Diagnosis Of Serous Tubal Intraepithelial Carcinoma Research Articles

Abstract 6166: A whole-organ ex vivo optical imaging technique for non-destructive, more precise identification of serous tubal intraepithelial carcinoma (STIC) in fallopian tubes

Abstract Objective With the recent discovery of the fallopian tube (FT) origin of the most common and lethal type of ovarian cancer, high grade serous cancer (HGSC), engineering solutions to overcome the limitations of standard histopathology to more reliably identify incipient HGSCs and their serous tubal intraepithelial carcinoma (STIC) precursors are much needed. This investigation tests the potential of whole-organ ex vivo optical imaging of freshly excised FTs to label and sample abnormal tubal epithelium prior to formalin fixation and paraffin embedding for standard histopathology. Methods This investigation prototyped “OVASEEK”, a whole-organ, near-infrared optical imaging platform for identification of STICs. This prospective biospecimen protocol with annotated clinical data was approved by the IRB. Following salpingectomy at the time of hysterectomy for benign indications, FTs from study participants are longitudinally bivalved. Half of the FT is retained for routine evaluation using the Sectioning and Extensively Examining the Fimbriated end (SEE-FIM) protocol by Johns Hopkins gynecologic pathologists (Gyn Path), while the other half is sent overnight in organ transplant media to MIT for imaging on OVASEEK. Hyperspectral “label free” first pass imaging is performed using a series of band-pass filters. Second pass fluorescence imaging is then performed using nanoparticles tagged with anti-LAMC1 antibodies targeting laminin γ1, a known STIC surface marker. Abnormal signal(s) on OVASEEK imaging of the FT epithelium are tattooed with black ink, the tissue is formalin fixed and returned to Gyn Path for serial sectioning. Research findings are reported in an addendum to the formal pathology report in the electronic medical record and discussed with the patient by the gynecologic oncologist co-investigator. Results OVASEEK enabled non-destructive imaging over a wide field-of-view ~ 12×12 cm, with features of interest in the 1,050-1,550 nm range. In this pilot study, OVASEEK identified histopathologic abnormalities missed by standard SEE-FIM in 20% of FTs (n=2 out of 10). In each case, OVASEEK found microscopic (~200 µm) foci of salpingitis, a lymphoplasmacytic infiltrate consistent with inflammation. Performance of serial sectioning and histopathologic examination of the tattooed epithelium yielded this diagnosis. Conclusion Work is ongoing to improve the resolution, speed and sensitivity of OVASEEK for STIC detection. Identification of µm-sized foci of inflammation using OVASEEK is proof-of-principle that whole-organ ex vivo imaging of freshly excised FTs may be an innovation that improves the diagnostic performance of routine histopathology. Accurate and reproducible diagnosis of STIC and concurrent microscopic HGSC is imperative to the understanding of the early pathogenesis of HGSC in clinically actionable ways. Citation Format: Neelkanth M. Bardhan, Vivek Rastogi, Rebecca L. Stone, Angela M. Belcher. A whole-organ ex vivo optical imaging technique for non-destructive, more precise identification of serous tubal intraepithelial carcinoma (STIC) in fallopian tubes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6166.

Aneuploidy Landscape in Precursors of Ovarian Cancer.

Serous tubal intraepithelial carcinoma (STIC) is now recognized as the main precursor of ovarian high-grade serous carcinoma (HGSC). Other potential tubal lesions include p53 signatures and tubal intraepithelial lesions. We aimed to investigate the extent and pattern of aneuploidy in these epithelial lesions and HGSC to define the features that characterize stages of tumor initiation and progression. We applied RealSeqS to compare genome-wide aneuploidy patterns among the precursors, HGSC (cases, n = 85), and histologically unremarkable fallopian tube epithelium (HU-FTE; control, n = 65). On the basis of a discovery set (n = 67), we developed an aneuploidy-based algorithm, REAL-FAST (Repetitive Element AneupLoidy Sequencing Fallopian Tube Aneuploidy in STIC), to correlate the molecular data with pathology diagnoses. We validated the result in an independent validation set (n = 83) to determine its performance. We correlated the molecularly defined precursor subgroups with proliferative activity and histology. We found that nearly all p53 signatures lost the entire Chr17, offering a "two-hit" mechanism involving both TP53 and BRCA1 in BRCA1 germline mutation carriers. Proliferatively active STICs harbor gains of 19q12 (CCNE1), 19q13.2, 8q24 (MYC), or 8q arm, whereas proliferatively dormant STICs show 22q loss. REAL-FAST classified HU-FTE and STICs into 5 clusters and identified a STIC subgroup harboring unique aneuploidy that is associated with increased proliferation and discohesive growth. On the basis of a validation set, REAL-FAST showed 95.8% sensitivity and 97.1% specificity in detecting STIC/HGSC. Morphologically similar STICs are molecularly distinct. The REAL-FAST assay identifies a potentially "aggressive" STIC subgroup harboring unique DNA aneuploidy that is associated with increased cellular proliferation and discohesive growth. REAL-FAST offers a highly reproducible adjunct technique to assist the diagnosis of STIC lesions.

