First Analysis of the Incidence of Serous Tubal Intraepithelial Carcinoma (STIC) in Germany – Evaluation of the Cancer Registry of the Federal State of Rhineland-Palatinate from 2016 to 2023

Abstract

Introduction

Serous tubal intraepithelial carcinomas (STIC) are classified as precursor lesions of high-grade serous carcinomas (HGSC) in women. STIC are rare and their incidence, prognosis and therapy remain unclear. Since 2021, all cases of isolated STIC in Germany must be reported, which means that all STICs in the German federal state of the Rhineland-Palatine (RLP) are available for evaluation.

Material and Methods

A systematic search of the pathology reports in the RLP cancer registry was carried out for the period 01/2016–12/2023 using keywords related to STIC, and the results of the search were evaluated.

Results

382 pathology reports were identified as relevant and screened. A total of seven patients with isolated STIC were reported to the RLP registry in the years 2020–2022. This corresponds to 0.014% of all reported cases of cancer in women in RLP in this period. Six patients had a diagnosis of isolated STIC, identified during risk-reducing salpingo-oophorectomy (RRSO). The mean patient age at the time of RRSO was 60.29 (± 7.09) years. RRSO was carried out on average 9.38 (± 6.75) years after a primary diagnosis of breast cancer/DCIS in five patients. No HGSC was reported for any of the patients with isolated STIC in the follow-up period until 01/2024. 43 synchronous STICs were reported for the period from 01/2016 to 12/2023.

Conclusion

2–3 diagnoses of isolated STIC were recorded annually in RLP in the years 2020–2022. To date, there have been no reports of HGSC in these patients. In the future, the systematic recording of STICs will be expanded to include the cancer registries of other federal states of Germany and it will be possible to obtain valid data on the incidence of STIC in Germany. The collected data will also provide the basic information for a national STIC registry.

Keywords

STIC - serous tubal intraepithelial carcinoma - cancer registry - incidence - STIC registry - Rhineland-Palatinate

Background

Serous tubal intraepithelial carcinomas (STIC) are classified as precursor lesions of high-grade serous carcinomas (HGSC) [1] [2] [3] [4] [5] [6].

As with HGSC, STIC are characterized by a TP53 mutation as well as aberrant p53 overexpression, a high mitotic index, and genomic instability [7]. Serous tubal intraepithelial lesions, known as STIL, do not meet all the histopathological criteria of a carcinoma in situ, but with a p53 signature they are classified as precursor lesions of HGSC. STIC occur in the infundibulum of the fallopian tubes and are usually diagnosed using the SEE-FIM (Sectioning and Extensively Examining the FIMbriated End) protocol [3]. The SEE-FIM protocol describes the approach used for complete investigation of the fallopian tube and infundibulum, which is based on an examination of cross sections of the ampulla and longitudinal sections of the infundibulum followed by staining, which makes it easier to detect lesions which are often not detected with routine processing.

Tubal and ovarian HGSC make up 70–80% of all malignant ovarian cancers and have the worst prognosis of all gynecological tumors. The lifelong risk of developing ovarian cancer up until the age of 70 years is estimated to be 1.3% in the general population, 36–53% in carriers of BRCA1 mutation and 10–25% in carriers of BRCA2 mutation [8]. Risk-reducing salpingo-oophorectomy (RRSO) is therefore recommended for this high-risk population, as RRSO is considered the most effective method of prevention [9] [10]. Occult malignancies and/or STIC are found in up to 10–15% of cases undergoing RRSO [11] [12] [13]. The detection rate of isolated STIC with RRSO is 2–3% [14] [15]. Depending on the study, the risk of developing advanced HGSC within the next 10 years for women diagnosed with isolated STIC is 21.6–27.5% [16] [17]. Some of the key clinical and prognostic features of STIC are still unknown. Confirmation of STIC is associated with a substantial risk of an invasive lesion and therefore with HGSC [14] [18] [19]. Occult lymph node metastases have also been found in patients with STIC lesions [18]. The rarity of STIC and the lack of information about STIC are a diagnostic and therapeutic challenge [20]. The current German S3-guideline recommends discussing the option of carrying out a staging operation to exclude higher grade lesions with the patient after she has been informed about her risk (AWMF Guideline on the Diagnosis, Therapy and Follow-up of Malignant Ovarian Tumors, Version 6.0 – October 2024) [21]. The NCCN (National Comprehensive Cancer Network) Guideline presents two options for isolated STIC: 1) observation with and without determination of the tumor marker CA-125, and 2) operative staging with follow-up. If no genetic testing has been previously carried out, genetic testing should be recommended following the diagnosis of STIC [22]. The most comprehensive recommendations were issued by the ESGO-ESMO-ESP consensus conference in 02/2024. The consensus conference included 46 participants from 15 countries. Recommendations include staging, preferably carried out as a minimally invasive procedure without lymphadenectomy. A hysterectomy should be considered, especially for patients with BRCA1 mutation (consensus: 82%) [23]. In 2020, a national survey was carried out in all gynecological oncology centers in Germany to review the diagnostic workup, pathological processing, and operative therapy of STIC [20]. The survey found major differences in the treatment of patients with STIC, especially with regard to carrying out follow-up surgery after staging: in 38.2% of hospitals, patients with STIC underwent laparoscopy while 25.9% of patients had open surgery.

