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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 3  |  Page : 587-592

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


1 Department of Obstetrics and Gynecology, Division of Gynecologic Oncological Surgery, Akdeniz University School of Medicine, Antalya, Turkey
2 Department of Pathology, Division of Gynecopathology, Akdeniz University School of Medicine, Antalya, Turkey
3 Department of Biostatistics and Medical Informatics, Akdeniz University School of Medicine, Antalya, Turkey

Date of Web Publication12-Jun-2018

Correspondence Address:
Dr. Tayfun Toptas
Dumlupinar Bulvari, Akdeniz University Hospital, H-Blok, 07070, Konyaalti, Antalya
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.172130

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 > Abstract 


Aims: 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.
Settings and Design: A prospective case-series with planned data collection.
Subjects and Methods: 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.
Statistical Analysis Used: 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).
Results: 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.
Conclusions: The absolute identification of the origin of tumor cell does not seem to significantly affect the clinical course of the patients with HGSC.

Keywords: High-grade serous carcinoma, serous tubal intraepithelial carcinoma, survival


How to cite this article:
Toptas T, Pestereli E, Simsek T, Bozkurt S, Erdogan G, Karaveli S. The clinical impact of serous tubal intraepithelial carcinoma on outcomes of patients with high-grade serous carcinoma of the ovary, fallopian tube, and peritoneum. J Can Res Ther 2018;14:587-92

How to cite this URL:
Toptas T, Pestereli E, Simsek T, Bozkurt S, Erdogan G, Karaveli S. The clinical impact of serous tubal intraepithelial carcinoma on outcomes of patients with high-grade serous carcinoma of the ovary, fallopian tube, and peritoneum. J Can Res Ther [serial online] 2018 [cited 2020 Jan 25];14:587-92. Available from: http://www.cancerjournal.net/text.asp?2018/14/3/587/172130




 > Introduction Top


High-grade serous carcinomas (HGSCs) account for the majority of malignant pelvic epithelial neoplasms including those arising in the ovaries,  Fallopian tube More Detailss, and peritoneum. In the early 2000s, with an increase in prophylactic salpingo-oophorectomies performed in the BRCA mutation carriers, the incidental findings of occult invasive and noninvasive serous carcinomas in the fallopian tubes began to be reported by several studies.[1],[2],[3] Consideration of these findings has led to the proposal of fallopian tubes as the probable source of pelvic serous carcinogenesis in a significant proportion of the patients with genetic mutations.[4]

Serous tubal intraepithelial carcinomas (STICs) are noninvasive intramucosal lesions of the fallopian tubes, most of which are typically located in the fimbria.[5] These lesions have cytological features similar to those seen in HGSCs and also show p53 mutation.[4],[5] With the introduction of pathologic examination protocols that allow maximum exposure of the fimbrial mucosa, the proportion of STICs detected in the fallopian tubes has increased not only in the BRCA mutation carriers but also in patients with sporadic HGSC.[5],[6]

In spite of these improvements in our understanding of pelvic serous carcinogenesis, we still have very limited information on possible clinical implications of recent findings. In the current study, we aimed to investigate whether the presence of STIC is associated with clinical outcomes in a nonselected (unknown BRCA status) cohort of patients with HGSC of the ovary, fallopian tube, and peritoneum.


 > Subjects and Methods Top


Patients and study design

Patients with HGSC of the ovary, fallopian tube, and peritoneum, who underwent primary cytoreductive surgery at our institution between January 2007 and December 2012, were included in this prospective case-series with planned data collection.

Clinical and pathological data including the age at surgery, preoperative serum Ca-125 level, date and extent of surgical procedure, number of lymph nodes (LNs) removed, LN involvement, primary cancer site, presence of STIC, tumor grade, stage of the disease, adjuvant treatment, disease status on/after primary chemotherapy, sensitivity to platinum-based chemotherapy, disease recurrence or progression, survival status, and the date of the last follow-up were all recorded, following the Institutional Ethics Committee approval.

