There are many different types of ovarian cancer that can be diagnosed, and the histological subtype determines the course of treatment for the women. Ovarian tumours can be classified according to their embryological cell of origin into three types: (1) surface epithelium (coelomic epithelium) (2) sex cord stroma (mesenchymal) (3) germ cells (mesonephric), and each one of them are divided into five subtypes (Table 1.1). More than 80% of ovarian cancers are epithelial, predominately serous carcinomas (Anagnostopoulos, Taylor et al. 2015).
Histological subtypes classification
Table 1.1: Classification of ovarian tumour
• Epithelial tumours
Approximately 85% to 90% of ovarian cancer are Epithelial Ovarian Cancers (EOC), which are divided based on tumour behaviour into borderline tumours and invasive epithelial
Surface epithelium Sex cord Germ cell
High grade serous Granulosa cell Dysgerminoma
Low grade serous Granulosa cell Dysgerminoma
Endometrioid Thecoma Yolk sac
Clear cell Fibroma Embryonal carcinoma
Mucinous Sertoli, Leydig Choriocarcinoma
11 tumours, and classified based on histological subtype into serous (low and high grade), endometrioid, clear cell, mucinous and transitional cell cancers (Figure 1.4)(Bast Jr, Hennessy et al. 2009). It is becoming increasingly evident that these tumours develop and behave like distinct entities. Serous tumours seem to arise from dysplastic epithelium in the distal fallopian tube (Vaughan, Coward et al. 2011, Bowtell, Böhm et al. 2015, Prazak and Gahres 2016, Dean, Davis et al. 2017, Pinto, Assis et al. 2017). Low grade serous tumours are associated with KRAS, BRAF, NRAS, HER2 mutations, and high grade serous tumours are strongly associated with p53, BRCA 1 & 2 mutations and homologous recombination deficiency (Figure 1.5) (Lawrenson, Ramus et al. 2009, Sudo 2012, Anagnostopoulos, Taylor et al. 2015, Bowtell, Böhm et al. 2015, Patch, Christie et al. 2015).
This kind of ovarian cancer generally presents at advanced stage. Endometrioid tumours are commonly low grade and associated with CTNNB1, PTEN gene mutation and Lynch syndrome. They appear to arise from endometriotic cysts, usually present at early stages, can be bilateral and accompanied by synchronous endometrial cancer. These low-grade tumours behave like endometrioid endometrial cancers, while their high- grade counterparts resemble HGSOC. Clear cell tumours are associated with ARID1A, CTNNB1 and PTEN mutations. They commonly arise on a background of endometriosis and are usually unilateral, respond poorly to chemotherapy and have a poor prognosis. Mucinous ovarian tumours do not usually originate in the ovary, but it is becoming increasingly evident that most of them may be metastatic to the ovary from the gastrointestinal tract, usually the appendix (Anagnostopoulos, Taylor et al. 2015). These tumours are associated with KRAS and HER2 mutations and are largely borderline with a small proportion being malignant and resistant to conventional chemotherapy. Borderline ovarian tumours show histological features that are intermediate between benign and malignant tumours. They are found in younger age women, can spread beyond the ovary to produce non-invasive implants in the omentum or peritoneum and can have late recurrences. It is probable that they represent premalignant disease for low grade ovarian carcinomas. There are major differences in incidence, tumour behaviour, and clinical outcome between each histological subtype. It has been estimated that ~50% of malignant ovarian tumours are serous carcinomas, while ~25%
12 are endometrioid carcinomas, ~10% are mucinous carcinomas, and ~5% are clear cell carcinomas (Davis, Tinker et al. 2014).
In terms of behaviour, serous carcinomas tend to be aggressive, high-grade neoplasms that spread rapidly throughout the pelvis, while endometrioid and mucinous carcinomas are usually low-grade tumours, confined to the ovary. Clear cell and endometrioid carcinomas, unlike other subtypes, are strongly linked to endometriosis (Djordjevic, Stojanovic et al. 2012). HGSOC is the most lethal type of gynaecological cancer with a high mortality due to late diagnosis (Chene, Chauvy et al. 2017).
13
Figure 1.4 : Histology of different epithelial ovarian cancer subtypes. (Bast Jr, Hennessy et al.
2009).
Figure 1.5: The frequency of key driver mutations in HGSOC
Percentage of primary tumours affected by homologous recombination pathway mutations and CCNE1 copy number gains, ranking mutations in BRCA1/2, followed by other germline, somatic, amplification, deletion and methylation events respectively (Patch, Christie et al. 2015).