STIC were confirmed in more than half of all ovarian, tubal, and primary peritoneal carcinomas [11] [24]. According to the current German S3-guideline from October 2024, all ovarian carcinomas and peritoneal carcinomas with confirmed STIC should now be referred to as tubal carcinomas [21].

The data about the risk of isolated STIC in the general low-risk population is inconsistent. A study published in 2018 reported eight STIC out of 9392 women with a benign diagnosis (< 0.01%) after processing the salpinges in accordance with the SEE-FIM protocol [25].

In summary, the incidence of STIC in Germany remains unclear. Since 2021, all STIC in Germany must be reported using the diagnostic code “D07.3” of the ICD-10-GM Code 2024 which stands for: “carcinoma in situ of other and unspecified female genital organs” (ICD-10-GM Version 2024, published by the German Federal Institute for Drugs and Medical Devices). Since 2016, the relevant pathology report of any cancer diagnosed in the federal state of Rhineland-Palatinate (RLP) is sent to the RLP cancer registry. Consequently, it is possible, for the first time, to use valid data to determine the incidence of STIC in Germany. The current population of RLP is about 4.17 million (as at 31.12.2023) [26]. RLP is the 6th most populous federal state in Germany. This permits a realistic estimate of the incidence of STIC in Germany. As part of the establishment of the national STIC registry by the University Medical Center Mainz and the Institute for Digital Health Data RLP (IDG RLP), hosting and managing the Cancer Registry of Rhineland-Palatinate, the frequencies and patient characteristics of all registered STIC cases in Rhineland-Palatinate were recorded and analyzed.

Methods

Screening of pathology reports

A systematic search of the pathology reports of the Rhineland-Palatinate cancer registry was carried out for the period 01/2016–12/2023 using keywords related to STIC. The keywords were developed together with the IDG RLP and are listed in Appendix 1.

The pathology reports of identified cases were screened on site in the IDG RLP in April 2024 by V.L. in accordance with all data protection regulations and evaluated.

The following clinically relevant data were extracted from the clinical findings of the pathology reports: indication for surgery, genetic predisposition, any other cancers included in the report (especially breast cancer).

Follow-up

After the relevant pathology reports had been identified, the IDG RLP was responsible for finding any other reports associated with the respective patient identification number which could be used to draw conclusions about possible other cancer diagnoses. This was also done for all other cancers after the diagnosis of isolated STIC had been recorded to identify possible HGSC.

Data about the vital status of the identified persons with STIC was also included, based on information from residents’ registration offices up until 01/2024.

Evaluation

Descriptive analysis was carried out using SPSS version 27 (SPSS, Chicago, IL, USA). For reasons of data protection, any data of fewer than 3 patients was not broken down further to ensure that the patients could not be identified.

Results

Isolated STIC

382 pathology reports were identified as relevant and screened. In the years 2020–2022 seven patients with isolated STIC were reported to the RLP registry out of a total of 50897 reports of female tumors in this period (corresponds to 0.014% of cases). Of all tumors reported in RLP for the period 2020–2022, 525 women were registered as having an ovarian, tubal, or peritoneal HGSC (2020: n = 165; 2021: n = 189; 2022: n = 171). In 2023, 129 women were registered as having HGSC.

Six patients had a diagnosis of isolated STIC detected in the context of RRSO carried out because of a genetic predisposition to familial breast and ovarian cancer. A few other cases of isolated STIC were diagnosed during laparoscopic supracervical hysterectomy. The diagnostic code of the ICD-10-GM Code 2024 used for STIC was found to be inconsistent. One isolated STIC was classed as an early invasive HGSC of the ovary. Tumor reports which were originally coded using a different ICD code or which had not been initially coded were processed accordingly by the cancer registry.

