Increase of fallopian tube and decrease of ovarian carcinoma: fact or fake?

Purpose Accurate disease classification is fundamental for the selection of the treatment approach, prognostication, selection of clinical trials and for research purposes in routine clinical practice. Extrauterine high-grade serous carcinoma (HG-SC) may arise from the ovary, the fallopian tube and rarely from the peritoneal surface epithelium. Regardless of its origin, the vast majority of patients with HG-SC share clinical symptoms, present with advanced stage disease and suffer from a poor prognosis. Recent data suggest that there is an increasing incidence of HG-SC arising from the fallopian tube.

Data from the Clinical Cancer Registry of Leipzig of surgically treated non-uterine pelvic carcinomas were analyzed regarding their sites of origin. Depending on the histology, cases were separated into high-grade serous and non-high-grade serous tumors. Based on different approaches in the assessment of the site of origin, three distinct time periods were defined. The frequency of the specific sites of origin was compared to the different time periods and histologic subtypes.

The majority of cases (57.9%; 279/482) were high-grade serous carcinomas, 42.1% of the cases presented with endometrioid, clear cell or mucinous histology. Overall, a 1.7-fold decrease of carcinomas with ovarian origin, paralleled by a 10.3-fold increase of tubal carcinomas was noted between 2000 and 2019. Based on the histopathological subtype, there was a 2.1-fold decrease of ovarian and a 7.1-fold increase of tubal carcinomas in patients with HG-SC. In non-high-grade serous tumors, the frequency of the different sites of origin did not change. 83.7% of tumors with non-high-grade serous histology originated from the ovary, whereas 86.8% of the carcinomas with tubal origin were of high-grade serous histology.

The present and published data of non-uterine pelvic cancers may suggest an increase of tubal and decrease of ovarian carcinomas. However, there is rising morphologic and molecular evidence that non-uterine HG-SC actually arise from the fallopian tubes via its precursor STIC instead of from the ovary. This evidence has had an impact on the handling and reporting of non-uterine surgical specimens and its definition of the site assessment. In conclusion, the increasing frequency of tubal carcinomas and the associated decrease in ovarian cancer appears to be due to the reclassification of tumors previously classified as ovarian and greater emphasis on examining the resection specimens of non-uterine pelvic carcinomas.

Fallopian tube, Ovary, Pelvic, Carcinoma, Incidence, Frequency, STIC, Site of origin, Assignment

Extrauterine high-grade serous carcinoma (HG-SC) may arise from the ovary, the fallopian tube and rarely from the peritoneal surface epithelium. Within the last decade, the pathogenetic mechanisms of ovarian carcinoma and its origin have become the subject of intense research (McCluggage et al. 2017; Perets und Drapkin 2016; Kurman und Shih 2016; Karnezis et al. 2017). Because the vast majority of patients present with ovarian (adnexal) mass, ovarian carcinomas were thought to arise from the ovarian surface epithelium. However, there has been accumulating evidence that a significant number, if not all, of HG-SC actually originate from the fimbriated end of the fallopian tube (Crum et al. 2007; Medeiros et al. 2006; Singh et al. 2016a, b; Perets und Drapkin 2016). There has been mixed acceptance of this theory among pathologists and clinicians dealing with high-grade serous “ovarian” carcinoma, resulting in a wide variation in the assignment of the primary site of the disease between different institutions (McCluggage et al. 2017; Samimi et al. 2018a). To overcome these differences, criteria for the assignment of the primary site have been published (McCluggage et al. 2015; Singh et al. 2016b). During the last several years, an increase of the incidence and frequency of tubal carcinoma, paralleled by a decrease of ovarian cancer has been reported (Trabert et al. 2018; Liao et al. 2018). To test this hypothesis and to assess the origin of non-uterine pelvic carcinomas over time, we designed a study to re-evaluate all surgically treated, histologically confirmed non-uterine pelvic carcinomas from our registry.

