Ovarian epithelial tumours are thought to arise from the simple cuboidal surface epithelium of the ovary, and account for 75% of all ovarian tumours, and 90-95% of ovarian malignancies.

Ovarian epithelial tumours are classified according to the following histological subtypes:

• serous,
• mucinous,
• endometrioid,
• clear cell,
• Brenner,
• transitional cell,
• small cell,
• mixed mesodermal and
• undifferentiated.
  

Usually each subtype can be classified as benign, borderline (low malignant potential, LMP), or malignant (invasive).

Serous tumours are further subdivided into the following:

• Serous cystadenoma
• Borderline serous tumour
• Serous cystadenocarcinoma
• Adenofibroma
• Cystadenofibroma

Mucinous tumours are further classified as:

• Mucinous cystadenoma
• Borderline mucinous tumour
• Mucinous cystadenocarcinoma
• Adenofibroma

Epidemiology studies have provided data showing increased risk for ovarian cancer with greater numbers of ovulation cycles. Multiple pregnancies and use of oral contraceptives are thought to have a protective effect because of decreased ovulation and hormonal influences. There are two theories explaining for the association of decreased risk with decreased number of ovulation cycles:
1 Theory of incessant ovulation: repeated ovarian follicular rupture and subsequent repair results in increased likelihood of genetic alterations within the surface epithelium.
2. The Gonadotrophin Theory hypothesis: persistent stimulation of the ovaries by gonadotrophins, together with local effects of endogenous hormones, results in increased proliferation and mitotic activity of the surface epithelium. This is consistent with ovarian cancer being associated with high gonadotrophin states such as the menopause, and less commonly associated with low gonadotrophin states such as oral contraceptive use and high parity.

Epithelial ovarian carcinoma develops sporadically in about 90-95% of patients. Environmental and dietary factors are thought to have a role. These include use of talc on the perineum and vulva, asbestos, pelvic irradiation, viruses (particularly mumps), high-fat diet, and lactose consumption. Other factors are associated with an increased number of ovulation cycles: low parity, delayed childbearing, early menarche and late menopause. However, genetic factors are the most important risk factor for ovarian epithelial carcinoma (See Genetics section of this review for further details).

Factors that decrease the risk for ovarian cancer predominantly reduce the number of ovulation cycles a women encounters-such as the use of oral contraceptives, breast-feeding and multiparity. Long-term use of oral contraceptives has reduced the risk of ovarian cancer by more than 50% in unselected women. Decreased risk of ovarian cancer has also been associated with tubal ligation and hysterectomy.

Epithelial ovarian cancer is the sixth most common cancer in women and is the second most common female genital tract malignancy after endometrial cancer. They are usually found in postmenopausal women and are the commonest cause of death among women with gynaecologic malignancies in the USA, accounting for approximately 15,000 deaths annually. The annual lifetime risk for ovarian cancer is 1.4 per 100 women in the USA. Epithelial ovarian cancer can occur in females as young as 15, however the mean presentation age is 56 years. The age-specific incidence gradually rises and peaks at 70 years of age (55 per 100,000 Caucasians), whereas it affects only 3 women per 100,000 before 30 years of age. The median age for ovarian adenocarcinoma (which accounts for 85-90% of all malignant tumours) is between 60-65 years. The LMP ovarian tumours present at a younger age; the mean age of diagnosis is 48 years, and no large peak of incidence is observed. Brenner tumours are diagnosed in peri- or postmenopausal women. The incidence of ovarian epithelial tumours varies globally, with highest rates being observed in Scandinavia, Israel and North America, whereas the lowest rates are found in developing countries and Japan. A racial predisposition to ovarian epithelial tumours is apparent, with lower risks for black women. Clear cell adenocarcinoma is more prevalent in Japanese than western countries.