Characteristics of isolated STIC

The mean age at the time of diagnosis with STIC was 60.29 (standard deviation [SD]: ± 7.09) years. 86% (n = 6) of patients had a positive familial history of breast or ovarian cancer. Four patients had BRCA1 mutation. Four patients developed breast cancer prior to RRSO. Fewer than three patients had a prior history of DCIS. The mean time from an initial diagnosis of breast cancer/DICS to RRSO was 9.38 (SD: ± 6.75) years. The mean age of the five affected patients when breast cancer/DCIS was reported was 50.4 (± 10.71) years. The follow-up time from diagnosis of STIC to ascertainment of the patient’s vital status (alive/dead) was 2.45 (SD: ± 0.97) years. No HGSC was reported for any of the patients diagnosed with isolated STIC in this period. An overview of the characteristics of patients with isolated STIC is given in [Table 1].

Table 1 Characteristics of patients with isolated STIC in RLP in the period from 2016–2023.

Characteristics	STIC patients (n = 7)
DCIS = ductal carcinoma in situ; RLP = Rhineland-Palatinate; RRSO = risk-reducing salpingo-oophorectomy; SD = standard deviation; STIC = serous tubal intraepithelial carcinoma
Mean age at STIC diagnosis (years ± SD)	60.29 (± 7.09) years
Positive familial history	6/7
Prior history of cancer
breast cancer/DCIS	5/7
Mean age at initial diagnosis of breast cancer/DCIS	50.4 (± 10.71) years
Mean time from initial diagnosis of breast cancer /DCIS to RRSO (date of findings) (years ± SD)	9.38 (± 6.75) years
Follow-up time (from diagnosis of STIC to last ascertainment of vital status in 01/2024)	2.45 (± 0.97) years
Incidence of pelvic high-grade serous carcinoma after STIC diagnosis	0

Evaluation of synchronous STIC

43 synchronous STIC were reported in the period from 01/2016 to 12/2023. 27 (62.8%) synchronous STICs were found in patients with ovarian carcinoma, five (11.6%) in patients with tubal carcinoma, three (7%) each in patients with endometrial carcinoma and peritoneal carcinosis respectively. Fewer than three patients had low-grade serous ovarian carcinoma (LGSOC), borderline ovarian tumor, primary peritoneal carcinosis or urothelial carcinoma, respectively. [Table 2] provides a summary of the cases with synchronous STIC. According to the current S3-guideline from October 2024, all ovarian cancers and primary peritoneal cancers with confirmed STIC are now classed as tubal carcinomas [21].

Table 2 Overview of cases with synchronous STIC in RLP in the period 2016–2023.

Number of synchronous STIC	N = 43
Note: For reasons of data protection, data from fewer than 3 patients was not broken down further to ensure that patients could not be identified. HGSOC = high-grade serous ovarian carcinoma; LGSOC = low-grade serous ovarian carcinoma; RLP = Rhineland-Palatinate; STIC = serous tubal intraepithelial carcinoma 1: According to the current S3-guideline “Diagnosis, Therapy and Follow-up of Malignant Ovarian Tumors” version 6.0, October 2024, all tumors with an STIC initially referred to as ovarian carcinomas or primary peritoneal carcinomas are now classed as tubal carcinomas.
2016	3
2017	3
2018	4
2019	6
2020	10
2021	4
2022	10
2023	3
HGSOC1	27
Tubal carcinoma	5
Endometrial carcinoma	3
Peritoneal carcinosis	3
LGSOC	< 3
Borderline ovarian tumor	< 3
Primary peritoneal carcinoma1	< 3
Urothelial carcinoma	< 3

Discussion

In the years 2020–2022, 2–3 diagnoses of isolated STIC were registered annually in RLP out of a total of 50897 tumors in women reported in this period. The diagnosis of isolated STIC therefore corresponds to 0.014% of all reported cancers in women in RLP for the period 2020–2022. When this figure is extrapolated to all of Germany with its current population of 84.7 million people (as at 30.06.2024) [27], it is assumed that 40–60 cases with isolated STIC were diagnosed annually in the period 2020–2022. This extrapolation needs to be qualified by noting that the estimated incidence may differ in areas with lower or higher numbers of RRSO/opportunistic salpingectomies.

No case with isolated STIC was identified in RLP in 2023. The reasons for this are not clear. One explanation could be that there was a delay in reporting, although in RLP there is a legal obligation to report cases within 4 weeks from the date of detection. Moreover, comparatively fewer HGSC of the ovary, fallopian tube or peritoneum were reported for women in 2023 in RLP compared to previous years.

