**3.3 Fallopian tube**

In 2001, small dysplastic lesions similar to HGSOC containing *BRCA* mutations were discovered in a patient's fallopian tubes [15]. Serous tubal intraepithelial carcinoma (STIC) is characterised by enlarged epithelial cells with atypia of nucleoli. The distal part of the fallopian tube is the main region where STIC is seen. This is most probably due to the close connection with the ovary where ovulation with chronic inflammatory and oxidative microenvironment takes place. Immunohistochemical study of STIC showed positivity of p53 as well as γH2AX, which is a marker of double-stranded DNA breaks [16].

The presence of STIC and HGSOC at the same time was confirmed in 11–61%. The incidence of STIC in asymptomatic risky patients after prophylactic adnexectomy was reported to be 0.4%–8.5%. The incidence in risk-free patients was 0.8%–3.1% [17]. Relatively wide incidence of STIC in HGSOC patients is due to non-identical diagnostic criteria of STIC. The criteria for STIC diagnosis are:


The knowledge of early tubal precursors increased a request for precise fallopian tubes assessment. On the other hand implementation of detailed investigation protocol uncovered more microscopic lesions with not known tasks. Apart from STIC, three other lesions need to be taken into consideration: p53 signature, secretory cell outgrowth (SCOUT), and serous intraepithelial lesion (STIL).

**p53 signature** represents a cluster of FTE reporting p53 positivity with Ki67 ˂ 10%. Morphological changes are not present and therefore a diagnostic process is focused on immunohistochemical examination. It can be a bilateral and multifocal lesion; the role is not fully clarified. It can be an initial step with subsequent progression or the lesion can persist.

**SCOUT** is defined as a proliferation of at least 30 secretory fallopian tube cells with Bcl2 positivity as well as P53 negativity. Another feature is loss of *PAX2*, which is seen in STIC as well as in HGSOC. This predicts *PAX2* inactivity as part of carcinogenesis and SCOUT can be a step of this process. The amount of SCOUT increases with age and most likely represents a precursor of p53 lesions [18]. However, they are not reported in clinical findings due to their unclear clinical importance.

**STIL** contains atypia but does not reach STIC. It represents a morphological intermediate stage between p53 and STIC [18].

The process of ovarian carcinogenesis starting in the FTE under the effect of ovulation takes more than 30 years. Development of p53 signature from secretory epithelial cells of the fallopian tubes lasts approximately 10 years, and it takes

**43**

**Figure 4.**

*Ovarian Cancer Tumour Biology: Genesis DOI: http://dx.doi.org/10.5772/intechopen.98289*

effects but certain risk of OC remains.

*3.3.1 STIC transport to ovaries*

cancer progression [21].

tube carcinoma can occur.

is seen.

opment of HGSOC from STIC (**Figure 4**) [19].

another 15 years for the development of STIC, and then 5 more years for the devel-

The knowledge of FTE hypothesis as the source of OC potentiates an idea of reduction of preventive surgery range in high-risk patients. Due to the lack of information about the role of fallopian tubes on general OC incidence, the risk reduction of OC occurrence after prophylactic salpingectomy cannot be established. The omission of oophorectomy in premenopausal women prevents menopausal side

Although the STIC as a precursor of HGSOC is clearly defined, infiltration of the fallopian tubes was not observed in a large proportion of patients with HGSOC [20]. The reason for this is the theory of transportation of early genomically altered secretory epithelial cells from the distal part of fallopian tubes into the OSE. Implantation of tissue in the CIC of OSE leads to formation of mCIC (**Figure 5**) where the ovarian microenvironment creates better conditions for

The question of whether OC originates in the ovary or the fallopian tube is not fully answered. The microenvironment plays a crucial role. Whereas the ovary accelerates the process of cancer initiation, progression, and growth, the fallopian tubes more likely have an inhibitory effect [21]. This may explain why the precursor in case of cancer originating from the ovary cannot be detected. The process in these cancers is so rapid that precancerous lesions are often not detected. Inversely, in the fallopian tubes there is a longer time window for detecting early lesions, and after their transportation into the ovary the acceleration of the cancer

Although the conditions for progression are apparently better in the ovaries, local progression of STIC in the fallopian tubes and formation of primary fallopian

*The biological course of ovarian carcinogenesis starting in fallopian tube epithelium.*

### *Ovarian Cancer Tumour Biology: Genesis DOI: http://dx.doi.org/10.5772/intechopen.98289*

*Ovarian Cancer - Updates in Tumour Biology and Therapeutics*

which is a marker of double-stranded DNA breaks [16].

of basement membrane penetration

• p53 overexpression (> 60%) or absence of expression

outgrowth (SCOUT), and serous intraepithelial lesion (STIL).

subsequent progression or the lesion can persist.

intermediate stage between p53 and STIC [18].