Written informed consent was obtained from all patients. The patients exhibiting a low-grade serous carcinoma (LGSC), endometrial intraepithelial or invasive serous carcinoma, primary synchronous malignancy, or that received neoadjuvant chemotherapy were excluded.

Surgical procedures

A vertical midline laparotomy was used in all patients in whom a comprehensive surgical staging or primary cytoreductive surgery was planned. All procedures were performed by two experienced gynecologic oncologists. Surgeons quantified and documented the extent of initial and residual disease detail in operative notes. Pelvic and para-aortic lymphadenectomy up to the renal vessels was performed in patients with tumor nodules outside the pelvis ≤2 cm or if the cytoreductive surgery was optimal. A maximal effort was performed to remove all visible disease in appropriate circumstances. The resection of the upper abdominal metastases was performed in patients who could tolerate this kind of surgery. The surgery was considered optimal if the residual tumor nodules were <1 cm in maximum diameter or thickness.[7]

Histopathological examination

In the current study, primary cancer sites (ovarian, tubal, or peritoneal) were assigned to the organ presenting with the dominant tumor mass on the basis of the conventional criteria of the World Health Organization (WHO).[8] The presence of an intraepithelial carcinoma was not included as a requirement for this assignment. Hence, the terms used to define primary cancer sites do not suggest that the origin of the tumor is known with absolute precision. Tumor grading was conducted according to that of the WHO,[8] and staging was classified according to the revised International Federation of Gynecology and Obstetrics criteria.[9]

Histological examination of the fallopian tubes included the sectioning and extensively examining the fimbriated end protocol proposed by Medeiros et al.[5] Tubes were entirely submitted for analysis and transversely sectioned at 2–3 mm intervals except for the distal 2 cm of the fimbrial ends that were sectioned longitudinally into four pieces. The diagnosis of STIC was based on the combination of morphological analysis of hematoxylin/eosin (H and E) and immunohistochemical studies using p53 antibody. Intraepithelial lesions that displayed cytologically malignant features (stratified epithelium with nuclear rounding and/or enlargement, hyperchromasia, prominent enlarged nucleoli, irregular chromatin clumping, or mitotic figures) combined with strong immunoreactivity of p53 in >75% of lesional cells, or complete absence of p53 staining were diagnosed as STIC.[10]

Adjuvant treatment, response evaluation, and follow-up

According to institutional practice, the postoperative adjuvant treatment strategy was as follows: Three cycles of chemotherapy for stages IA-grade 2 and IB-grade 2; and 6 cycles of chemotherapy for stages IA-B-grade 3 and stages IC-IV disease. The chemotherapy regimen included paclitaxel 175 mg/m 2 plus carboplatin dosed at an area under the curve of 5 to 6.

According to the assessment made in the 1st month after primary adjuvant chemotherapy, a complete clinical remission was defined as no objective evidence of disease (negative physical examination, negative Ca-125 levels, and negative imaging studies with <1 cm LNs); partial remission, as a reduction of ≥50% in measurable disease volume without reaching a complete remission; stable disease, as a reduction of <50% or an increase of <25% in measurable disease volume; and progression, as an increase of ≥25% in measurable disease volume or macroscopic appearance of new tumor foci.[11],[12] Refractory disease was defined as progression after two consecutive chemotherapy regimens without ever sustaining a clinical benefit.[13]

The standard surveillance practice was to follow-up patients who achieved complete clinical remission after primary therapy every 3 months for 2 years, every 3–6 months for the next 3 years, and then annually. Recurrence was defined as any documented relapse of the disease, either locally or systemically, after a disease-free interval of ≥3 months. The patients whose disease recurred in <6 months after primary chemotherapy were considered to be platinum resistant; between 6 and 12 months to be partially resistant; and more than 12 months to be platinum sensitive.