Data were obtained from the Clinical Cancer Registry of the University Hospital of Leipzig (CCRL) from 2000 to 2019. All women diagnosed with primary carcinomas of the ovary, fallopian tube and peritoneum (i.e., non-uterine pelvic carcinomas) were included. All cases with metastases within these sites were excluded. The site of origin was defined according to the International Classification of Diseases for Oncology (ICD-O) (3rd edition) topography codes for fallopian tube (C57), ovary (C56) and peritoneum (C48) with the histology/ behavior code for carcinoma. The different histopathological subtypes were obtained from hospital files and separated into high-grade serous carcinomas and tumors with non-high-grade serous histology (i.e., endometrioid, clear cell and mucinous carcinomas). The patients were divided into three time intervals: 2000–2005; 2006–2010 and 2011–2019. The time intervals were defined according to previous studies (Liao et al. 2018; Trabert et al. 2018). Additionally, the time intervals reflect the different approaches in the handling and reporting of surgical specimens of non-uterine serous carcinoma at our institution (see Fig. 1). Between 2000 and 2005, the primary site of origin was assigned based on the site of greatest volume/size of the tumor (i.e., dominant mass theory), the standard of care at the time (McCluggage et al. 2015; Singh et al. 2016a, b). The SEE-FIM protocol (Sectioning and Extensively Examining the FIMbriated end of the fallopian tube) was initially published for the examination of risk-reducing salpingectomies for BRCA-mutation carriers (Medeiros et al. 2006) and later expanded to other settings. The primary goal of the SEE-FIM protocol was the detection of small invasive serous carcinomas and their precursor, a serous tubal in situ carcinoma (STIC; Medeiros et al. 2006). The “original” SEE-FIM protocol requests the complete embedding and examination of the whole fallopian tube (Medeiros et al. 2006) which is mandatory in patients at risk because of a BRCA mutation (McCluggage et al. 2015). A pragmatic alternative is to ensure that at least the fimbrial end of the fallopian tube will be examined according to the SEE-FIM protocol (amputating the distal 2 cm of the fallopian tube, slicing in 2–3 mm intervals with complete embedding) with additional embedding of more representative sections of the rest of the fallopian tube (Malpica et al. 2018; Kulac und Usubutun 2013; McCluggage et al. 2017; Soong et al. 2018), representing a SEE-FIM-like protocol (Fig. 2). Between 2006 and 2010, the SEE-FIM-like protocol was at most used sporadically at our institution, and the site assignment was performed using the tumor mass theory. Cases with invasive tumor within the fallopian tube(s) were classified as tubal in origin. The presence of STIC was included in the pathology report, but the site assignment was based on the presence of the bulky tumor. Starting in 2011, the SEE-FIM-like protocol (Fig. 2) was routinely performed in all cases of macroscopically visible fallopian tube(s) during the macroscopic description and cutting of the resection specimen at our institution (Leonhardt et al. 2011) as recommended by the International Society of Gynecological Pathologists (ISGyP; Malpica et al. 2018). According to the recommendations of the International Collaboration of Cancer Reporting (ICCR; McCluggage et al. 2015), the International Society of Gynecological Pathologists (ISGyP; (Malpica et al. 2018) and previous publications (Singh et al. 2016a, b; Perrone et al. 2020), no additional immunohistochemical stains were performed to identify serous tubal intraepithelial carcinomas (STIC). In cases with uni- or bilateral “adnexal masses”, these masses were cut perpendicular to the horizontal axis in about 0.5 cm intervals from the uterine to the pelvic side to identify residual ovarian and/or tubal tissue (Fig. 3), with appropriate embedding of one block per 2 cm tumor size from each side of the adnexal mass (McCluggage et al. 2015; Gramlich et al. 1990). Starting in 2011 and as recommended by the ICCR (McCluggage et al. 2015) and others (Singh et al. 2016a), the site of origin was defined as illustrated in Fig. 4.