Most early ovarian carcinomas and the serous and mucinous cystadenomas are asymptomatic. Two-thirds of patients present with extensive intra-abdominal metastases. Patients with advanced carcinomas usually present with vague abdominal swelling or discomfort, abdominal bloating, dyspepsia and early satiety, lack of appetite, malaise, urinary frequency and weight change (either gain or loss). Pelvic examination revealing firmness, fixation, nodularity, lack of tenderness, ascites, or cul-de-sac nodules are indicative of malignancy. 50% of all ovarian carcinomas are bilateral. Malignant serous tumours constitute over 40% of invasive epithelial carcinomas. Both borderline and malignant serous tumours are often bilateral. Mucinous carcinomas are diagnosed at stage I in approximately half of patients, whereas serous tumours are usually diagnosed at advanced stages.

Brenner tumours are virtually always benign, and the exceptional malignant cases resemble transitional cell carcinoma of the bladder. As with the other types of ovarian neoplasm, it is usually asymptomatic until it has grown to a large size.

Serous

Benign serous tumours are loculated, have a single layer of flattened or cuboidal epithelium and the absence of mitoses. Papillae are sometimes present on the external or internal surfaces. Examples of serous cystadenomas can be found at:
http://www-medlib.med.utah.edu/WebPath/FEMHTML/FEM054.html - gross appearance
http://www-medlib.med.utah.edu/WebPath/FEMHTML/FEM073.html - gross appearance
http://www-medlib.med.utah.edu/WebPath/FEMHTML/FEM052.html - gross appearance
http://www-medlib.med.utah.edu/WebPath/FEMHTML/FEM053.html -demonstrates internal papillae
http://www-medlib.med.utah.edu/WebPath/FEMHTML/FEM051.html - illustrates external papillae
http://www-medlib.med.utah.edu/WebPath/FEMHTML/FEM056.html - H and E staining
http://pathweb.uchc.edu/eAtlas/GYN/1314.htm
http://pathweb.uchc.edu/eAtlas/GYN/1315.htm
http://pathweb.uchc.edu/eAtlas/GYN/1316.htm
http://pathweb.uchc.edu/eAtlas/GYN/61.htm
http://pathweb.uchc.edu/eAtlas/GYN/159.htm
Histological analysis of borderline serous tumours reveals papillary cystic pattern, stratification, tufting, increased mitotic figures and cytologic atypia. H and E histology of borderline serous tumour can be viewed at:
http://www-medlib.med.utah.edu/WebPath/FEMHTML/FEM055.html.

Malignant serous tumours are soft, multiloculated, partially cystic, partially solid tumours with friable papillae. Their capsule may be smooth or irregular or show papillary projections. Internal papillae are soft and tan in colour. Cyst fluid is clear, thin and colourless. The gross appearance of serous cystadenocarcinoma can be viewed at:
http://pathweb.uchc.edu/eAtlas/GYN/463.htm
Histological review of malignant serous tumours indicates significant stromal invasion. Calcifications (Psammoma bodies) are present in one-third of patients. Characteristic microscopic features include finger-like papillae with fibrovascular core, covered by multilayered cuboidal or columnar epithelium, hyperchromatic nuclei, prominent nucleoli, frequent mitoses, Psammoma bodies and desmoplasia (invasion of stroma with fibrosis). Examples can be viewed at:
http://pathweb.uchc.edu/eAtlas/GYN/1927.htm
http://pathweb.uchc.edu/eAtlas/GYN/1928.htm
http://pathweb.uchc.edu/eAtlas/GYN/1929.htm
http://pathweb.uchc.edu/eAtlas/GYN/1097.htm
http://pathweb.uchc.edu/eAtlas/GYN/1098.htm
http://pathweb.uchc.edu/eAtlas/GYN/1099.htm
http://www-medlib.med.utah.edu/WebPath/FEMHTML/FEM072.html -shows Psammoma bodies