14
• Sex cord-stromal tumours
Sex cord-stromal tumours represent approximately 7% of all malignant ovarian tumours. They arise from the hormone producing cells of the ovary and stromal fibroblasts. 70% of sex cord-stromal tumours are granulosa cell tumours. They usually present in women older than 60 years, but young or pre-pubertal women are uncommon. They are usually unilateral and can secrete sex hormones, mainly oestrogen. The vast majority of these tumours are diagnosed at an early stage with a favourable prognosis. Late recurrences can also occur. Fertility sparing surgery is suggested for younger women while chemotherapy (bleomycin, etoposide and cisplatin), is used for advanced disease or recurrences. Thecomas, fibromas, Sertoli Leydig cell tumours are rare, usually unilateral and can produce androgen leading to virilisation (Anagnostopoulos, Taylor et al. 2015).
• Malignant germ cell tumours
The commonest malignant germ cell tumour is dysgerminoma. Dysgerminomas occur mainly in adolescence and early adulthood and can be bilateral in up to 20%. Since over 60% are confined to one ovary at diagnosis, fertility sparing surgery with unilateral salpingo-oophorectomy or even ovarian cystectomy in selected cases is an option. Dysgerminomas spread through the lymphatic system and though highly radiosensitive, platinum-based chemotherapy is preferable due to fertility preservation. Yolk sac tumour, embryonal carcinoma, polyembryoma, nongestational choriocarcinoma and teratoma tumours are treated with chemotherapy (bleomycin, etoposide and cisplatin). Cure rates approaching 100% in early stage and 75% in advanced disease are usually achieved (Anagnostopoulos, Taylor et al. 2015).
15
Staging of ovarian cancer
The main purpose of staging systems is to understand the severity of a patient’s clinical condition, predict the outcome, and plane a suitable treatment. The steps of staging typically begin by establishing the histopathological diagnosis, according to the tumour cell type, and assessing prognosis based on extent of disease and other known prognostic parameters. The first FIGO ovarian cancer staging was published in 1973. Since that time there have been two other changes including one in 1988 and 2013 (Table 1.2) (Mutch and Prat 2014, Ataseven, Chiva et al. 2016).
16
Table 1.2: 2014 FIGO ovarian, fallopian tube, and peritoneal cancer staging system and corresponding TNM
(Note 1: includes extension of tumour to capsule of liver and spleen without parenchymal involvement of either organ). (Note 2: Parenchymal metastases are Stage IV B).
FIGO Stage
FIGO Classification TNM
I Tumor confined to ovaries or fallopian tube(s) T1
IA Tumor limited to one ovary (capsule intact) or fallopian tube, No tumour on ovarian or fallopian tube surface
No malignant cells in the ascites or peritoneal washings
T1a
IB Tumor limited to both ovaries (capsules intact) or fallopian tubes No tumour on ovarian or fallopian tube surface
No malignant cells in the ascites or peritoneal washings
T1b
IC Tumor limited to one or both ovaries or fallopian tubes, with any of the following:
IC1 Surgical spill intraoperatively
IC2 Capsule ruptured before surgery or tumour on ovarian or fallopian tube surface
IC3 Malignant cells present in the ascites or peritoneal washings
T1c
II Tumor involves one or both ovaries or fallopian tubes with pelvic extension (below pelvic brim) or peritoneal cancer (Tp)
T2
IIA Extension and/or implants on the uterus and/or fallopian tubes/and/or ovaries
T2a
IIB Extension to other pelvic intraperitoneal tissues T2b
III Tumor involves one or both ovaries, or fallopian tubes, or primary peritoneal cancer, with cytologically or histologically confirmed spread to the peritoneum outside the pelvis and/or metastasis to the
retroperitoneal lymph nodes
T3
IIIA Metastasis to the retroperitoneal lymph nodes with or without microscopic peritoneal involvement beyond the pelvis
T1, T2, T3aN1
IIIA1 Positive retroperitoneal lymph nodes only (cytologically or histologically proven)
IIIA1(i) Metastasis ≤ 10 mm in greatest dimension (note this is tumour dimension and not lymph node dimension)
T3a/T3aN1
IIIA1(ii) Metastasis N 10 mm in greatest dimension
IIIA 2 Microscopic extra pelvic (above the pelvic brim) peritoneal involvement with or without positive retroperitoneal lymph nodes
T3a/T3aN1
IIIB Macroscopic peritoneal metastases beyond the pelvic brim ≤2 cm in greatest dimension, with or without metastasis to the retroperitoneal lymph nodes
T3b/T3bN1
IIIC Macroscopic peritoneal metastases beyond the pelvic brim > 2 cm in greatest dimension, with or without metastases to the retroperitoneal nodes (Note 1)
T3c/T3cN1
IV Distant metastasis excluding peritoneal metastases Stage IV A: Pleural effusion with positive cytology
Stage IV B: Metastases to extra-abdominal organs (including inguinal lymph nodes and lymph nodes outside of abdominal cavity) (Note 2)
Any T, Any N, M1 T3c/T3cN1)
17