The Clinical Cancer Registry Leipzig located at the University Hospital of Leipzig (CCRL) is responsible for the registration of all patients treated for malignant disease and living within the city of Leipzig, the district of greater Leipzig and Northern Saxony (total population of 1.049.240 people of which 533.043 are females). The completeness of the registration of the items evaluated in the present study was 95%. 482 cases with different histopathological subtypes of non-uterine pelvic carcinomas were included. The patient characteristics are summarized in Table 1. Table 1. | All cases (N = 482) | Cases with high-grade serous histology (N = 279) | Cases with non-serous histology* (N = 203) | | |---|---|---|---| | Stage distribution | ||| | pT1a | 54 (11.20%) | 6 (2.20%) | 48 (23.60%) | | pT1b | 4 (0.80%) | 0 (0%) | 4 (2.10%) | | pT1c1 | 45 (9.30%) | 14 (5.00%) | 31 (15.30%) | | pT1c2 | 1 (0.20%) | – | 1 (0.50%) | | pT1c3 | – | – | – | | pT1cX** | 25 (5.20%) | 11 (4.00%) | 14(6.90%) | | pT2a | 11 (2.30%) | 5 (1.80%) | 6 (2.90%) | | pT2b | 26 (5.40%) | 18 (6.50%) | 8 (4.00%) | | pT2c | 10 (2.10%) | 6 (2.20%) | 4 (2.00%) | | pT3a | 31 (6.40%) | 27 (9.70%) | 4 (2.00%) | | pT3b | 50 (10.40%) | 28 (10.00%) | 22 (10.80%) | | pT3c | 224 (46.5%) | 163 (58.40%) | 61 (30.00%) | | pT4 | 1 (0.20%) | 1 (0.4) | – | | Lymph node involvement | ||| | pN0 | 268 (55.60%) | 120 (43.00%) | 148 (72.90%) | | pN1a/b | 192 (39.80%) | 149 (53.40%) | 43 (21.20%) | | pNX | 22 (4.60%) | 10(3.60%) | 12 (5.90%) | *This includes carcinomas with endometrioid, clear cell and mucinous histology (and low-grade serous) **T1CX designates tumors limited to one or both ovaries or Fallopian tubes without malignant cells in ascites of peritoneal washings without any available information if the capsule ruptured before surgery or if there was a surgical spill or the tumor was present on ovarian and/or Fallopian tubals surface Overall, 57.9% (279/482) of non-uterine pelvic malignancies were high-grade serous carcinomas; 42.1% (203/482) were non-high-grade serous carcinomas, e.g., presenting with endometrioid, clear cell or mucinous histology. 86.8% of the carcinomas with tubal origin presented with high-grade serous histology. In contrast, 83.7% of non-high-grade serous tumors were of ovarian origin. Depending of the site assignment approach, three different time periods were defined (see Fig. 1): 2000–2005; 2006–2010 and 2011–2019. Regardless of the histopathological subtype, there was a 1.7-fold decrease of carcinomas with ovarian origin from 2000 to 2005 compared to 2011–2019 (78.4% versus 46.7%). In contrast, a 10.3-fold increase of carcinomas with tubal origin was seen (4.2% versus 43.4%). Based on detailed analyses including the histopathological subtypes, there was a 2.1-fold decrease of ovarian derived high-grade serous carcinomas from 2000 to 2005 to 2011–2019 (63.4% versus 30.5%) and a 7.1-fold increase of tubal carcinomas (8.4% versus 59.6%). In cases with non-high-grade serous histology, there was no change in the frequency of the different sites of origin (see Table 2; Figs. 5c, 6c). Table 2. | Ovarian origin (C56) | Tubal origin (C57) | Peritoneal origin (C48) | p value | | |---|---|---|---|---| | All cases* | |||| | 2000–2005 (N = 167) | 131 (78.40%) | 7 (4.20%) | 29 (17.40%) | 0.004 | | 2006–2010 (N = 103) | 71 (68.90%) | 22 (21.40%) | 10 (9.70%) | 0.661 | | 2011–2019 (N = 212) | 99 (46.70%) | 92 (43.40%) | 21 (9.90%) | 0.729 | | Cases with high-grade serous histology only | |||| | 2000–2005 (N = 71) | 45 (63.40%) | 6 (8.50%) | 20 (28.20%) | 0.103 | | 2006–2010 (N = 67) | 43 (64.20%) | 15 (22.40%) | 9 (13.40%) | 0.609 | | 2011–2019 (N = 141) | 43 (30.50%) | 84 (59.60%) | 14 (9.9) | 0.48 | | Cases with non-high-grade serous histology | |||| | 2000–2005 (N = 96) | 86 (89.60%) | 1 (1.0%) | 9 (9.40%) | 0.618 | | 2006–2010 (N = 36) | 28 (77.80%) | 7 (19.40%) | 1 (2.80%) | 0.243 | | 2011–2019 (N = 71) | 56 (78.90%) | 8 (11.30%) | 7 (9.9) | 0.741 | *Regardless of the histopathological subtype Detailed analyses of the histopathologic subtypes revealed that the vast majority of non-uterine pelvic cancers are of high-grade serous histology. There was a significant decrease of carcinomas with ovarian origin between 2000 and 2019 which was associated with a significant increase in tumors of tubal origin. These changes were related to carcinomas with high-grade serous histology. The frequency of carcinomas with primary peritoneal origin (PPC) remained unchanged within the study period (Table 2; Figs. 5, 6). The vast majority of PPCs presented as high-grade serous carcinomas (43/60; 71.7%). The frequencies of the different sites of origin are summarized in Fig. 5 and Table 2. The annual case numbers and their linear decrease and increase are illustrated in Fig. 6a–c. Characteristic morphologic findings within the largest group of non-uterine pelvic cancer (high-grade serous histology) are shown in Fig. 7.