Mucinous

Benign mucinous tumours are larger than serous tumours, and may grow to an enormous size. They are usually unilocular cysts or may have a few septae, with a smooth external surface. The cyst fluid is slimy, yellow and clear. Mucinous tumours are the most heterogeneous group of epithelial tumours. Benign mucinous tumours have a single layer of tall, columnar cells and clear, mucin-producing cells, with a bland stroma. Microscopic images of mucinous cystadenoma can be viewed at:
http://pathweb.uchc.edu/eAtlas/GYN/1930.htm
http://pathweb.uchc.edu/eAtlas/GYN/1931.htm
http://pathweb.uchc.edu/eAtlas/GYN/1932.htm
http://pathweb.uchc.edu/eAtlas/GYN/1933.htm
http://pathweb.uchc.edu/eAtlas/GYN/1310.htm
http://pathweb.uchc.edu/eAtlas/GYN/1311.htm
http://pathweb.uchc.edu/eAtlas/GYN/1312.htm
http://pathweb.uchc.edu/eAtlas/GYN/1313.htm

Borderline mucinous tumours have complex patterns, two to three cell layer stratification, cytological atypia and mitotic figures. Carcinoma is diagnosed when the stratification exceeds three cell layers or if there is a significant stromal invasion . Mucinous cystadenocarcinomas contain a smooth capsule, are cystic, multiloculated and large tumours (can be 50 cm in diameter). The cystic fluid is clear, yellow and sticky. The gross appearance of a mucinous cystadenocarinoma can be viewed at:
http://pathweb.uchc.edu/eAtlas/GYN/530.htm
Their microscopic appearance resembles intestinal adenocarcinoma. Multiple glands comprising mucin-containing cells are present, demonstrating nuclear atypia, hyperchromasia with prominent nuclei and desmoplasia.

Borderline/LMP
Borderline/LMP tumours are characterised by epithelial multilayering of more than 4 cell layers, and less than 4 mitoses per 10 high-power field, mild nuclear atypia, increased nuclear/cytoplasmic ratio, slight-to-complex branching of epithelial papillae and pseudopapillae, epithelial budding and cell detachment into the lumen and no destructive stromal invasion. Borderline mucinous tumours have similar gross morphology to their benign counterparts, cysts with smooth surfaces. The epithelial layer is characterised by stratification of 2-3 layers, nuclear atypia, enlarged nuclei and mitotic figures. Histological examples of borderline mucinous tumours can be found at:
http://pathweb.uchc.edu/eAtlas/GYN/1934.htm
http://pathweb.uchc.edu/eAtlas/GYN/1935b.htm
Approximately 25% of borderline tumours show cell proliferations on the outer surface only. Of these, 90% develop peritoneal implants, which can be invasive or non-invasive. Both have a similar appearance, glandular or papillary proliferations with cell detachments, sometimes Psammoma bodies, cellular atypia and desmoplastic fibrosis. However, epithelial cells infiltrate the stroma in the invasive implants.

Brenner tumours
Brenner tumours are solid or cystic, yellow-tan colour and firm upon gross examination. Histological examination of Brenner tumour reveals epithelial nests or cysts of cells, resembling urothelium, separated by a cellular, fibrous stroma (composed of spindle-like cells). The nuclei are relatively uniform, lacking pleomorphism, hyperchromasia or macronucleoli, and mitoses are not identified. There is a moderate amount of eosinophilic cytoplasm. Examples of Brenner tumours can be viewed at:
http://pathweb.uchc.edu/eAtlas/GYN/1941b.htm
http://pathweb.uchc.edu/eAtlas/GYN/1942.htm
http://pathweb.uchc.edu/eAtlas/GYN/1943.htm
http://pathweb.uchc.edu/eAtlas/GYN/1299.htm
http://pathweb.uchc.edu/eAtlas/GYN/1300.htm
http://pathweb.uchc.edu/eAtlas/GYN/1301.htm
http://pathweb.uchc.edu/eAtlas/GYN/1302.htm