A questionnaire-based survey on the diagnostic and therapeutic approaches for patients with STIC in Germany

PurposeDespite the growing understanding of the carcinogenesis of pelvic high-grade serous carcinoma (HGSC) of the ovary and peritoneum and its precursor lesion serous tubal intraepithelial carcinoma (STIC), evidence-based proven recommendations on the clinical management of patients with STIC are lacking so far.MethodsA questionnaire containing 21 questions was developed to explore the clinical experience with patients with the diagnosis of STICs and the diagnostic, surgical and histopathological approaches in Germany. Overall, 540 clinical heads of department in all German gynaecological centres were asked to participate.Results131 questionnaires (response rate 24.3%) were included in this survey. 45.8% of the respondents had treated one to three STIC patients during their career. 75.6% of the respondents performed opportunistic bilateral salpingectomies during other gynaecological surgeries. Most of the participants (31.3%) started with the SEE-FIM (Sectioning and Extensively Examining the FIMbria) protocol in 2014. It was requested by 39.7% centres for prophylactic salpingectomies, by 13.7% for both prophylactic and opportunistic salpingectomies and by 22.1% for neither of both. 38.2%, 1.5% and 24.4% of the participants would use the laparoscopic, transverse and midline laparotomic approach for a surgical staging procedure, respectively. 25.6% (54.7%) of the respondents recommended a hysterectomy in premenopausal (versus postmenopausal) patients with a STIC, 24.4% (88.4%) a bilateral oophorectomy and 50.0% (4.7%) an affected side oophorectomy (all p values < 0.001). Omentectomy, pelvic and para-aortic lymphadenectomy would be performed by 60.5% (64.0%), 9.3% (11.6%) and 9.3% (11.6%) of respondents in premenopausal (versus postmenopausal) patients (all p values > 0.05).ConclusionOur survey highlights significant inconsistency in the management of patients with STIC. Prospective data are urgently needed to elucidate the clinical impact of a STIC lesion and its clinical management.

The clinical impact of serous tubal intraepithelial carcinoma on outcomes of patients with high-grade serous carcinoma of the ovary, fallopian tube, and peritoneum.

To investigate whether the presence of serous tubal intraepithelial carcinoma (STIC) is associated with clinical outcomes in a nonselected (unknown BRCA status) cohort of patients with a high-grade serous carcinoma (HGSC) of the ovary, fallopian tube, and peritoneum. A prospective case-series with planned data collection. The study was conducted in a total of 131 patients, who underwent primary cytoreductive surgery between 2007 and 2012. Histological examination of the fallopian tubes included the "sectioning and extensively examining the fimbriated end" protocol. The diagnosis of STIC was based on the combination of morphology and immunohistochemistry. The patients were divided into two groups according to the absence or presence of STIC and compared clinicopathologically. Analyses were performed using PASW 18 (SPSS/IBM, Chicago, IL, USA) software. The primary outcome was progression-free survival (PFS), and the secondary outcome was overall survival (OS). STIC was identified in 20.6% of patients. Median follow-up time was 49.5 months for the STIC-positive group and 38.0 months for the STIC-negative group. Study groups were comparable in terms of clinicopathological characteristics with the exception that patients with STIC had less lymph node involvement (55.0% vs. 65.4%, P = 0.001), and more diagnosis of primary tubal carcinoma (29.6% vs. 3.8%, P = 0.001) compared to those without STIC. No statistically significant differences in terms of PFS (P = 0.462) and OS (P = 0.501) were observed between the groups. The absolute identification of the origin of tumor cell does not seem to significantly affect the clinical course of the patients with HGSC.

A Case of High-Grade Serous Tubal Intraepithelial Carcinoma Diagnosed with Adenocarcinoma by Ascitic Fluid Cytology