Ovarian carcinomas are the most lethal gynecologic malignancy in Germany (Rottmann et al. 2017), Europe (Coleman et al. 2011) and the United States (Siegel et al. 2020). High-grade serous carcinomas (HG-SC) are the most common histologic subtype of non-uterine carcinomas and represent 92% of tubal, 88.7% of primary peritoneal and 56.9% of ovarian carcinomas (Moss et al. 2015). Historically, it has been assumed that the majority of extra-uterine HG-SC arise from the ovary where the bulk of the disease can often be found (dominant mass theory). However, increasing evidence suggests that the distal part of the fallopian tube, especially its fimbriated end, is the primary site of origin (Crum et al. 2007; Medeiros et al. 2006; Singh et al. 2017; Perets und Drapkin 2016; Soong et al. 2018; Chen et al. 2017). Normal tubal epithelial cells undergo malignant transformation (STIC) with a detachment of the transformed cells (see Fig. 8) from their tubal residence and dissemination to the ovary and peritoneum, growing into a mass lesion which generally clinically presents as advanced stage disease at the time of diagnosis, referred to as the fallopian tubal theory (Soong et al. 2018; Visvanathan et al. 2018b; Leonhardt et al. 2011). The frequency of the detection of STIC as the precursor of invasive HG-SC differs widely and depends on the cohorts studied and the methodology used for the examination of the fallopian tubes (Medeiros et al. 2006; Leonhardt et al. 2011; Samimi et al. 2018a). Within 10.523 consecutive surgeries unrelated to cancer surgery and prophylactic/risk-reducing procedures, 40 (0.38%) STIC were identified using the SEE-FIM-like protocol for the examination of the fallopian tubes (Samimi et al. 2018a). Within the same setting, Meserve et al. (2017) identified two STIC (0.11%) within 1.747 specimens among women > 50 years. Using the SEE-FIM approach, 4 cases of STIC (0.8%) were detected in 522 women who underwent surgery for benign indications (Rabban et al. 2014). These findings indicate that the frequency (i.e., sporadic number) of STIC ranges between 0.1 and 0.8% in the general population. Trabert et al. (2018) calculated an incidence of STIC of 0.19 per 1 million women. Samimi et al. describe an association between the overall detection rate of SITC and older age, with a reported odds ratio of 1.44 ([95% CI (1.30–1.6)]; p < 0.01) per 5-year increase of age (Samimi et al. 2018a). A significant number of STIC occur unilaterally (Morrison et al. 2015; Leonhardt et al. 2011). About 60% of STIC present as a papillary lesion, one third with flat morphology (Seidman 2015; see Fig. 7c–f). In a cohort of 202 patients with HG-SC, the mean size of all detected STIC was 1.7 mm (range 0.1–0.8 mm), with a larger size in papillary compared to flat STIC (2.3 mm versus 0.8 mm; < 0.0001; Seidman 2015). In women with incidentally identified STIC, the size of the associated invasive component ranged between 1 and 4 mm (Morrison et al. 2015). The vast majority of STIC (and associated invasive carcinomas) are located within the fimbriated end of the fallopian tube (Leonhardt et al. 2011; Morrison et al. 2015; Seidman 2015; see Fig. 7g). It is therefore not surprising that extensive sampling and examination of the fallopian tubes can lead to an increased detection of STIC (Visvanathan et al. 2018a) and small invasive foci of HG-SC (Rabban et al. 2009; Medeiros et al. 2006). As a result, the SEE-FIM protocol was recommended for the examination of fallopian tubes, especially in the setting of risk reducing salpingectomies in BRCA-mutation carriers (Singh et al. 2016a, b). The “original” SEE-FIM protocol warrants the complete embedding and examination of the whole fallopian tube (Medeiros et al. 2006) which is mandatory within the processing of fallopian tubes in patients at risk (BRCA mutation; McCluggage et al. 2015; Visvanathan et al. 2018a). A practical alternative is to ensure that at least the fimbrial end of the fallopian tube will be examined according to the SEE-FIM protocol (amputating the distal 2 cm part of the fallopian tube, slicing in 2–3 mm intervals with complete embedding) with additional embedding of representative sections of the rest of the fallopian tube (Malpica et al. 2018; Kulac und Usubutun 2013), referred