Clear Cell Carcinoma
Clear cell carcinoma accounts for 5-12% of ovarian adenocarcinomas. The gross appearance of clear cell carcinoma shows a smooth, lobulated external surface. These tumours are usually solid and firm, but can be cystic. They have a yellow-tan colour. Microscopic examination reveals cells arranged in tubules, nests or cysts, with clear, glycogen rich cytoplasm, sharply demarcated cell borders, and hyperchromatic, pleomorphic nuclei. Hobnail cells with nucleus standing on a stalk of cytoplasm are visible microscopically. Examples of clear cell carcinoma can be found using the following weblinks:
http://pathweb.uchc.edu/eAtlas/GYN/1937.htm
http://pathweb.uchc.edu/eAtlas/GYN/1938.htm
http://pathweb.uchc.edu/eAtlas/GYN/1939.htm
http://pathweb.uchc.edu/eAtlas/GYN/1940.htm
http://pathweb.uchc.edu/eAtlas/GYN/1049.htm
http://pathweb.uchc.edu/eAtlas/GYN/1050.htm
http://pathweb.uchc.edu/eAtlas/GYN/1051.htm
http://pathweb.uchc.edu/eAtlas/GYN/1052.htm
http://pathweb.uchc.edu/eAtlas/GYN/1053.htm

Endometrioid Carcinoma
Endometrioid carcinomas are solid, white, firm tumours with smooth or irregular surfaces. They may contain a cystic component and have areas of necrosis and haemorrhage. Histological analysis reveals glands, or glands mixed with solid areas, round-oval vesicular, clear nuclei with prominent nucleoli. Endometrioid carcinoma is indistinguishable from endometrial carcinoma. An example of endometrioid carcinoma can be found at:
http://pathweb.uchc.edu/eAtlas/GYN/437.htm

Mixed Mesodermal
The gross appearance of mixed mesodermal ovarian tumours are exemplified in the following weblinks:
http://pathweb.uchc.edu/eAtlas/GYN/134.htm
http://pathweb.uchc.edu/eAtlas/GYN/135.htm
http://pathweb.uchc.edu/eAtlas/GYN/136.htm
They are usually large variegated lesions with necrotic and haemorrhagic regions, and may have adhesions. Microscopic examination reveals serous or endometrioid epithelial component displaying squamous differentiation. Stroma may comprise spindle cell or soft tissue differentiation including cartilage, skeletal muscle or smooth muscle.

The primary treatment of epithelial ovarian cancer is aggressive surgical tumour debulking, including total abdominal hysterectomy and bilateral salpingo-oophorectomy. Most women with ovarian epithelial tumours, except some stage Ia patients, receive chemotherapy. Postoperative treatment usually involves taxane-platinum combination chemotherapy; cisplatin or carboplatin with paclitaxel is the usual first-line treatment. High response rates, about 80%, are obtained, however most patients relapse, and other combination therapies fail. The mean disease-free interval for patients with stage III and IV disease is about 18 months. Only 20-30% of stage III and IV cases are long-term survivors. Postoperative intraperitoneal chemotherapy or external radiation therapy are used to treat patients with minimal residual disease. Clear cell adenocarcinoma is usually resistant to platinum-based chemotherapy. A strong association exists between ovarian mucinous tumours and appendiceal mucinous neoplasms. Consequently the appendix should be removed in patients with mucinous neoplasms. Repeat laparotomy or peritoneal lavage is required to remove gelatinous material in the persistent recurrences of Pseudomyxoma peritonei . Brenner tumours are cured with surgical resection. Prophylactic oophorectomy at an early age has significantly reduced the risk of coelomic epithelial cancer. Oral contraceptives have a protective effect against ovarian cancer in carriers of BRCA1 or BRCA2 mutations.

Epithelial ovarian cancer initially spreads by direct seeding of the peritoneal surfaces, and is found on the underside of the diaphragm, paracolic gutters, bladder, cul-de-sac, surface of liver, mesentery and serosa of large and small bowel, omentum, uterus and paraaortic and pelvic lymph nodes. The tumour cells may remain confined to the surface of the coated abdominal viscera without penetrating it. They may also spread to the pleural cavity, lungs and groin lymph nodes. Mucinous tumours tend to form large masses, whereas serous tumours tend to distribute more diffusely, and are more often bilateral. Endometrioid and clear cell tumours usually invade locally and retroperitoneally. Sometimes mucus-secreting ovarian carcinomas fill the peritoneal cavity with a gelatinous neoplastic mass, referred to as pseudomyxoma peritonei .