Fallopian tube cancer is a very rare disease that is difficult to detect in its early stages. To our knowledge, we encountered the first case of serous tubal intraepithelial carcinoma (STIC) diagnosed with adenocarcinoma by ascitic fluid cytology. The patient was a 51-year-old woman who visited our department because of a leiomyoma detected during a uterine cancer screening. Transvaginal ultrasound found multiple leiomyomas and an endometrial cyst of the left ovary. The patients’ cancer antigen 125 level was elevated and the leiomyomas showed a tendency to grow. Therefore, surgical treatment was considered to be appropriate. Preoperative imaging showed no evidence of malignancy. We performed abdominal hysterectomy and bilateral salpingo-oophorectomy. The patient had stage IV endometriosis according to the revised American Society of Reproductive Medicine classification, and no macroscopic abnormalities were found in either fallopian tube. Postoperative histopathological findings led to the diagnosis of STIC in the right fallopian tube; cytological examination of the ascitic fluid also confirmed the presence of adenocarcinoma. We performed a staging laparotomy and found no evidence of metastasis to the lymph nodes or the greater omentum; the staging classification was determined to be IC3. After surgery, six cycles of paclitaxel + carboplatin therapy were administered. The patient has since been relapse-free for 15 months to date. Much attention has been directed to the fallopian tubes as the origin of malignant epithelial ovarian tumors, and STIC is now considered to be the origin of high-grade serous ovarian cancer. To avoid overlooking early-stage fallopian tube cancer, surgery for benign disease should also be accompanied by a detailed histopathological examination of the fallopian tubes.

Outcomes of Incidental Fallopian Tube High-Grade Serous Carcinoma and Serous Tubal Intraepithelial Carcinoma in Women at Low Risk of Hereditary Breast and Ovarian Cancer.

The natural history and optimal management of serous tubal intraepithelial carcinoma (STIC), regardless of BRCA status, is unknown. We report the follow-up findings of a series of incidental fallopian tube high-grade serous carcinomas (HGSCs) and STICs identified in women at low risk for hereditary breast and ovarian cancer (HBOC), undergoing surgery for other indications. Cases of incidental STIC and HGSC were identified from 2008. Patients with known BRCA1 or BRCA2 mutations, or a family history of ovarian or breast cancer before the diagnosis of STIC or HGSC were excluded. A retrospective chart review was conducted to obtain clinical data. Eighteen cases were identified with a median follow-up of 25 months (range, 4-88 months). Twelve of 18 patients had a diagnosis of STIC with no associated invasive HGSC and 6 had STIC associated with other invasive malignancies. Completion staging surgery was performed on 7 of the 18 patients, including 5 of 12 in which there was STIC only identified on primary surgery; 3 cases were upstaged from STIC only to HGSC based on the staging surgery. Recurrence of HGSC occurred in 2 of the 18 patients. BRCA testing was performed on 3 patients, 1 of whom tested positive for a pathogenic BRCA1 mutation. Our study suggests that completion staging surgery for incidental STICs in non-BRCA patients may be considered. These patients should be offered hereditary testing. The Pelvic-Ovarian cancer INTerception (POINT) Project is an international registry set up to add to our understanding of STICs.

The Diagnostic and Biological Implications of Laminin Expression in Serous Tubal Intraepithelial Carcinoma

There is compelling evidence to suggest that serous tubal intraepithelial carcinoma (STIC) is the likely primary site for the development of many pelvic high-grade serous carcinomas (HGSCs). Identifying molecules that are upregulated in STIC is important not only to provide biomarkers to assist in the diagnosis of STIC but also to elucidate our understanding of the pathogenesis of HGSC. In this study, we performed RNA sequencing to compare transcriptomes between HGSC and normal fallopian tube epithelium (FTE), and we identified LAMC1 encoding laminin γ1 as one of the preferentially upregulated genes associated with HGSC. Reverse transcription polymerase chain reaction further validated LAMC1 upregulation in HGSC as compared with normal FTE. Immunohistochemical analysis was performed on 32 cases of concurrent HGSC and STIC. The latter was diagnosed on the basis of morphology, TP53 mutations, and p53 and Ki-67 immunohistochemical patterns. Laminin γ1 immunostaining intensity was found to be significantly higher in STIC and HGSC compared with adjacent FTE in all cases (P<0.001). In normal FTE, laminin γ1 immunoreactivity was predominantly localized in the basement membrane or on the apical surface of ciliated cells, whereas in STIC and HGSC cells, laminin γ1 staining was diffuse and intense throughout the cytoplasm. More importantly, strong laminin γ1 staining was detected in all 13 STICs, which lacked p53 immunoreactivity because of null mutations. These findings suggest that the overexpression of laminin γ1 immunoreactivity and alteration of its staining pattern in STICs can serve as a useful tissue biomarker, especially for those STICs that are negative for p53 and have a low Ki-67 labeling index.