to as the SEE-FIM-like protocol (Fig. 2). The SEE-FIM-like protocol was applied in the present study. In a survey among pathologists for the processing of fallopian tubes in cases with extra-uterine HG-SC (McCluggage et al. 2017), the SEE-FIM-like protocol was used by 40% of the responders. The fact that almost all STIC occur within the distal part of the fallopian tube, including the infundibulum and its fimbriated end, makes the SEE-FIM-like protocol seem even more appropriate (Leonhardt et al. 2011; Seidman 2015). The use of additional techniques, like immunohistochemical stains for p53, p16 or Ki-67 to highlight the STIC-lesions is not recommended in the above mentioned protocols and is not necessary in the vast majority of cases to establish the diagnosis (Singh et al. 2016b; McCluggage et al. 2015). Additional immunohistological stains should be reserved for those uncommon cases where morphology alone is insufficient (Singh et al. 2016b; Perrone et al. 2020). That recommendation is in line with the results of a survey among pathologists which reported that the majority of pathologists (73%) feel that immunohistochemical stains are not routinely indicated for the detection of STIC (McCluggage et al. 2017). The approach for the examination of the fallopian tubes is variable. A survey of laboratories within the United States reported the use of the SEE-FIM protocol to process the specimens in risk reducing surgeries in 74.1%, for cases with the diagnosis of HG-SC in 56.9% (Samimi et al. 2018b). A similar frequency of 57% for the use of the SEE-FIM protocol was reported by a survey among pathologists in the processing of fallopian tubes in cases with non-uterine HG-SC (McCluggage et al. 2017). Almost all extra uterine HG-SC may be eligible for the correct definition of the site of primary tumor when adopting the SEE-FIM/SEE-FIM-like protocol (Medeiros et al. 2006; Singh et al. 2016a) and the published recommendations for site assessment by the ICCR (McCluggage et al. 2015) and others (Singh et al. 2016a) (see Fig. 4). Using deeper sections and/or embedding additional blocks may be helpful in questionable cases for the correct site assessment. An “undesignated” site assignment should be avoided as much as possible (Singh et al. 2016b; McCluggage et al. 2015). Based on conventional criteria (tumor mass theory), 70%, 17% and 13% of extra-uterine HG-SC qualified as ovarian, peritoneal, and tubal in origin, respectively (Przybycin et al. 2010). Using STIC as a supplemental criterion to define a case as tubal in origin, the distribution was modified to 28%, 8% and 64% in the same study. It has been suggested that previously undiagnosed STIC represent the source of primary high-grade serous peritoneal carcinomas (PPC; Leonhardt et al. 2011) even when diagnosed years after a benign surgery including (bilateral) salpingectomy (Seidman et al. 2011) or risk reducing salpingo-oophorectomy (Harao et al. 2018). In the latter setting, it has been postulated that cells from a previously unrecognized STIC have detached from their tubal residence (see Fig. 8) and disseminated to the peritoneum to grow to a mass lesion (Visvanathan et al. 2018b). Alternatively, normal tubal epithelium may be detached from the fimbriated end of the fallopian tube with seeding on the peritoneal surface where it undergoes a malignant transformation (Soong et al. 2018), clinically and pathologically presenting as PPC. In 2014, the WHO-classification stated that a diagnosis of PPC should only be made in the complete absence of ovarian and tubal involvement (Daya et al. 2014). Even in cases with only superficial ovarian involvement (Fig. 9), the tumor should be assigned as tubal or ovarian in origin. There may be a variation regarding the perceived importance of assigning the primary site of extra-uterine HG-SC given the limited prognostic and therapeutic significance (McCluggage et al. 2017) and the fact that the disease presents with similar clinical symptoms (Goff 2012; Sørensen et al. 2015). A recent survey reported a wide acceptance of the fallopian tube as the site of origin of extra-uterine HG-SC among both pathologists and clinicians (86% for pathologists and 92% for clinicians; McCluggage et al. 2017). Interestingly, clinicians feel a stronger