**3.4 Endometriosis**

Endometriosis is a clinically complex syndrome with chronic hormone-dependent inflammation and notable proliferative potential. Although endometriosis incidence is around 10%, it accounts for less than 1% of malignancies [26].

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 cell death or formation of pathogenic clone cells.

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 important role in these situations as well.

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 carcinoma remains still not completely answered.

Benign and atypical (premalignant) endometriosis can be defined using histopathological criteria. There is a significant association of atypical endometriosis (AE) with EAOC. While benign endometriosis (BE) does not contain atypia and has greater incidence, AE is less frequently seen and the atypia can be defined in two grades [27]. Cellular atypia, also called cytological atypia, defines epithelial layer changes such as hyperchromasia and pleomorphism. However, structural atypia, also called hyperplasia, deputises hyperplastic changes similar to ectopic endometrium, which includes simple or complex hyperplasia with or without cellular atypia [28]. Although plenty of studies refer to AE as tissue with cytological and structural atypia, cytological atypia are seen in cancer-free patients, whereas structural atypia are typically present in OC patients (**Figure 7**) [27].

The different potential of both types of atypia have been confirmed by studies of COX-2, Ki-67, and BAF250a. In the case of BE, immunohistochemical COX-2 positivity is significantly higher compared to that in AE. In both types of atypia in AE, rapidly higher COX-2 positivity in cytological atypia has been observed. This predicts BE as well as cytological atypia of AE into reactive changes. In Ki-67 examinations lower values in BE and cytological atypia of AE were detected. Thus, the structural atypia of AE can be concluded as the tissue with greater proliferative potential. The decrease in BAF250a was confirmed in both OC and AE patients. Comparing both types of atypia in AE, we can see lower BAF250a expressions in structural atypia patients [27].

EAOC tissue can be present with or without endometriosis. If endometriosis is confirmed, both types can be seen (BE as well as AE). In some cases even gradual transition from BE to AE and BOC can be detected. Approximately one of 10 women suffers from endometriosis and only less than 1% (0.3%–0.8%) of endometriosis patients will progress to cancer. When checked for AE incidence in endometriosis patients, 8% show atypia in their histology. The incidence of AE increases in patients with OC, whereas one-third of EAOC patients present with AE [27]. Detailed analysis of AE patients showed those with long-term history of disease, advanced stage, and older age when compared to BE patients. Current accepted criteria for AE include eosinophilic cytoplasm, large hyperchromatin or pale nuclei with moderate-to-marked pleomorphism, increased nucleus-to-cytoplasm ratio, and cell aggregation.

The endometriosis was solidly confirmed as the precursor of some OC, preferentially of certain portion of EAOC. Due to the low incidence of endometriosis

**47**

**4. Conclusion**

**Table 2.**

and CCOC.

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

*Simplified process of ovarian carcinogenesis.*

Ectopic Müllerian epithelium

overthrow, predictive factors are not fully clarified. There is significantly greater association of endometriomas with malignancy when compared to deep infiltrating endometriosis. In those cases, the ovarian microenvironment plays a crucial role. Thus, even in endometriosis overthrow a tubo-ovarian junction is inevitably needed to ensure endometrial reflux to the ovary and then cellular progression in the endometrioma. From the clinical characteristics of OC, patients with long-term history of disease as well as large endometriomas (> 9 cm) may be defined as high-risk patients for progression and thus require more precise observation (**Table 2**) [29].

**Initial structure Biological process Final structure**

ES Transport to the ovary Serous BOC FTE Transport to the ovary mCIC STIC Local progression PFTC STIC Transport to the ovary HGSOC PTH Transport to the ovary BOC/LGSOC

Local progression transport to the ovary Primary peritoneal cancer

mCIC

EOC, CCOC

OSE Mutation + incorporation into small cyst CIC OSE Metaplasia + incorporation into small cyst mCIC

Endometriosis Retrograde reflux/transport to tubo-

ovarian junction

Incidence of OC is relatively low when compared to other onco-gynaecological diseases. Nevertheless, OC is the fifth leading cause of cancer deaths among women

Disease localisation in the abdominal cavity allows asymptomatic growth at the early stages. The diagnostic timing of symptomatic disease does not affect the parameters of survival. To increase survival rate, it is important to detect the disease at the early asymptomatic stage. Knowledge of disease etiopathogenesis increases

The source of OC can be OSE through CIC or mCIC. Local progression is seen less frequently, whereas transport of the precursor to the ovarian surface is more common. Retrograde menstruation may be a cause of some EAOCs, mainly EOC

the probability of detecting precancerous lesions or early-stage cancers.

with 95% of deaths occurring in women older than 45 years.