Statistical analysis

Analyses were performed by a professional biostatistician using PASW 18 (SPSS/IBM, Chicago, IL, USA) software. We expressed data as median and range for continuous variables. We reported binary variables as counts and percentages. When appropriate, we compared groups with a Mann–Whitney U-test, Student's t-test, Chi-square test, or Fisher's exact test. The primary outcome was progression-free survival (PFS), and the secondary outcome was overall survival (OS). We measured PFS from the date of surgery to the date of disease progression or relapse or death; and OS, from the date of surgery to the date of death. The patients alive with no evidence of disease were censored at the date they were last known to be alive in PFS analyses. The patients still alive with or without disease were censored at the date they were last known to be alive in OS analyses. The log-rank test was used to compare the Kaplan-Meier curves for PFS and OS. The Cox proportional hazards regression model was used to obtain the hazard ratios (HRs) and 95% confidence interval (95% CI). All P values were two-sided with the level of significance set at <0.05.


 > Results Top


In total, 155 patients were assessed for inclusion. Twenty-four patients were excluded from this analysis. Ten had LGSC, one had serous endometrial intraepithelial carcinoma, three had serous invasive endometrial carcinoma, two had primary synchronous malignancy, and eight received neoadjuvant chemotherapy. Hence, final analyses were performed in a total of 131 patients including 27 (20.6%) patients in the STIC-positive group and 104 (79.4%) patients in the STIC-negative group.

[Table 1] compares the clinical and pathological characteristics of patients. The median follow-up time was 49.5 months (range, 8–96) for the STIC-positive group and 38.0 months (range, 11–92) for the STIC-negative group. Study groups were comparable for age (P = 0.442), preoperative serum Ca-125 level (P = 0.665), adequacy of primary cytoreductive surgery (optimal vs. suboptimal) (P = 0.756), number of LNs removed (P = 0.261), tumor grade (P = 0.744), stage of the disease (P = 0.696), disease status on/after primary chemotherapy (P = 0.782), platinum sensitivity (P = 0.736), disease recurrence (P = 0.844), median time to recurrence (P = 0.681), and median follow-up time (P = 0.796). Primary cancer sites were significantly different between the groups (P = 0.001). The fallopian tubes as primary cancer site were identified more in patients with STIC (29.6% vs. 3.8%). In addition, patients with STIC were found to have less LN metastasis when compared with STIC-negative patients (55.0% vs. 65.4%, P = 0.001).
Table 1: Clinical and pathological characteristics of the patients

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The presence of STIC was associated with similar survival outcomes in comparison with STIC-negative group [Table 2]. Although the estimated 3- and 5-year PFS rates of patients with STIC (66.67% and 40.74%, respectively) and patients without STIC (61.53% and 39.42%, respectively) were comparable, there was a nonstatistically significant slight trend for improved PFS in the STIC-positive group (HR [95% CI] =0.81 [0.47–1.41], P = 0.462) [Figure 1]a. A similar slight trend was also evident for the OS (HR [95% CI] =0.74 [0.31–1.79], P = 0.501) [Figure 1]b.
Table 2: Survival analyses

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Figure 1: Survival analyses (a) progression-free survival, (b) overall survival

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 > Discussion Top


There are growing evidences for the role of the fallopian tube in pelvic serous carcinogenesis, yet little is known about its impact on the clinical course of the patients. The current study represents the clinicopathological comparison of pelvic HGSC patients with and without STIC. The study revealed that HGSC patients with a lesion of STIC had less LN involvement, more diagnosis of primary tubal carcinoma, and similar survival as compared to those without STIC.

The frequency of STICs in nonselected groups of patients has been reported as ranging from 18% to 52%.[6],[14],[15],[16] This lesion was identified in only 20.6% of our series. The discrepancies between the studies might be due in part to patient and tumor characteristics, to some differences in the diagnostic criteria of STIC, to diagnostic reproducibility problems, and to the extent to which the tubes were examined. Most pelvic HGSCs behave in an aggressive manner and extensively involve pelvic structures. Therefore, it is likely that some STICs are obscured due to overgrowth by the invasive carcinoma and determining the site, and cell of origin is difficult.[17] Roh et al.[18] pointed out that the presence of a dominant ovarian mass was infrequently associated with the finding of STIC (11%) as compared to those patients without a dominant ovarian mass (45%). In a diagnostic reproducibility study of STIC based only on histological assessment with H and E, Carlson et al.[19] reported a poor interobserver agreement among twelve reviewers, and concluded that a diagnosis of STIC should be corroborated by a second pathologist, if feasible.