need to assign the primary site of origin than pathologists (71% versus 49%). Importantly, that study reported a strong effort of the pathologists to assign a primary site by appropriate handling and reporting of the specimens (85%; McCluggage et al. 2017), without any differences between pathologists from North America or the United Kingdom (as a member of the European Union at that time). It may be hard to determine the site of origin when the cases present with large adnexal masses. In the authors’ opinion, careful macroscopic description and handling of the specimens, performing perpendicular slices of the adnexal tumor, starting from the tubal edges of the uterus in towards the pelvic side wall in about 0.5 cm intervals may help the correct site assignment (see Fig. 3). Additionally, appropriate embedding of one block per 2 cm tumor size (Gramlich et al. 1990; McCluggage et al. 2015) may be helpful to identify tubal tissue within the tumor bulk. A recent survey among pathologists reported that the vast majority (85%) try to assign the correct site of origin by appropriate handling of the specimens (McCluggage et al. 2017), with 93% of the pathologists using the SEE-FIM/SEE-FIM-like protocol. The vast majority of non-uterine HG-SC present as uni- or bilateral “adnexal mass” (Goff 2012; Sørensen et al. 2015). It has therefore been advocated that primary site should be assigned as tubal without the presence of STIC when the tube is partly or fully incorporated and inseparable from the tubo-ovarian mass (Singh et al. 2016b). Using the recommended criteria for the site assessment for non-uterine HG-SC published by the ICCR (McCluggage et al. 2015) and others (Singh et al. 2016b; Fig. 4), 83% of the 53 prospectively studied chemotherapy-naive cases were classified as tubal, 17% as ovarian and 0% as peritoneal primaries (Singh et al. 2015). 482 cases with non-uterine pelvic carcinomas between the years 2000 and 2019 were analyzed as part of the present study. Regardless of the histopathological subtype, a 1.7-fold decrease of carcinomas with ovarian origin (4.2% versus 43.4%) and a 10.3-fold increase of carcinomas with tubal origin (4.2% versus 43.4%) was noted comparing the years 2000–2005 with the years 2011–2019. The change in frequency was strongly related to high-grade serous carcinomas, where a significant 2.1-fold decrease of ovarian derived carcinomas (63.4% versus 30.5%), paralleled by a 7.1-fold increase of tubal carcinomas (8.4% versus 59.6%). In cases of non-high-grade serous histology, the frequencies of the different sites of origin were unchanged (see Table 2 and Figs. 5, 6) and consisted of 83.7% ovarian origins. Using the North American Association of Central Cancer Registries (NAACR) database, Goodman and Shvetsov (Goodman und Shvetsov 2009) found an increase in fallopian tube cancer by 79.3% and a decrease in ovarian cancer by 26.5% from 1973 to 2005. Within the same setting, an analysis of 11,264 cases of different histologic subtypes from the Danish Cancer Registry showed a decrease by 15.2% for ovarian cancer comparing the diagnostic years 1993–2003 with the years 2004–2013, and an increase of tubal cancer by 22.9% within the same time periods (Gottschau et al. 2016). Both studies included all histologic subtypes without separation into serous and non-serous histology. In an analysis of the data from the United State Cancer Statistics (USCS) of 146,470 women diagnosed with non-uterine cancers with serous histology only in the years 2001–2014, 6.4% were of fallopian tubal, 82.9% ovarian and 10.7% peritoneal in origin (Liao et al. 2018). There was an increase in fallopian tubal cancers of 8.7% from 2001 to 2006 and an additional increase of 17.5% from 2006 to 2012. In contrast, ovarian cancer consistently decreased by 0.96% during that time period (Liao et al. 2018). Translating these results into an incidence, there was an increase in fallopian tube cancers from 0.19 from 2001 to 2005 to 0.63 between 2011 and 2014, paralleled by a decrease in ovarian cancer incidence form 5.31 to 4.86 in the same time period without any change in the incidence of peritoneal cancer (0.64 vs. 0.62). An analysis of 165,284 cases of the North American Association of Central Cancer Registries (NAACR) database