It is assumed that the number of STIC diagnoses will increase, especially in the low-risk population, due to the rise in opportunistic salpingectomy procedures. The rate of opportunistic salpingectomies in the context of hysterectomy procedures for benign cause in Germany increased from 4% in 2011 to 45% in 2020 [28]. A population-based retrospective cohort study from British Columbia, which included 25889 patients with opportunistic salpingectomy, has shown that the rate of ovarian and tubal HGSC in the group with opportunistic salpingectomy was significantly lower compared to the control group (n = 32080) [29]. Opportunistic salpingectomy procedures are considered safe and feasible in the context of routine gynecological procedures, e.g., during laparoscopic and vaginal hysterectomies [30] [31].

The German S3-guideline recommends that at the very least “the infundibulum must be carefully examined in its entirety following opportunistic salpingectomy. Examination of the fallopian tube may be based on several representative sections” [21]. It is assumed that the number of cases with an incidental finding of STIC will increase due to the recommendation to carry out more detailed histopathological examinations of the fallopian tubes and fimbriae.

There is still no effective screening method for the prevention of ovarian and tubal HGSC in non-BRCA-mutated patients. In the data we collected, all patients with a genetic predisposition for breast and ovarian cancer had a BRCA1 mutation. The development of HGSC after STIC occurs more commonly in patients with BRCA1 mutation compared to patients with BRCA2 mutation [16] [32]. The follow-up period of 2.45 years was short and the number of cases was low, meaning that, to date, no HGSC was recorded in patients with isolated STIC in RLP. Intensive monitoring for at least seven years after a diagnosis of isolated STIC is recommended [33]. This corresponds to the literature which describes the development of HGSC after a diagnosis of STIC within 28 to 118 months [16]. It is not clear what form oncological follow-up should take.

The mean age of 60 years at diagnosis of STIC and therefore at RRSO was high [34]. In the current national guideline and in international recommendations, the recommended age for RRSO is 35–40 years of age for BRCA1-mutated patients and 40–45 years for women with BRCA2 mutation [21] [35] [36]. It should be noted that the time of RRSO depends both on family planning and on the age when other family members developed cancer. The mean time from the initial diagnosis of breast cancer/DCIS to RRSO was 9.38 years for the five patients with previous breast cancer/DCIS. The mean age when the diagnosis of breast cancer/DCIS was reported was 50.4 years. It is assumed that this was the point when genetic counseling and testing for an increased familial risk of breast and ovarian cancer was carried out. Possible additional reasons for the belated RRSO procedures could be the wish to delay early postmenopausal symptoms, as they are associated with a lower quality of life and higher cardiovascular risk [37]. Three prospective studies are currently ongoing which aim to investigate the oncological safety and/or quality of life following primary prophylactic bilateral salpingectomy and delayed bilateral oophorectomy in high-risk patients [37] [38]. One of these studies is the TUBA-WISP II trial, an international collaboration between the Dutch TUBA study group and the WISP study group in the USA. The study aims to include 1500 patients with BRCA1 mutation and 1500 patients with BRCA2 mutation. The first data from the TUBA-WISP II trial are expected at the end of recruitment in 2026 and after a follow-up of 10 years in 2036 [39].

Strengths and Limitations

This analysis is the first time that valid figures on the estimated incidence of STIC in Germany have been presented. One of the strengths of this study is that the mean population of the German federal state of Rhineland-Palatinate is 4.17 million (as at 31.12.2023) [26]. One of the limitations is that most of the analysis is only based on pathology reports. It was often not possible to deduce whether the SEE-FIM protocol has been followed. It must currently be assumed that STIC is underdiagnosed and that examination of the fallopian tubes and especially of the infundibulum is not always done correctly and completely. Some of the requests for processing sent to pathology departments may have only mentioned a familial risk constellation for breast and ovarian cancer and not explicitly requested processing in accordance with the SEE-FIM protocol or addressed the question of a STIC. Moreover, it is also possible that STIC was not properly documented in the pathology report.

Important patient information could be missing, e.g., information about other previous illnesses or reasons for the belated RRSO procedure. In individual cases, it is possible that the patient relocated to RLP from another federal state and a previous cancer diagnosis was entered in a different federal cancer registry. Another limitation is the short follow-up time of 2.45 years.

Outlook: Expansion of the Survey to Include Cancer Registries of All Federal States

In view of the inconsistent codes, it is worth considering whether isolated and synchronous STIC should be entered with their own specific ICD-10-GM codes to standardize data capture.