• increased proliferative index Ki67 (> 10% positive cells in lesion)

is likely due to low biological activity of ES.

**3.3 Fallopian tube**

Relevant clinical data about ES are scarce, although recent studies show its association with gynaecological malignancies [13]. A significant relationship between ES and borderline ovarian carcinoma (BOC) has been observed. One third of serous BOC patients present with ES in their histology and incidence of ES increases to 70% in recurrent serous BOC [14]. The connection with slowly progressing cancers

In 2001, small dysplastic lesions similar to HGSOC containing *BRCA* mutations

The presence of STIC and HGSOC at the same time was confirmed in 11–61%. The incidence of STIC in asymptomatic risky patients after prophylactic adnexectomy was reported to be 0.4%–8.5%. The incidence in risk-free patients was 0.8%–3.1% [17]. Relatively wide incidence of STIC in HGSOC patients is due to non-identical diagnostic criteria of STIC. The criteria for STIC diagnosis are:

• morphological abnormalities including change of nucleus/cytoplasm ratio, enlarged nucleus with prominent nucleoli, ciliary cells reduction, and absence

The knowledge of early tubal precursors increased a request for precise fallopian tubes assessment. On the other hand implementation of detailed investigation protocol uncovered more microscopic lesions with not known tasks. Apart from STIC, three other lesions need to be taken into consideration: p53 signature, secretory cell

**p53 signature** represents a cluster of FTE reporting p53 positivity with Ki67 ˂ 10%. Morphological changes are not present and therefore a diagnostic process is focused on immunohistochemical examination. It can be a bilateral and multifocal lesion; the role is not fully clarified. It can be an initial step with

with Bcl2 positivity as well as P53 negativity. Another feature is loss of *PAX2*, which is seen in STIC as well as in HGSOC. This predicts *PAX2* inactivity as part of carcinogenesis and SCOUT can be a step of this process. The amount of SCOUT increases with age and most likely represents a precursor of p53 lesions [18]. However, they are not reported in clinical findings due to their unclear clinical

**SCOUT** is defined as a proliferation of at least 30 secretory fallopian tube cells

**STIL** contains atypia but does not reach STIC. It represents a morphological

The process of ovarian carcinogenesis starting in the FTE under the effect of ovulation takes more than 30 years. Development of p53 signature from secretory epithelial cells of the fallopian tubes lasts approximately 10 years, and it takes

were discovered in a patient's fallopian tubes [15]. Serous tubal intraepithelial carcinoma (STIC) is characterised by enlarged epithelial cells with atypia of nucleoli. The distal part of the fallopian tube is the main region where STIC is seen. This is most probably due to the close connection with the ovary where ovulation with chronic inflammatory and oxidative microenvironment takes place. Immunohistochemical study of STIC showed positivity of p53 as well as γH2AX,

**42**

importance.

another 15 years for the development of STIC, and then 5 more years for the development of HGSOC from STIC (**Figure 4**) [19].

The knowledge of FTE hypothesis as the source of OC potentiates an idea of reduction of preventive surgery range in high-risk patients. Due to the lack of information about the role of fallopian tubes on general OC incidence, the risk reduction of OC occurrence after prophylactic salpingectomy cannot be established. The omission of oophorectomy in premenopausal women prevents menopausal side effects but certain risk of OC remains.

## *3.3.1 STIC transport to ovaries*

Although the STIC as a precursor of HGSOC is clearly defined, infiltration of the fallopian tubes was not observed in a large proportion of patients with HGSOC [20]. The reason for this is the theory of transportation of early genomically altered secretory epithelial cells from the distal part of fallopian tubes into the OSE. Implantation of tissue in the CIC of OSE leads to formation of mCIC (**Figure 5**) where the ovarian microenvironment creates better conditions for cancer progression [21].