revealed a rise in the incidence rates of STIC from < 0.1 per 1 million women in 1999–2001 to 0.34 from 2011 to 2012, for early stage fallopian tubal carcinoma from 0.15 to 0.71 and for advanced tubal cancers from 0.71 to 4.09 within the same time periods (Trabert et al. 2018). In that study there was an absence of increasing trends for non-serous histologic subtypes for invasive fallopian tubal carcinomas (Trabert et al. 2018), as was seen in the present study. Liao et al. (2018) found no change in the incidence of PPC comparing the years 2001–2005 and 2011–2014 (0.63 versus 0.62; Liao et al. 2018). In the present study, the frequency of PPC was nearly unchanged between 2000 and 2019 (see Table 2 and Figs. 5, 6). Interestingly, the vast majority of PPCs within the present study presented with high-grade serous morphology. Using the strict definition of the primary site as peritoneal only when both tubes and ovaries are grossly and microscopically free of HG-SC (Daya et al. 2014; Singh et al. 2016a, b), PPC will become an extraordinarily rare disease (Sørensen et al. 2015; Singh et al. 2015). There may be some limitations of the present study including its monocentric approach and the analysis of a limited number of cases. However, the strengths of the study are the definition of distinct time periods reflecting the different approaches for site assignment (see Fig. 1). Additionally, the cases were divided in two main separate morphologic groups comparing carcinomas with high-grade serous and those with non-high-grade serous histology, reflecting the different pathogenetic pathways (Kurman und Shih 2016; McCluggage et al. 2017; Perets und Drapkin 2016; Karnezis et al. 2017) of non-uterine pelvic cancer, based on molecular findings. For the first time, the present study demonstrates that the increase of the frequency of fallopian tubal carcinomas is restricted to tumors with high-grade serous histology, whereas the frequency of the other sites of origin remains stable in tumors with non-high-grade serous features. The analyses of the trends in fallopian tubal, ovarian and peritoneal cancers raises the question of the true causes behind this phenomenon. The reported results with the dramatic increase of the incidence of early stage tubal carcinomas may be predominantly caused by improved sampling and examining the fallopian tubes using the SEE-FIM/SEE-FIM-like protocol (Samimi et al. 2018a). The strong increase of the reported rates of tubal cancers suggests that pathologists are increasingly classifying extra uterine HG-SC as tubal in origin (Samimi et al. 2018a). This is done in recognition of the increasing morphologic and molecular evidence that the vast majority of these cancers originate from the fallopian tubes rather than the ovaries (Piek et al. 2001; Crum et al. 2007; Karnezis et al. 2017; Perets und Drapkin 2016; Chen et al. 2017) and the increased recognition of the recommendations for site assignment (Singh et al. 2016a, b; McCluggage et al. 2015). Concluding the available data, all indications are that the increasing number of non-uterine HG-SC will increase as a function of more careful handling of the resection specimens focusing on the fallopian tubes and the recognition of the classification rules published by the ICCR (McCluggage et al. 2015) and others (Singh et al. 2016a). This is also supported by the data of the present study (see Figs. 5, 6) comparing different time periods with different approaches in defining the site of origin in non-uterine pelvic cancer at our institution. Accepting the theory that the vast majority of non-uterine HG-SC originates from the (distal) fallopian tubes (Visvanathan et al. 2018a; Soong et al. 2018; Fig. 7c, g) raises the question of potential prevention strategies. In a cohort of 247 BRCA-1 and -2 mutational carriers, women who underwent risk-reducing salpingo-oophorectomies had a lower risk of ovarian cancer, including those with prior breast cancer (1% vs. 6%, respectively; hazard ratio 0.14 [95% CI (0.04–0.59)] and a lower ovarian cancer-specific mortality (0.4% vs 3%; HR, 0.21 [95% CI, 0.06–0.80]) compared to women without prophylactic surgery (Domchek et al. 2010). A large Swedish population-based cohort study reported a significantly lower risk for ovarian