Ki-67 Labeling Index as an Adjunct in the Diagnosis of Serous Tubal Intraepithelial Carcinoma

There is mounting evidence that serous tubal intraepithelial carcinoma (STIC) may be the immediate precursor of ovarian high-grade serous carcinoma (HGSC) but the criteria for its diagnosis are not well established as highlighted in a recent study showing that interobserver reproducibility, even among expert gynecologic pathologists, was moderate at best. Given the clinical significance of a diagnosis of STIC in a patient who has no other evidence of ovarian carcinoma, this is a serious issue that we felt needed to be addressed. Although it is not clear, at this time, whether such a patient should or should not be treated, the importance of an accurate and reproducible diagnosis of precursors of ovarian carcinoma cannot be underestimated. We hypothesized that an elevated Ki-67 labeling index may aid the diagnosis of STIC. Accordingly, we compared the Ki-67 index of STIC and HGSC to normal fallopian tube epithelium (FTE) in the same patients and to a control group of patients without carcinoma, matched for age. A total of 41 STICs were analyzed, of which 35 were associated with a concurrent HGSC. In FTE, immunoreactivity for Ki-67 was restricted to a few scattered cells (mean 2.0%). No statistically significant difference was found between patients with and without HGSC (P>0.05). However, both STICs and HGSC had significantly higher Ki-67 indices than normal FTE (P<0.0001). STICs uniformly had an elevated Ki-67 labeling index that ranged from 11.7% to 71.1% (average 35.6%). There was no correlation of the Ki-67 labeling index in the STICs and the associated HGSC, as the labeling index was lower in STIC in 18/35 (51.4%) whereas it was higher in 17/35 (48.6%) (P=0.86). In conclusion, the findings in this study indicate that compared with FTE, STICs have a significantly higher Ki-67 index similar to HGSC. Accordingly, the Ki-67 index can aid the diagnosis of intraepithelial tubal proliferations suspicious for STIC. Therefore, we propose that a Ki-67 index of 10% is a useful diagnostic tool to distinguish STICs from normal FTE.

Diagnosis of Serous Tubal Intraepithelial Carcinoma Based on Morphologic and Immunohistochemical Features

There is compelling evidence that serous tubal intraepithelial carcinoma (STIC) is a precursor of high-grade serous ovarian carcinoma. Large-scale studies are now required to determine its biological significance and clinical implication. Before conducting these studies, a reproducible classification for STIC is needed, and that is the goal of this study. This study involved 6 gynecologic pathologists from 4 academic institutions and 3 independent rounds of review. In round 1, sixty-seven lesions ranging from normal, atypical, to STICs were classified by 5 pathologists on the basis of predetermined morphologic criteria. Interobserver agreement for the diagnosis of STIC versus not STIC was fair [κ = 0.39; 95% confidence interval (CI) 0.26, 0.52], and intraobserver reproducibility ranged from fair to moderate on the basis of percentage agreement and κ. Round 2 involved testing revised criteria that incorporated morphology and immunohistochemistry (IHC) for p53 protein expression and Ki-67 labeling in 10 sets by 3 of the pathologists. The result was an improvement in interobserver agreement for the classification of STIC (κ = 0.62; 95% CI 0.18, 1.00). An algorithm was then created combining morphology and IHC for p53 and Ki-67, and reproducibility was assessed as part of round 3. In 37 lesions reviewed by 6 pathologists, substantial agreement for STIC versus no STIC was observed (κ = 0.73; 95% CI 0.58, 0.86). In conclusion, we have developed reproducible criteria for the diagnosis of STIC that incorporate morphologic and IHC markers for p53 and Ki-67. The algorithm we propose is expected to help standardize the classification of STIC for future studies.

Serous Tubal Intraepithelial Carcinoma: Diagnostic Reproducibility and its Implications

Serous tubal intraepithelial carcinoma (STIC) is detected in between 5% and 7% of women undergoing risk-reduction salpingooophorectomy for mutations in the BRCA1 or 2 genes (BRCA+), and seems to play a role in the pathogenesis of many ovarian and "primary peritoneal" serous carcinomas. The recognition of STIC is germane to the management of BRCA+ women; however, the diagnostic reproducibility of STIC is unknown. Twenty-one cases were selected and classified as STIC or benign, using both hematoxylin and eosin and immunohistochemical stains for p53 and MIB-1. Digital images of 30 hematoxylin and eosin-stained STICs (n=14) or benign tubal epithelium (n=16) were photographed and randomized for blind digital review in a Powerpoint format by 6 experienced gynecologic pathologists and 6 pathology trainees. A generalized kappa statistic for multiple raters was calculated for all groups. For all reviewers, the kappa was 0.333, indicating poor reproducibility; kappa was 0.453 for the experienced gynecologic pathologists (fair-to-good reproducibility), and kappa=0.253 for the pathology residents (poor reproducibility). In the experienced group, 3 of 14 STICs were diagnosed by all 6 reviewers, and 9 of 14 by a majority of the reviewers. These results show that interobserver concordance in the recognition of STIC in high-quality digital images is at best fair-to-good for even experienced gynecologic pathologists, and a proportion cannot be consistently identified even among experienced observers. In view of these findings, a diagnosis of STIC should be corroborated by a second pathologist, if feasible.