFBI may favor an immunosuppressive microenvironment in STICs that persists in advanced HGSOC. Furthermore, TGFBI may be an effector of the tumor-promoting actions of TGFβ and a potential therapeutic target. SIGNIFICANCE: Analysis of ECM changes during neoplastic transformation reveals a role for TGFBI secreted by macrophages in immunosuppression in early ovarian cancer.