**2. Ovarian cancer - background**

### **2.1 Classification**

Histo-anatomy and tumour biology are main determining factors in OC classification.

Up to 90% of all OC is derived from the epithelium. The remaining 10% represents non-epithelial cancers with sex-cord stromal tumours and germ cell tumours. Epithelial OC is either mucinous (3%) or non-mucinous (97%). The most represented group, non-mucinous, includes serous OC, endometrioid ovarian cancer (EOC), clear cell ovarian cancer (CCOC), transitional cell carcinoma, and others.

The model of two different tumour types in epithelial OC is widely supported and was officially accepted by the World Health Organisation (WHO) in 2004 [4]. Type 1 OC is defined from precursor through borderline variants. These cancers usually have an indolent course and good prognosis. Type 2 OC, such as high-grade serous ovarian cancer (HGSOC), reports fast progression, aggressiveness, and poor prognosis (**Figure 1**). Ninety percent of all deaths from OC are caused by this type [5].

The most common secondary cancers are metastatic lesions in the gastrointestinal tract or breasts [6].

## **2.2 Carcinogenesis: basic orientation**

The cells of origin for OC are well studied, although some OC may not originate in the ovaries. OC in extra-ovarian tissue can also occur. For example, mucinous OC can resemble other endocervical glands and gastro-intestinal epithelium.

EOC and CCOC often show the presence of endometriosis in their histology. Histopathological criteria can clearly define a couple of types of endometriosis with different biological potential. While benign endometriosis faces the onset of the endometriosis overthrow, atypical endometriosis is already an ongoing process. The range as well as the time interval of oxidative load significantly affect which deposit of benign endometriosis progresses. The degradation processes typically seen in ectopic endometrium are the source of oxidative stress, and close contact with the

### **Figure 1.**

*Ovarian cancer classification due to histo-anatomy and tumour biology with possible initial source.*

**39**

**Table 1.**

*to the OC development.*

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

tions and pronounced genomic instability [5].

infiltrating endometriosis.

ovary potentiates this process. This explains why ovarian endometriomas have the greatest potential for progression and why there is less risk of progression in deep

Serous OC can originate in the ovary as well as extra-ovarian tissue. The close relationship was observed with fallopian tube, mainly its fimbriated end. Fallopian tube epithelium (FTE) plays an important role in the development of ovarian malignancy. The precursor originating from the FTE can locally progress or, more often, adhere to the more favourable environment of the ovary. Local progression of the precursor derived from the FTE is rare. The reason for this is the inhibitory effect of the fallopian tube microenvironment on carcinogenesis when compared to the ovarian microenvironment. Oxidative stress resulting from incessant ovulation leads to accumulation of DNA changes in the FTE with subsequent exfoliation of precursors to the ovarian surface epithelium. Even more tissues for ovarian carcinogenesis with different biological potential have been recognised in the FTE. Type 1 OC, although containing oncogene alterations of RAS-PMK or PI3K-AKT, is genomically stable, for example, as in wild-type p53. Type 2 OC reports p53 muta-

Generally, the initial tissue for OC development can be located in the ovary,

Age older than 64 years is a risk factor for OC mortality and risk of disease increases significantly with advancing age. Within a genetic predisposition only limited clinically relevant mutations are currently known. Knowledge about tumour suppressor genes, *BRCA* mutations, and Lynch syndrome help to construct a preventive surgery programme for patients. An oxidative microenvironment due to incessant ovulation in the tubo-ovarian junction or degradative processes in endometriomas are considerable risk factors for DNA alterations. Thus, decreased ovulation may act as a protective factor against OC, although not every situation

**Group of factors Factor + — +/−**

BRCA mutation **•** Lynch syndrome **•**

Parity **•** Lactation **•**

Fallopian tube occlusion **•**

Menarche **•** Menopause **•**

Hormone replacement therapy **•**

Pelvic inflammatory disease **•**

Alcohol/cigarettes/caffeine **•**

**Age** Age **• Genetic** Family history **•**

**Reproduction** Incessant ovulation **•**

**Hormonal** Hormonal contraceptives **•**

**Gynaecological** Endometriosis **•**

**Others** Obesity **•**

*The share of individual factors in protection (+), predisposition (*−*) or controversial position (+/*−*) in relation* 

ectopic Müllerian epithelium, fallopian tube, or endometrium (**Figure 1**).