The question of whether OC originates in the ovary or the fallopian tube is not fully answered. The microenvironment plays a crucial role. Whereas the ovary accelerates the process of cancer initiation, progression, and growth, the fallopian tubes more likely have an inhibitory effect [21]. This may explain why the precursor in case of cancer originating from the ovary cannot be detected. The process in these cancers is so rapid that precancerous lesions are often not detected. Inversely, in the fallopian tubes there is a longer time window for detecting early lesions, and after their transportation into the ovary the acceleration of the cancer is seen.

Although the conditions for progression are apparently better in the ovaries, local progression of STIC in the fallopian tubes and formation of primary fallopian tube carcinoma can occur.

**Figure 5.**

*The process of incorporation of fallopian tube cells into ovarian surface epithelium.*

## *3.3.2 Papillary tubal hyperplasia*

The fallopian tubes play a role in some type 1 cancers. Papillary tubal hyperplasia (PTH) represents a cluster of epithelial cells and small papillae with or without psammomatous bodies in the lumen of the fallopian tube (**Figure 6**). They float freely in tubal lumen or protrude from the epithelium into the lumen. This is a crucial difference from tubal hyperplasia. It was suggested that PTH represents the most advanced stage of tubal hyperplasia and has a significant association with some ovarian and extra-ovarian low-grade tumours. Earlier stages of tubal hyperplasia do not show such a prominent association [22].

PTH arises as the consequence of chronic inflammatory processes and can be diffuse or focal. Anatomically the most common place of appearance is the tubal ampoule. After its transport into the ovary, PTH can progress and form serous BOC and subsequently low-grade serous ovarian cancer (LGSOC). Many morphological similarities of PTH and LGSOC have been confirmed. Both contain ciliary and secretory cells as well as intraepithelial lymphocytes. Psammomatous bodies commonly present in PTH as well as LGSOC. After its transportation on peritoneal surfaces, PTH represents a precursor of ES or non-invasive implants.

Chronic inflammatory changes (i.e., chronic salpingitis or other forms of pelvic inflammatory disease) leading to architectural reconstruction of the fallopian tube induce FTE proliferation resulting in PTH. Mutation of *KRAS* or *BRAF* genes represent the main trigger of carcinogenesis. After its transportation into the ovary, the final structure is usually mCIC. Not all studies have confirmed this algorithm and significant association of PTH with LGSOC or serous BOC was not seen [23, 24]. More studies in this area are still needed.

### *3.3.3 Primary fallopian tube carcinoma*

Primary fallopian tube carcinoma (PFTC) represents a rare entity accounting for 0.14%–1.8% of all female genital tract cancers. Nevertheless, the incidence in the last several years has increased due to the change in fallopian tube assessment. Wide implementation of the SEE-FIM protocol into clinical practice increased detection of different precursors from FTE as well as the incidence of PFTC. Unfortunately, they represent mainly asymptomatic lesions or, like in some PFTC cases, are indicated for surgery due to adnexal mass. At present, PFTC is considered to be the presence of STIC or invasion of the carcinoma into the fallopian tube mucosa or if the fallopian tube is incorporated into the tumour mass [25].

The precursor in HGSOC or high-grade serous extra-ovarian cancer is STIC with a typical p53 mutation. In case of HGSOC or extra-ovarian cancer, STIC is

**45**

**3.4 Endometriosis**

**Figure 6.**

*Ovarian Cancer Tumour Biology: Genesis DOI: http://dx.doi.org/10.5772/intechopen.98289*

detached from the FTE and implanted on surfaces without invasion of tissue under the basement membrane of the FTE. However, in case of PFTC a local progression of STIC with invasion into deeper structures is seen. Localisation of PFTC in the tubal lumen leads to its distension with earlier clinical symptoms. Therefore, PFTC diagnosis is done earlier than that for HGSOC. In addition, the partially closed space of tubal lumen can delay spread of disease in the abdominal cavity.