The most important determinant for a favourable prognosis is diagnosis of ovarian carcinoma at an early stage. The prognosis of invasive epithelial ovarian cancer is poor, and relates to stage (see Tables 1 and 2), tumour grade and residual disease after surgery. The prognosis or early-stage ovarian invasive cancers and borderline tumours of all stages is significantly better. 5-year survival rates for patients with stage I disease are more than 90%, but less than 25% for advanced stage cancers. Patients with borderline tumours have an excellent prognosis. Age at diagnosis and the presence of invasive peritoneal implants are associated with a poorer prognosis in borderline tumours. The recurrence rate is 20%, with a mean time from diagnosis to relapse is 3.1 years in women with borderline serous tumours with non-invasive implants. However, borderline serous tumours with invasive implants have much higher recurrence rates of 32-45%, which occur much earlier (median time 24 months).

Clear cell adenocarcinoma has a worse prognosis that the other histological subtypes as it is resistant to platinum-based chemotherapy. Some data suggests familial ovarian cancers have prolonged survival in comparison to the nonfamilial cases. In one study, patients with familial ovarian cancer exhibited a 67% 5-year survival, in comparison with a 17% 5-year survival in the nonfamilial ovarian cancer cases.

STAGE	DEFINITION
Stage I	Growth limited to ovaries
Stage Ia	Growth limited to one ovary, no ascites, no tumour on external surface, capsule intact
Stage Ib	Growth limited to both ovaries, no ascites, no tumour on external surface, capsule intact
Stage Ic	Tumour either stage Ia or Ib, but with tumour on one or both ovaries, with capsule ruptured, with ascites present containing malignant cells, or with positive peritoneal washings
Stage II	Growth involving one or both ovaries with pelvic extension
Stage IIa	Extension and/or metastases to the uterus and/or tubes
Stage IIb	Extension to other pelvic tissues
Stage IIc	Tumour either stage IIa or IIb, with tumour on the surface of one or both ovaries, but with capsule(s) ruptured, with ascites present containing malignant cells, or with positive peritoneal washings
Stage III	Tumour involving one or both ovaries with peritoneal implants outside the pelvis and/or positive retroperitoneal or inguinal nodes. Superficial liver metastases equal stage III. Tumour limited to the true pelvis but with histologically proven malignant extension to small bowel or omentum
Stage IIIa	Tumour grossly limited to the true pelvis with negative nodes but with histologically confirmed microscopic seeding of abdominal peritoneal surfaces.
Stage IIIb	Tumour involving one or both ovaries with histologically confirmed implants of abdominal peritoneal surfaces, none exceeding 2cm in diameter. Nodes are negative.
Stage IIIc	Abdominal implants >2cm in diameter and/or positive retroperitoneal or inguinal nodes.
Stage IV	Growth involving one or both ovaries with distant metastases.

Table 1 Definitions of the FIGO classification scheme for Staging Primary Ovarian Carcinoma (taken from Jones, 2000)

STAGE No	PATIENTS TREATED	SURVIVAL3-yr (%)	SURVIVAL 5-yr (%)
I	5,559	87.5	82.1
II	3,364	72.1	64.5
III	2,530	47.0	38.1
IV	492	20.7	14.0
TOTAL	11,945	71.6	65.4

Table 2 Survival Rates of Ovarian Carcinoma according to Disease Stage (adapted table from Jones, 2000)