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

*Ovarian Cancer - Updates in Tumour Biology and Therapeutics*

and others.

type [5].

tract or breasts [6].

**2.2 Carcinogenesis: basic orientation**

Up to 90% of all OC is derived from the epithelium. The remaining 10% represents non-epithelial cancers with sex-cord stromal tumours and germ cell tumours. Epithelial OC is either mucinous (3%) or non-mucinous (97%). The most represented group, non-mucinous, includes serous OC, endometrioid ovarian cancer (EOC), clear cell ovarian cancer (CCOC), transitional cell carcinoma,

The model of two different tumour types in epithelial OC is widely supported and was officially accepted by the World Health Organisation (WHO) in 2004 [4]. Type 1 OC is defined from precursor through borderline variants. These cancers usually have an indolent course and good prognosis. Type 2 OC, such as high-grade serous ovarian cancer (HGSOC), reports fast progression, aggressiveness, and poor prognosis (**Figure 1**). Ninety percent of all deaths from OC are caused by this

The most common secondary cancers are metastatic lesions in the gastrointestinal

The cells of origin for OC are well studied, although some OC may not originate in the ovaries. OC in extra-ovarian tissue can also occur. For example, mucinous OC

EOC and CCOC often show the presence of endometriosis in their histology. Histopathological criteria can clearly define a couple of types of endometriosis with different biological potential. While benign endometriosis faces the onset of the endometriosis overthrow, atypical endometriosis is already an ongoing process. The range as well as the time interval of oxidative load significantly affect which deposit of benign endometriosis progresses. The degradation processes typically seen in ectopic endometrium are the source of oxidative stress, and close contact with the

can resemble other endocervical glands and gastro-intestinal epithelium.

*Ovarian cancer classification due to histo-anatomy and tumour biology with possible initial source.*

**38**

**Figure 1.**

ovary potentiates this process. This explains why ovarian endometriomas have the greatest potential for progression and why there is less risk of progression in deep infiltrating endometriosis.

Serous OC can originate in the ovary as well as extra-ovarian tissue. The close relationship was observed with fallopian tube, mainly its fimbriated end. Fallopian tube epithelium (FTE) plays an important role in the development of ovarian malignancy. The precursor originating from the FTE can locally progress or, more often, adhere to the more favourable environment of the ovary. Local progression of the precursor derived from the FTE is rare. The reason for this is the inhibitory effect of the fallopian tube microenvironment on carcinogenesis when compared to the ovarian microenvironment. Oxidative stress resulting from incessant ovulation leads to accumulation of DNA changes in the FTE with subsequent exfoliation of precursors to the ovarian surface epithelium. Even more tissues for ovarian carcinogenesis with different biological potential have been recognised in the FTE. Type 1 OC, although containing oncogene alterations of RAS-PMK or PI3K-AKT, is genomically stable, for example, as in wild-type p53. Type 2 OC reports p53 mutations and pronounced genomic instability [5].

Generally, the initial tissue for OC development can be located in the ovary, ectopic Müllerian epithelium, fallopian tube, or endometrium (**Figure 1**).

Age older than 64 years is a risk factor for OC mortality and risk of disease increases significantly with advancing age. Within a genetic predisposition only limited clinically relevant mutations are currently known. Knowledge about tumour suppressor genes, *BRCA* mutations, and Lynch syndrome help to construct a preventive surgery programme for patients. An oxidative microenvironment due to incessant ovulation in the tubo-ovarian junction or degradative processes in endometriomas are considerable risk factors for DNA alterations. Thus, decreased ovulation may act as a protective factor against OC, although not every situation


### **Table 1.**

*The share of individual factors in protection (+), predisposition (*−*) or controversial position (+/*−*) in relation to the OC development.*

confirms this fact (**Table 1**). The main factors influencing risk-reduction strategies are genetic predispositions, ageing, and parity.

## **3. Ovarian cancer: etiopathogenesis**

### **3.1 Ovary**

The infiltration of the ovaries by cancer cells even in the early stages of OC has been confirmed. Due to this fact, the initial concept was that the origin of OC is in the ovary. The ovarian surface epithelium (OSE) covers the ovary and during ovulation invagination of the OSE may occur, leading to the formation of small cystic lesions located in the ovarian cortex called cortical inclusion cysts (CICs).

