**2. High-grade serous ovarian cancer (see figure 1)**

At this point it seems appropriate to recall the anatomy and embryology involved in order to clarify the close relationship and interaction between Fallopian tube and ovary. During embryonic development, the coelomic epithelium gives rise to the peritoneum and ovarian surface epithelium (OSE). The Mullerian duct develops as an invagination of the coelomic epithelium in direct continuity of the OSE. So the OSE and Fallopian tube share the same origin. Moreover, there is a direct histological connection between the epithelium of the fimbria and the OSE [6] (see figure 1). As we will show below, all these various elements suggest that we should no longer use the term ovarian cancer, but rather tubo-ovarian cancer.

**Figure 1.** A-In this laparoscopic view, we can see the close anatomical interaction between the fallopian tube and the ovary; In the high-grade serous ovarian carcinogenesis, serous tubal intraepithelial carcinoma (STIC in photo B) may be the non-invasive precursor of high-grade ovarian cancer (E). STIC is characterized by a p53 immunohistochemical sig‐ nature (C); On the other hand, ovarian epithelial dysplasia (see the inclusion cysts in D) may be also a preinvasive le‐ sion in the high-grade serous ovarian carcinogenesis. This raises the question of the temporal relationships and chronology of events: what is the exact relationship between ovarian dysplasia and STIC ? In the clear cell (H) and en‐ dometrioid (I) ovarian carcinogenesis, endometriosis (F) may be a non-invasive precursor when there is loss of ARID1A expression (G). The fallopian tube may be considered as both as a source in the high-grade serous ovarian carcinogen‐ esis and as a conduit for endometriosis in the clear cell and endometrioid ovarian carcinogenesis [60]*.*

#### **a.** Once upon a time the ovarian hypothesis:

**Low grade serous Clear cell Endometrioid Mucinous High grade**

KRAS HER2

Sequence: Adenoma/ Borderline

Chemoresistance

(15-20%) Good (80%)

ARID1A PTEN B-catenine KRAS

Endometriosis Adenofibroma

Good

PI3K inhibitors mTOR inhibitors MEK inhibitors

Genomic instability low low low low high

Frequency 5% 10% 10% 3% 70%

Prognosis Favourable Intermediate Favourable Favourable Poor

**Table 2.** Diagram of quintuple-pathway oncogenesis [3, 4]. This classification shows the clinico-pathological differences along with potential therapeutic targets for each histological sub-type. An advantage of this new

We propose to discuss the origin of HGSC and EAOC cancers and the potential clinical

At this point it seems appropriate to recall the anatomy and embryology involved in order to clarify the close relationship and interaction between Fallopian tube and ovary. During embryonic development, the coelomic epithelium gives rise to the peritoneum and ovarian surface epithelium (OSE). The Mullerian duct develops as an invagination of the coelomic epithelium in direct continuity of the OSE. So the OSE and Fallopian tube share the same origin. Moreover, there is a direct histological connection between the epithelium of the fimbria and the OSE [6] (see figure 1). As we will show below, all these various elements suggest that we

should no longer use the term ovarian cancer, but rather tubo-ovarian cancer.

Endometriosis Adenofibroma

Chemoresistance

(15%)

classification is that it describes the heterogeneous nature of ovarian cancer.

**2. High-grade serous ovarian cancer (see figure 1)**

Molecular signatures BRAF KRAS HER2

144 Contemporary Gynecologic Practice

Precursors Borderline serous

Intermediate (20-30%)

BRAF inhibitors MEK inhibitors

Initial response to platinum salt chemotherapy

therapeutic targets

implications.

Potential

ARID1A HNF 1B PI3KCA PTEN

**serous**


PARP inhibitors Cell cycle inhibitors

(STIC) -Ovary (dysplasia)

TP53 BRCA

> In 1971, Fathalla [7] developed the theory of incessant ovulation after noting the high frequency of ovarian cancer in nulliparous women and the high prevalence of peritoneal carcinosis of ovarian origin in battery hens (ovulation every 28 hours, rate of spontaneous ovarian cancer between 30 and 40% at 4 years of age). Inversely, the protective role of oral contraception, pregnancy and breastfeeding thanks to their inhibition of ovulation has been well-established [8-10]: repeated ovulations are pro-inflammatory events and could result in the formation of ovarian epithelium inclusion cysts in the OSE. These inclusion cysts, exposed as they are to cellular, paracrine and hormonal growth factors in the pro-inflamatory stromal microenvir‐ onment, could thus be the origin of a neoplastic process.