In the future, the search will be expanded to include the other federal cancer registries with the aim of obtaining valid data about the incidence of STIC in Germany. At present, the Center for Cancer Registry Data (ZfKD) at the Robert Koch Institute in Berlin offers the option to request data for all of Germany based on data supplied by the cancer registries of the individual federal states. The law on the merging of data from German cancer registries entered into force on 31.08.2021. This will expand the potential to use patients’ clinical data collected in the course of diagnosis and treatment [40].

National STIC/STIL registry

In view of the restricted study situation, the heterogeneous treatment strategies, and the high risk of developing HGSC, a national retrospective/prospective STIC registry will be useful to record all data on STIC as well as STIL with regards to diagnostics, therapy, follow-up and patient characteristics.

This data collection will serve as the future basis for evidence-based diagnostic and therapeutic recommendations. The aim is to improve the care and secondary prophylaxis of patients with isolated STIC (STIL). The national STIC registry started collecting data in October 2024. More information and details on participation are available using the QR code shown in [Fig. 1] or under https://stic-register.de

Fig. 1 QR code of the STIC registry.

Summary

This is the first time that the incidence of isolated STIC in Germany has been investigated based on the analysis of data from a cancer registry. A total of seven patients with isolated STIC were reported in RLP during the period from 2016 to 2023. Recently in the period 2020–2022, 2–3 cases with isolated STICs were reported annually in RLP. This corresponds to 0.014% of all cancers in women reported in RLP in this period. It is therefore estimated that 40–60 women receive an initial diagnosis of isolated STIC in Germany annually. To date, there have been no cases with recurrence of HGSC in the patients from RLP, most probably because of the short follow-up time. The mean age of 60 years at diagnosis of STIC is at the upper range. On average, RRSO was carried out 9.38 years following a diagnosis of breast cancer/DCIS in affected women. In the future, the search will be expanded to include the cancer registries of other German federal states to obtain valid data about the incidence of STIC in Germany, as this will also provide basic information to the national STIC registry.

Ethics

The analysis was carried out in accordance with the ethical principles for medical research involving human subjects of the current version of the Declaration of Helsinki. The data collected for this analysis are based on an evaluation of the cancer registry of the federal state of Rhineland-Palatine in the Institute for Digital Health Data RLP. The evaluation reflects sec. 3 subsection 2 of the Law on the Rhineland-Palatinate Cancer Registry (Landeskrebsregistergesetz Rheinland-Pfalz) regarding the provision of data for scientific research. An application to use the data was submitted to the RLP cancer registry and approved before starting the analysis.

A specific ethics vote was not required for this study. Written consent of the participants was not required as the patients cannot be identified.

Funding

This analysis did not receive funding from any sponsor or funding agency.

Availability of Data and Materials

All data generated or analyzed during this evaluation are included in this article. Any further inquiries or requests should be directed to the author(s) or the cancer registry of the federal state of Rhineland-Palatinate in the Institute for Digital Health Data RLP (Institut für digitale Gesundheitsdaten RLP).

Supplementary Material

STIC search terms developed for internal data queries and retrievals from the cancer registry of the federal state of Rhineland-Palatinate.

Contributorsʼ Statement

Study design: V.L., A.B., A.H.; data collection: V.L, P.L.; data analysis: V.L, A.B., P.L., N. H-S.; compilation of the manuscript: V.L., A.B., P.L., N. H-S., K.S., A.H. All of the authors revised the article and gave their consent to its publication.

Conflict of Interest

The author A.H. received honoraria from AstraZeneca, Celgen, GSK, LEO Pharma, MedConcept GmbH, Med update GmbH, Medicultus, Pfizer, Promedicis GmbH, Softconsult, Roche Pharma AG, Streamedup! GmbH, and TESARO Bio Germany GmbH. She is a member of the advisory boards of AstraZeneca, GSK, LEO Pharma, PharmaMar, Promedicis GmbH, Roche Pharma AG, TESARO Bio Germany GmbH, and MSD Sharp & Dohme GmbH.

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• 39 Steenbeek MP, van Bommel MHD, intHout J. et al. TUBectomy with delayed oophorectomy as an alternative to risk-reducing salpingo-oophorectomy in high-risk women to assess the safety of prevention: the TUBA-WISP II study protocol. Int J Gynecol Cancer 2023; 33: 982-987
• 40 Klinisch-epidemiologisches Krebsregister Brandenburg-Berlin. Unsere überregionale Zusammenarbeit. Zugriff am 24. September 2024 unter: https://kkrbb.de/unsere-ueberregionale-zusammenarbeit/

Publikationsverlauf

Eingereicht: 22. Oktober 2024

Angenommen nach Revision: 09. März 2025

Artikel online veröffentlicht:
15. Mai 2025