The engagement of ovulation in carcinogenesis has been known for about 50 years. The oxidative stress accompanying ovulation alters the cells of the OSE. The accumulation of DNA damages arising due to the pro-inflammatory and prooxidative microenvironment and subsequent inability to repair them leads to the formation of pathological clone cells (**Figure 2**). In addition, women with a *BRCA* mutation and decreased ability of DNA repair are more prone to this process [7].

Incorporated CICs containing DNA-altered cells, as well as ambient pluripotent stem cells, are exposed to cyclic inflammatory activity. It has already been described that stem cell activity is silenced in cancerous OSE [8]. Thus, dysregulated pluripotency of stem cells may contribute to growth promotion and differentiation, finally leading to cancer formation [7]. Inadequate host tissue stem cell activity as the factor potentiating growth and malignant transformation in other cancers such as colorectal carcinoma has also been described [9].

The histology of certain HGSOC shows similarity to tissue developmentally derived from Müllerian ducts (**Figure 3**). One possible reason for this is that the relatively unstable, undifferentiated nature of OSE may mould the tissue of a Müllerian phenotype through the process of metaplasia [10]. Metaplastic OSE with different phenotype create after its incorporation into CIC Müllerian type of cortical inclusion cyst (mCIC), finally progressing into OC. This represents a theory of OC development from Müllerian epithelium but initially arising from metaplastic OSE. Another theory is the transport of Müllerian epithelium into the OSE from extra-ovarian localisation (e.g., ectopic Müllerian epithelium, endosalpingiosis, or fallopian tubes).

### **3.2 Ectopic Müllerian epithelium**

As early as 1999, the theory that all epithelial OC originated initially from the ovary was challenged. As a primary source was indicated extra-ovarian müllerian epithelium (**Figure 3**). It was observed that Müllerian epithelium has more similar patterns to HGSOC than to OSE. The theory was supported by proof of the absence of ovarian tissues in primary peritoneal cancers without ovarian invasion but that were clinically and histopathologically consistent with HGSOC. Secondary Müllerian tissue as the residue of ectopic Müllerian epithelium (outside of the cervix, endometrium, or fallopian tubes) as the source of cells for carcinogenesis has been confirmed [11].

### *3.2.1 Endosalpingiosis*

Endosalpingiosis (ES) represents an ectopic presence of FTE. When compared to endometriosis, ES shows ciliary epithelium and absence of inflammatory

**41**

present when compare to endometriosis.

*The development of female genitals and role of Müllerian ducts.*

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

**Figure 2.**

**Figure 3.**

*from ovulation.*

reaction. In addition, there is a difference in incidence related to age among these two conditions. The discovery of fallopian tube importance in the process of ovarian carcinogenesis and subsequent implementation of sectioning and extensively examining the fimbriated end protocol (SEE-FIM) led to increased ES rates. In women aged 31–50 years, ES incidence is 37%. In menopausal women, incidence increases to 66% [12]. Endometriosis incidence rapidly decreases after menopause, whereas an opposite effect is seen in ES. This is caused by the different biology of the diseases, although both entities probably arise from dissemination of physiologically localised tissue. While endometriosis represents a hormone-dependent disease, ES probably arises from tissue detachment of FTE. Due to the hormonal attenuation after menopause, endometriosis regresses; however, increasing age increases the probability of exfoliation of FTE from fallopian tubes. Different biological potential can also be present. In ES tissues degradative processes are missing, which means less oxidative load. Thus also malignant potential of ES should be

*Cortical inclusion cyst formation from ovarian surface epithelium under the effect of oxidative stress resulting* 

The theories of ES development discuss two possibilities. One envisages a metaplasia of pluripotent coelomic peritoneal epithelium to FTE tissue. More likely it is a process of primary dissemination of FTE. This second theory explains the presence of ES in women only and that the most common localization of ES is in the ovaries.

### **Figure 2.**

*Ovarian Cancer - Updates in Tumour Biology and Therapeutics*

are genetic predispositions, ageing, and parity.

colorectal carcinoma has also been described [9].