While 90% of cases of ovarian cancer are sporadic, 10% are hereditary in nature with a high proportion linked with BRCA mutations. There is a 35 to 60% cumulative risk at age 70 in case of BRCA 1 mutation. The risk is a little lower in case of BRCA2 mutations, lying between 10 and 27% [11]. These patients, their ovaries and tubes provide an excellent model for studies aiming at a better understanding of ovarian carcinogenesis. Due to the fact that bilateral adnexectomy is recommended in this group at risk, after the age of 35 and after completion of childbearing, these ovaries (and then the tubes, see below) have received particular attention in histopathological and molecular level studies. As a consequence histopathological anoma‐ lies called ovarian epithelial dysplasia (by analogy with other preinvasive lesions of the genital tract) were initially described in ovaries with a genetic risk (BRCA mutation) [12]. In view of the high risk of ovarian cancer in these patients if bilateral ovariectomy does not take place, these dysplastic lesions were therefore considered to be preinvasive with a potential towards cancer.

Similar dysplastic lesions were also revealed in areas adjacent to ovarian cancer, and also in the contralateral ovary in case of unilateral ovarian cancer without any genetic predisposition [13-18]. The molecular and histopathological similarities thus suggested that these dysplastic lesions were the initial phases of ovarian carcinogenesis.

More recently dysplastic anomalies were revealed in ovaries from patients who had undergone an ovulation stimulation process in a context of infertility [19, 20]. However since the histo‐ pathological, immunohistochemical and molecular characteristics differed from those of dysplastic lesions found in patients with a BRCA genetic mutation, it would appear that there may be several types of dysplasia that evolve differently (towards cancer in case of BRCA mutation, unlike the case after an *in vitro* fertilisation protocol) [21, 22].

**b.** ...and all of a sudden the tubal hypothesis:

In 2001, Piek *et al* [23] revealed for the first time 6 cases of tubal dysplasia including one case of severe dysplasia in a cohort of 12 patients with a genetic predisposition for ovarian cancer. Other studies have corroborated these results with nearly 10% Serous Tubal Intraepithelial Carcinoma (or STIC), 57% to 100% of which were located in the fimbriated end of the Fallopian tube [24-27]. These lesions consist of nonciliated cells exhibiting 3 or more of the following features: abnormal chromatin pattern, nuclear enlargement, marked nuclear pleomorphism, epithelial stratification and/or loss of polarity, and nuclear moulding. They are also charac‐ terised by high immunohistochemical expression of TP53 (expression level between 80% and 92%) and highly positive levels for proliferation marker Ki67 and DNA double-strand break marker γ-H2AX [24-27].

Other even earlier tubal lesions have also been described and it was possible to propose a serous carcinogenic sequence with a tubal origin: after a genotoxic stress and subsequent to various mutations (such as TP 53 mutation and BRCA mutation or epigenetic loss which play an important role in the maintenance of genomic integrity), very early histopathological anomalies of the tube would appear: these SCOUT lesions (Secretory Cell Outgrowths), characterised by a succession of at least 30 pseudostratified secretory epithelial cells with a low expression of PAX2, PTEN and Ki67, and no p53 mutation, would then evolve towards p53 signatures [28, 29]. These p53 signatures, defined by a succession of at least 12 secretory cells with intense nuclear p53 staining and a low proliferative index, could evolve towards STIC (same TP53 molecular mutation suggesting a clonal relationship and a genetic identity). However, these p53 signatures are found in around 50% of normal control Fallopian tubes and it is not possible at the time of writing to tell which signature(s) might evolve towards STIC and which would not undergo this unfavourable evolution [30].

Finally, STIC lesions may metastase in the ovary and adjacent peritoneum [31].

Several series of sporadic high-grade serous ovarian and serous peritoneal cancers (without BRCA mutation) were re-analysed and revealed the presence of the same serous carcinogenic sequence in almost 50% of cases [31].