There is far more cytogenetic data available on ovarian carcinomas than for the other subtypes of ovarian tumours (germ cell tumours, sex-cord stromal tumours). At present, there are over 400 published karyotypes of ovarian carcinomas. The cytogenetic aberrations are non-random and complex. However, no pathognomonic rearrangements have been identified thus far. The karyotypes often show severe aneuploidy, with hypodiploid or near-triploid stemline chromosome numbers. The different subtypes of ovarian carcinoma show no marked cytogenetic differences, except seropapillary tumours more frequently display chromosome aberrations than the other subtypes. Complex chromosomal aberrations are present in invasive carcinomas, but not in benign or LMP tumours. The complexity of the karyotypes obtained from advanced tumours have obscured the initiating events in the pathogenesis of these tumours. Often normal karyotypes or simple cytogenetic aberrations were found in low-grade tumours. However, a correlation exists between karyotypic complexity and tumour grade. Simple chromosome changes (numerical changes only or a single structural rearrangement) were found in well-differentiated carcinomas, whereas complex karyotypes were found in poorly differentiated tumours. Patients with aberrant tumour karyotypes, particularly complex ones, were associated with short survival. Approximately 10-20% of ovarian carcinomas display homogeneously staining regions (hsr), although the loci they contain are unknown. However dmin are rarely observed. The most prevalent numerical changes are gains of chromosomes 1, 2, 3, 6, 7, 9, 12 and 20 losses of chromosomes 4, 8, 11, 13, 14, 15, 17 and 22. Structural rearrangements primarily involve deletions and unbalanced translocations involving 1p, 1q, 3p, 3q, 6q, 7p, 10q, 11p, 11q and 12q. In the review of 244 primary ovarian adenocarcinomas 201/244 tumours displayed clonal chromosomal abnormalities and hsr were identified in 20 cases. Using log-rank and proportional hazards regression analysis, it has been found that the presence of a chromosome breakpoint in any of 21 nonrandomly involved regions and breaks in 9 distinct regions (1p1, 1q2, 1p3, 3p1, 6p2, 11p1, 11q1, 12q2, and 13p1) were associated with reduced patient survival rate and time. Furthermore, only breakpoints within 1p1 and 3p1 retained independent, deleterious effects on survival and clinical variables associated with survival. In one review, 37% of serous LMP tumours displayed chromosomal anomalies, commonly trisomies of 7, 8 and 12. A much higher proportion, 91%, of invasive serous carcinomas of low-grade malignancy display clonal chromosomal abnormalities. A combination of karyotyping and microsatellite analyses identified a small deletion of 6q27, between D6S149 and D6S193, in both benign and advanced ovarian epithelial tumours, suggesting the presence of a putative tumour suppressor gene which is involved in the early events of the genesis of this tumour.

Invasive serous and undifferentiated ovarian carcinomas have complex cytogenetic rearrangements, including amplification of oncogenes. Complex chromosomal anomalies are rarely found in mucinous and endometrioid carcinomas (mainly in advanced stages), and are never found in serous LMP tumours. Epithelial ovarian tumours are characterised by gains at 3q, 8q and 20q, often with high level amplification. Thus the cytogenetic profiles of ovarian carcinomas differ from that of ovarian granulosa cell tumours, trisomy 14 and monsomy 22 are rarely found in ovarian carcinomas. Chromosome 1 and 3 abnormalities are the commonest aberrations found in ovarian metastatic tumours. Cytogenetic investigation of 11 individuals with bilateral ovarian carcinoma showed identical baseline karyotypes, suggesting both tumours arise from the same transformed cell, rather than the tumours arising independently.

46/52 ovarian carcinomas had complex karyotypes, often with a stemline chromosome number that was approaching near-triploid or hypodiploid. Chromosome losses of X, 22, 17, 13, 14 and 8, (lost in 15 imbalances

Their analyses hypothesised that the temporal order of imbalances were as follows: 1q-, 6q-, +7 and +8q occurred early, -4, -8, +1q, +12 and +20 were intermediate imbalances, and the remaining imbalances were late events. It has been concluded that karyotypic evolution in ovarian carcinomas followed at least 2 cytogenetic pathways. The first pathway involved chromosomal gains of +7/+8q/+12 and was associated with low-stage and low-grade tumours. The second pathway involved chromosomal losses of 6q- and 1q- was found in tumours of moderate stage and grade. The early stages of karyotypic evolution result from the step-wise acquisition of changes resulting in Phase I tumours. Chromosome instability resulted in the transition to Phase II tumours, possibly as a result of extensive telomere crisis and breakage fusion breakage cycles, which is linked to imbalances characteristic of the 6q-/1q- pathway. Consequently, low-grade and borderline tumours cannot progress unless they have mixed-pathway features. The 6q-/1q- pathway was associated with triploidization. The 6q-/1q- pathway is instrumental in the progression of ovarian carcinomas. The proposed pathway of karyotypic evolution in ovarian carcinomas is summarised in Figure 1.