**3. Ovarian cancer: etiopathogenesis**

**3.1 Ovary**

confirms this fact (**Table 1**). The main factors influencing risk-reduction strategies

The infiltration of the ovaries by cancer cells even in the early stages of OC has been confirmed. Due to this fact, the initial concept was that the origin of OC is in the ovary. The ovarian surface epithelium (OSE) covers the ovary and during ovulation invagination of the OSE may occur, leading to the formation of small cystic lesions located in the ovarian cortex called cortical inclusion cysts (CICs). The engagement of ovulation in carcinogenesis has been known for about 50 years. The oxidative stress accompanying ovulation alters the cells of the OSE. The accumulation of DNA damages arising due to the pro-inflammatory and prooxidative microenvironment and subsequent inability to repair them leads to the formation of pathological clone cells (**Figure 2**). In addition, women with a *BRCA* mutation and decreased ability of DNA repair are more prone to this process [7]. Incorporated CICs containing DNA-altered cells, as well as ambient pluripotent stem cells, are exposed to cyclic inflammatory activity. It has already been described that stem cell activity is silenced in cancerous OSE [8]. Thus, dysregulated pluripotency of stem cells may contribute to growth promotion and differentiation, finally leading to cancer formation [7]. Inadequate host tissue stem cell activity as the factor potentiating growth and malignant transformation in other cancers such as

The histology of certain HGSOC shows similarity to tissue developmentally derived from Müllerian ducts (**Figure 3**). One possible reason for this is that the relatively unstable, undifferentiated nature of OSE may mould the tissue of a Müllerian phenotype through the process of metaplasia [10]. Metaplastic OSE with different phenotype create after its incorporation into CIC Müllerian type of cortical inclusion cyst (mCIC), finally progressing into OC. This represents a theory of OC development from Müllerian epithelium but initially arising from metaplastic OSE. Another theory is the transport of Müllerian epithelium into the OSE from extra-ovarian localisation (e.g., ectopic Müllerian epithelium, endosalpingiosis, or

As early as 1999, the theory that all epithelial OC originated initially from the ovary was challenged. As a primary source was indicated extra-ovarian müllerian epithelium (**Figure 3**). It was observed that Müllerian epithelium has more similar patterns to HGSOC than to OSE. The theory was supported by proof of the absence of ovarian tissues in primary peritoneal cancers without ovarian invasion but that were clinically and histopathologically consistent with HGSOC. Secondary Müllerian tissue as the residue of ectopic Müllerian epithelium (outside of the cervix, endometrium, or fallopian tubes) as the source of cells for carcinogenesis

Endosalpingiosis (ES) represents an ectopic presence of FTE. When compared

to endometriosis, ES shows ciliary epithelium and absence of inflammatory

**40**

fallopian tubes).

**3.2 Ectopic Müllerian epithelium**

has been confirmed [11].

*3.2.1 Endosalpingiosis*

*Cortical inclusion cyst formation from ovarian surface epithelium under the effect of oxidative stress resulting from ovulation.*

### **Figure 3.**

*The development of female genitals and role of Müllerian ducts.*

reaction. In addition, there is a difference in incidence related to age among these two conditions. The discovery of fallopian tube importance in the process of ovarian carcinogenesis and subsequent implementation of sectioning and extensively examining the fimbriated end protocol (SEE-FIM) led to increased ES rates. In women aged 31–50 years, ES incidence is 37%. In menopausal women, incidence increases to 66% [12]. Endometriosis incidence rapidly decreases after menopause, whereas an opposite effect is seen in ES. This is caused by the different biology of the diseases, although both entities probably arise from dissemination of physiologically localised tissue. While endometriosis represents a hormone-dependent disease, ES probably arises from tissue detachment of FTE. Due to the hormonal attenuation after menopause, endometriosis regresses; however, increasing age increases the probability of exfoliation of FTE from fallopian tubes. Different biological potential can also be present. In ES tissues degradative processes are missing, which means less oxidative load. Thus also malignant potential of ES should be present when compare to endometriosis.

The theories of ES development discuss two possibilities. One envisages a metaplasia of pluripotent coelomic peritoneal epithelium to FTE tissue. More likely it is a process of primary dissemination of FTE. This second theory explains the presence of ES in women only and that the most common localization of ES is in the ovaries.

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 is likely due to low biological activity of ES.