cancer among women with a previous salpingectomy (HR = 0.65 [95% CI = 0.52–0.81]; Falconer et al. 2015). Furthermore, a bilateral salpingectomy was associated with a 50% decrease in the risk of ovarian cancer compared with the unilateral procedure (HR = 0.35 [95% CI = 0.17–0.73] versus 0.71 [95% CI = 0.56–0.91]) in the Swedish study. An ongoing prospective study in British Columbia and retrospective data from all of Canada show that an elective/opportunistic salpingectomy, although associated with a prolongation of operating time, is a clinically feasible and safe procedure (Salvador et al. 2017; Hanley et al. 2018) with a suspected potential reduction in the rate of HG-SC by 40% over the next 20 years. In addition to these hopeful studies, recent results of the pathogenesis in non-uterine HG-SC (Kurman und Shih 2016; Chen et al. 2017; Perets und Drapkin 2016) and the site assessment results (Trabert et al. 2018, present study) suggest that elective/opportunistic salpingectomies may be an appropriate approach for risk reduction for extra uterine HG-SC in the general population. Consequently, the American College of Obstetricians and Gynecologists recommends that gynecologists counsel women about a salpingectomy when planning hysterectomy for benign disease with ovarian preservation and/ or (laparoscopic) sterilization (Committee opinion no. 620: Salpingectomy for ovarian cancer prevention 2015) which has been defined as a feasible method (ACOG Committee Opinion No. 774 Summary: Opportunistic Salpingectomy as a Strategy for Epithelial Ovarian Cancer Prevention 2019). A study evaluating the data for gynecologic surgery found that a hysterectomy for benign disease with bilateral salpingectomy (and ovarian preservation) increased from 4.717 to 17.350 cases between 2008 and 2013 (Hicks-Courant 2016). Monitoring the incidence of highly aggressive and lethal gynecologic cancers such as high-grade serous ovarian, tubal and peritoneal carcinomas remains an important public health measure (Trabert et al. 2018; Liao et al. 2018). The correct assignment of the primary site has a strong impact on epidemiology, registration and entry into clinical trials (McCluggage et al. 2017; Singh et al. 2016a) as well as for the understanding of the disease, potential prevention strategies, treatment approaches and disease control. Abstracting the data from previous publications and the present study, a uniform approach for the primary site assignment of non-uterine high-grade serous Müllerian carcinomas is strongly recommended using the previously published recommendations summarized in Figs. 2, 3, 4 (McCluggage et al. 2015; Singh et al. 2016a, b; Malpica et al. 2018). Adopting a homogenous worldwide approach will ensure accurate data collection for comparisons of disease outcomes in daily practice and clinical trials. Additionally, it will promote a better understanding of the biology of HG-SC and the use of standardized pathology protocols in specimen dissection and reporting (Singh et al. 2016b). Furthermore, a correct site assessment will have a great impact on the strategy of risk reducing surgery, i.e., elective/opportunistic salpingectomies in women undergoing gynecologic surgeries for non-malignant uterine disease or tubal sterilization (Domchek et al. 2010; Falconer et al. 2015; Hanley et al. 2018). In conclusion, the reported increase of tubal cancer worldwide (Liao et al. 2018; Trabert et al. 2018) and confirmed by the present study is a result of a more careful handling of the specimens (SEE-FIM-like protocol) and the change of the definition of the origin of non-uterine HG-SC based on histopathologic and molecular findings (Leonhardt et al. 2011; Kurman und Shih 2016; Perets und Drapkin 2016; Chen et al. 2017; Karnezis et al. 2017; McCluggage et al. 2017; Singh et al. 2017; Trabert et al. 2018). Funding The authors declare that there was no funding of the study. Compliance with ethical standards Conflict of interest The authors declare that they have no conflict of interest. Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent Informed consent was obtained from all individual participants included in the study. Footnotes Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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