Available data on effects of primary cancer site on the clinical course of the patients with HGSC are conflicting. In a retrospective, multi-institutional, case–control study, Moore et al.[20] reported an improved 5-year OS for patients with fallopian tube carcinoma to that of a matched sample of patients with epithelial ovarian carcinoma in the early stages (95% vs. 76%, P = 0.02) but no difference in advanced stages (3-year OS; 59% for both groups). However, in this study, most of the early-stage fallopian tube carcinomas were stage IA tumors found incidentally at the time of surgery for benign indications. When these were excluded, there was no significant difference in survival rates. In a large population-based analysis, Wethington et al.[21] noted that fallopian tube carcinomas present earlier, and only at advanced stages have a better OS than epithelial ovarian carcinomas (5-year OS; 54% [95% CI, 48–60%] vs. 30% [95% CI, 29–31%]). This study also has its limitations including lack of central pathology review and information regarding the adjuvant chemotherapy, cytoreductive status, and time and location of recurrences. A recent retrospective study by Lengyel et al.[16] that investigated whether serial sectioning of the fallopian tubes affected patient outcomes identified a significant increase in the number of patients diagnosed with fallopian tube carcinoma as the primary site of tumor origin but no differences in PFS or OS. Nevertheless, they noted a trend toward improved OS in patients diagnosed with fallopian tube or ovarian carcinoma as compared to those with primary peritoneal carcinoma (P = 0.09).

Although not statistically significant, a minor trend toward improved outcome in tumors with origin in the tubal mucosa was observed also in our study. On the other hand, it is obvious that both the previous study [16] and our current study are underpowered to apparently prove this trend is true. Further, trials with a larger cohort of patients are needed to explore these issues more thoroughly. Major strengths of our study include its prospective cohort design, the analysis of a single histologic type, performance of procedures with a strict surgical policy by experienced gynecologic oncologists, histological examination of the fallopian tubes with a widely accepted standard protocol, and the detailed analysis of various clinicopathological factors, these may have an impact on clinical outcome.


 > Conclusions Top


The current study supports the suggestion that STIC may be the precursor for HGSC of the ovary, fallopian tube, and peritoneum, at least in a certain group of patients. However, the absolute identification of the origin of tumor cell does not seem to significantly affect the clinical course of the patients. Further, trials with a larger cohort of patients and longer follow-up are needed to confirm these findings.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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Colgan TJ, Murphy J, Cole DE, Narod S, Rosen B. Occult carcinoma in prophylactic oophorectomy specimens: Prevalence and association with BRCA germline mutation status. Am J Surg Pathol 2001;25:1283-9.  Back to cited text no. 1
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Piek JM, van Diest PJ, Zweemer RP, Jansen JW, Poort-Keesom RJ, Menko FH, et al. Dysplastic changes in prophylactically removed Fallopian tubes of women predisposed to developing ovarian cancer. J Pathol 2001;195:451-6.  Back to cited text no. 2
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Kindelberger DW, Lee Y, Miron A, Hirsch MS, Feltmate C, Medeiros F, et al. Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: Evidence for a causal relationship. Am J Surg Pathol 2007;31:161-9.  Back to cited text no. 6
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Seidman JD, Zhao P, Yemelyanova A. “Primary peritoneal” high-grade serous carcinoma is very likely metastatic from serous tubal intraepithelial carcinoma: Assessing the new paradigm of ovarian and pelvic serous carcinogenesis and its implications for screening for ovarian cancer. Gynecol Oncol 2011;120:470-3.  Back to cited text no. 14
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Lengyel E, Fleming S, McEwen KA, Montag A, Temkin SM. Serial sectioning of the fallopian tube allows for improved identification of primary fallopian tube carcinoma. Gynecol Oncol 2013;129:120-3.  Back to cited text no. 16
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