**c.** Tubal or ovarian origin?

While 90% of cases of ovarian cancer are sporadic, 10% are hereditary in nature with a high proportion linked with BRCA mutations. There is a 35 to 60% cumulative risk at age 70 in case of BRCA 1 mutation. The risk is a little lower in case of BRCA2 mutations, lying between 10 and 27% [11]. These patients, their ovaries and tubes provide an excellent model for studies aiming at a better understanding of ovarian carcinogenesis. Due to the fact that bilateral adnexectomy is recommended in this group at risk, after the age of 35 and after completion of childbearing, these ovaries (and then the tubes, see below) have received particular attention in histopathological and molecular level studies. As a consequence histopathological anoma‐ lies called ovarian epithelial dysplasia (by analogy with other preinvasive lesions of the genital tract) were initially described in ovaries with a genetic risk (BRCA mutation) [12]. In view of the high risk of ovarian cancer in these patients if bilateral ovariectomy does not take place, these dysplastic lesions were therefore considered to be preinvasive with a potential towards

Similar dysplastic lesions were also revealed in areas adjacent to ovarian cancer, and also in the contralateral ovary in case of unilateral ovarian cancer without any genetic predisposition [13-18]. The molecular and histopathological similarities thus suggested that these dysplastic

More recently dysplastic anomalies were revealed in ovaries from patients who had undergone an ovulation stimulation process in a context of infertility [19, 20]. However since the histo‐ pathological, immunohistochemical and molecular characteristics differed from those of dysplastic lesions found in patients with a BRCA genetic mutation, it would appear that there may be several types of dysplasia that evolve differently (towards cancer in case of BRCA

In 2001, Piek *et al* [23] revealed for the first time 6 cases of tubal dysplasia including one case of severe dysplasia in a cohort of 12 patients with a genetic predisposition for ovarian cancer. Other studies have corroborated these results with nearly 10% Serous Tubal Intraepithelial Carcinoma (or STIC), 57% to 100% of which were located in the fimbriated end of the Fallopian tube [24-27]. These lesions consist of nonciliated cells exhibiting 3 or more of the following features: abnormal chromatin pattern, nuclear enlargement, marked nuclear pleomorphism, epithelial stratification and/or loss of polarity, and nuclear moulding. They are also charac‐ terised by high immunohistochemical expression of TP53 (expression level between 80% and 92%) and highly positive levels for proliferation marker Ki67 and DNA double-strand break

Other even earlier tubal lesions have also been described and it was possible to propose a serous carcinogenic sequence with a tubal origin: after a genotoxic stress and subsequent to various mutations (such as TP 53 mutation and BRCA mutation or epigenetic loss which play an important role in the maintenance of genomic integrity), very early histopathological anomalies of the tube would appear: these SCOUT lesions (Secretory Cell Outgrowths), characterised by a succession of at least 30 pseudostratified secretory epithelial cells with a low expression of PAX2, PTEN and Ki67, and no p53 mutation, would then evolve towards

lesions were the initial phases of ovarian carcinogenesis.

**b.** ...and all of a sudden the tubal hypothesis:

marker γ-H2AX [24-27].

mutation, unlike the case after an *in vitro* fertilisation protocol) [21, 22].

cancer.

146 Contemporary Gynecologic Practice

STIC lesions present preinvasive characteristics, as shown by the following elements:


But, other arguments plead in favour of an ovarian origin. Notably, the fact that STIC lesions are not found in all genetic or sporadic series of ovarian cancer. If there are no STIC lesions or at the very least histological scarring due to STIC of the tube, what would the origin of the cancer be? So this raises the question of the temporal relationships and chronology of events: like for the chicken and the egg, do STIC lesions precede invasive cancer, or the contrary?

To conclude, although during the last century the postulate was raised that ovarian cancer originates in the ovary itself (which seemed logical and is the case for other organs), it would today appear that ovarian cancer has a dual origin, both tubal (predominating in case of genetic risk with BRCA mutation) and ovarian. It remains to be seen how and why one patient will have a cancer of tubal origin while another will have one of ovarian origin [31]. Furthermore, what triggers the transformation of normal secretory Fallopian tube epithelium into HGSC?

The solution is likely in in the interaction between the tube and the ovary. Some authors have described the chronic inflamatory therory [39, 40]. They stated that there is less retrograde flow of inflamatory mediators from the genital tract and through the tube with tubal ligature, hysterectomy, oral contraception or pregnancy (closed cervix). For other authors, the release of inflamatory follicular fluid during ovulation may cause damage on the ovarian and fallopian tube epithelial cells [41, 42]. All these arguments point to the concept of tubo-ovarian cancer, i.e. a disease both in tube and ovary.

The potential clinical implications are discussed in the following paragraphs.