*Papillary tubal hyperplasia. Numerous small papillae/thin arrows/psamomatous bodies/gross arrows/.*

Endometriosis is a clinically complex syndrome with chronic hormone-dependent inflammation and notable proliferative potential. Although endometriosis incidence

The common features of endometriosis and cancer cells have been clearly described. These include angiogenic potential of stem cells as well as their ability to evade apoptosis. Haemolysis, the process typical for endometriosis, is highly associated with oxidation. An oxidative microenvironment results in accumulation of DNA mutations and leads to, under the supervision of the immune system, either

The similar effect like in FTE, which is for better conditions of malignization transported into ovary is also in endometriosis seen. Inflamed stroma with mutated epithelium can progress to cancer when located on the ovary. This explains why malignant overthrow is uncommon in the case of deep infiltrating endometriosis even when containing similar DNA mutations [26]. The microenvironment plays an

Endometriosis-associated ovarian cancer (EAOC) includes mainly endometrioid ovarian cancer (EOC), clear cell ovarian cancer (CCOC), and sero-mucinous borderline ovarian cancer. Nevertheless, not every case of EAOC presents with endometriosis. EAOCs are characterised as well-differentiated tumours occurring at a younger age and initially diagnosed at an earlier stage when compared to endometriosis-free EAOC. The question which endometriotic lesion tend to progress into

is around 10%, it accounts for less than 1% of malignancies [26].

cell death or formation of pathogenic clone cells.

carcinoma remains still not completely answered.

important role in these situations as well.

*Ovarian Cancer - Updates in Tumour Biology and Therapeutics*

plasia do not show such a prominent association [22].

*The process of incorporation of fallopian tube cells into ovarian surface epithelium.*

seen [23, 24]. More studies in this area are still needed.

*3.3.3 Primary fallopian tube carcinoma*

The fallopian tubes play a role in some type 1 cancers. Papillary tubal hyperplasia (PTH) represents a cluster of epithelial cells and small papillae with or without psammomatous bodies in the lumen of the fallopian tube (**Figure 6**). They float freely in tubal lumen or protrude from the epithelium into the lumen. This is a crucial difference from tubal hyperplasia. It was suggested that PTH represents the most advanced stage of tubal hyperplasia and has a significant association with some ovarian and extra-ovarian low-grade tumours. Earlier stages of tubal hyper-

PTH arises as the consequence of chronic inflammatory processes and can be diffuse or focal. Anatomically the most common place of appearance is the tubal ampoule. After its transport into the ovary, PTH can progress and form serous BOC and subsequently low-grade serous ovarian cancer (LGSOC). Many morphological similarities of PTH and LGSOC have been confirmed. Both contain ciliary and secretory cells as well as intraepithelial lymphocytes. Psammomatous bodies commonly present in PTH as well as LGSOC. After its transportation on peritoneal

Chronic inflammatory changes (i.e., chronic salpingitis or other forms of pelvic

Primary fallopian tube carcinoma (PFTC) represents a rare entity accounting for 0.14%–1.8% of all female genital tract cancers. Nevertheless, the incidence in the last several years has increased due to the change in fallopian tube assessment. Wide implementation of the SEE-FIM protocol into clinical practice increased detection of different precursors from FTE as well as the incidence of PFTC. Unfortunately, they represent mainly asymptomatic lesions or, like in some PFTC cases, are indicated for surgery due to adnexal mass. At present, PFTC is considered to be the presence of STIC or invasion of the carcinoma into the fallopian tube mucosa or if the fallopian tube is incorporated into the tumour mass [25].

The precursor in HGSOC or high-grade serous extra-ovarian cancer is STIC with a typical p53 mutation. In case of HGSOC or extra-ovarian cancer, STIC is

inflammatory disease) leading to architectural reconstruction of the fallopian tube induce FTE proliferation resulting in PTH. Mutation of *KRAS* or *BRAF* genes represent the main trigger of carcinogenesis. After its transportation into the ovary, the final structure is usually mCIC. Not all studies have confirmed this algorithm and significant association of PTH with LGSOC or serous BOC was not

surfaces, PTH represents a precursor of ES or non-invasive implants.

*3.3.2 Papillary tubal hyperplasia*

**Figure 5.**

**44**

**Figure 6.** *Papillary tubal hyperplasia. Numerous small papillae/thin arrows/psamomatous bodies/gross arrows/.*

detached from the FTE and implanted on surfaces without invasion of tissue under the basement membrane of the FTE. However, in case of PFTC a local progression of STIC with invasion into deeper structures is seen. Localisation of PFTC in the tubal lumen leads to its distension with earlier clinical symptoms. Therefore, PFTC diagnosis is done earlier than that for HGSOC. In addition, the partially closed space of tubal lumen can delay spread of disease in the abdominal cavity.