**Figure 7.**

*The development of changes in ectopic endometrium.*

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


### **Table 2.**

*Ovarian Cancer - Updates in Tumour Biology and Therapeutics*

are typically present in OC patients (**Figure 7**) [27].

structural atypia patients [27].

and cell aggregation.

Benign and atypical (premalignant) endometriosis can be defined using histopathological criteria. There is a significant association of atypical endometriosis (AE) with EAOC. While benign endometriosis (BE) does not contain atypia and has greater incidence, AE is less frequently seen and the atypia can be defined in two grades [27]. Cellular atypia, also called cytological atypia, defines epithelial layer changes such as hyperchromasia and pleomorphism. However, structural atypia, also called hyperplasia, deputises hyperplastic changes similar to ectopic endometrium, which includes simple or complex hyperplasia with or without cellular atypia [28]. Although plenty of studies refer to AE as tissue with cytological and structural atypia, cytological atypia are seen in cancer-free patients, whereas structural atypia

The different potential of both types of atypia have been confirmed by studies of COX-2, Ki-67, and BAF250a. In the case of BE, immunohistochemical COX-2 positivity is significantly higher compared to that in AE. In both types of atypia in AE, rapidly higher COX-2 positivity in cytological atypia has been observed. This predicts BE as well as cytological atypia of AE into reactive changes. In Ki-67 examinations lower values in BE and cytological atypia of AE were detected. Thus, the structural atypia of AE can be concluded as the tissue with greater proliferative potential. The decrease in BAF250a was confirmed in both OC and AE patients. Comparing both types of atypia in AE, we can see lower BAF250a expressions in

EAOC tissue can be present with or without endometriosis. If endometriosis is confirmed, both types can be seen (BE as well as AE). In some cases even gradual transition from BE to AE and BOC can be detected. Approximately one of 10 women suffers from endometriosis and only less than 1% (0.3%–0.8%) of endometriosis patients will progress to cancer. When checked for AE incidence in endometriosis patients, 8% show atypia in their histology. The incidence of AE increases in patients with OC, whereas one-third of EAOC patients present with AE [27]. Detailed analysis of AE patients showed those with long-term history of disease, advanced stage, and older age when compared to BE patients. Current accepted criteria for AE include eosinophilic cytoplasm, large hyperchromatin or pale nuclei with moderate-to-marked pleomorphism, increased nucleus-to-cytoplasm ratio,

The endometriosis was solidly confirmed as the precursor of some OC, preferentially of certain portion of EAOC. Due to the low incidence of endometriosis

**46**

**Figure 7.**

*The development of changes in ectopic endometrium.*

*Simplified process of ovarian carcinogenesis.*

overthrow, predictive factors are not fully clarified. There is significantly greater association of endometriomas with malignancy when compared to deep infiltrating endometriosis. In those cases, the ovarian microenvironment plays a crucial role. Thus, even in endometriosis overthrow a tubo-ovarian junction is inevitably needed to ensure endometrial reflux to the ovary and then cellular progression in the endometrioma. From the clinical characteristics of OC, patients with long-term history of disease as well as large endometriomas (> 9 cm) may be defined as high-risk patients for progression and thus require more precise observation (**Table 2**) [29].

### **4. Conclusion**

Incidence of OC is relatively low when compared to other onco-gynaecological diseases. Nevertheless, OC is the fifth leading cause of cancer deaths among women with 95% of deaths occurring in women older than 45 years.

Disease localisation in the abdominal cavity allows asymptomatic growth at the early stages. The diagnostic timing of symptomatic disease does not affect the parameters of survival. To increase survival rate, it is important to detect the disease at the early asymptomatic stage. Knowledge of disease etiopathogenesis increases the probability of detecting precancerous lesions or early-stage cancers.

The source of OC can be OSE through CIC or mCIC. Local progression is seen less frequently, whereas transport of the precursor to the ovarian surface is more common. Retrograde menstruation may be a cause of some EAOCs, mainly EOC and CCOC.

*Ovarian Cancer - Updates in Tumour Biology and Therapeutics*