A cohort of 114 ovarian neoplasms was analysed, including benign, borderline and invasive carcinomas by conventional and molecular cytogenetics. The chromosome abnormalities were categorised as follows:

Group 1: Abnormalities found in all subtypes. This included losses of chromosomes 6, 8, 10, 11, 15, 16, 17, 18, 19, 20, 21, 22 and X together with 6q24-qter deletions; and gains of chromosomes 1, 3, 5 and 12.

Group 2: Abnormalities present in malignant but not benign subtypes. This included losses of chromosomes 2, 7, 13 and 14, and gains of chromosome 4 and marker chromosomes.

Group 3: Abnormalities unique to invasive carcinomas such as loss of chromosome 4, 6q16-q24 deletions, gains of chromosomes 2, 7, 8, 9, 10, 16, 17, 18, 19, 20 and 21, and structural rearrangements of 3p, 3q, 13q and 21q.

The presence of cytogenetic aberrations common to all subtypes suggests these tumours develop by progression.

The main conclusions from cytogenetic investigations of ovarian epithelial tumours are as follows:

Nonrandom breakpoints in ovarian adenocarcinoma do not occur independently.

Breakpoints in 1p3 and 11p1 are early events, and associated with poor prognosis

Breakpoints in 1p1, 3p1 and 1q2 distinguish a class of ovarian tumours, and breakpoints at 1p1 and 3p1 are associated with a poor prognosis.

Interphase cytogenetics demonstrated a high frequency of gain of copy number of 20q13.2 (70%) and cyclin D1 (CCND1 at 11q13, 72%) which were associated with poor prognosis. Another study addressing amplification of 20q12-q13.2 using a series of FISH probes in 24 sporadic and 7 hereditary ovarian carcinomas found amplification of at least one of the regions in 54% of sporadic cases and all of the hereditary cases, and amplification of AIB1 (20q12), a steroid receptor coactivator correlated with poor survival.Online access to summaries of the recurrent DNA copy number amplifications and losses identified by CGH in ovarian epithelial neoplasms (and other tumour entities) can be viewed at http://www.helsinki.fi/cmg/cgh_data.html, and undergo regular updates. The criteria for recurrent losses and gains employed were as follows. For losses, 10% of the cases should have the loss, and there must be at least 3 aberrant cases. Highly frequent aberrations which do not meet the criteria of 10% of cases or 3 cases are indicated by parentheses-such as 1p21-p31. Recurrent amplicons were defined as at least 3 cases and >5% frequency display the amplicon. The recurrent losses and gains are summarised in Table 4.

Ovarian Neoplasm Subtype	Loss	Amplification	Percentage (number of cases)
Ovarian Cancer	(1p21-p31)		7 (5/72)
	1p34.1-p34.3		11 (5/44)
		1q	7 (5/71)
		2p15p22	4 (1/24)
		2q22-q24	5 (1/20)
		3cen-q23	4 (1/24)
		3q25-q27	13 (6/47)
	4q21-q32		16 (30/184)
	4q32-qter		16 (15/91)
	4q32-qter		16 (15/91)
	5q12-q23		16 (30/184)
		6p21	7 (3/144)
		6q13-qter	5 (1/20)
	6q16-qter		13 (23/184)
		7q36	7 (2/27)
	8p21-pter		17 (32/184)
		8q	4 (1/24)
		8q22-qter	18 (8/44)
	9p		10 (16/159)
		9p24	4 (1/27)
	9q		13 (17/136)
		10p15	4 (1/27)
	10q11-qter		17 (10/59)
		12p12	19 (9/47)
		12p12	9 (4/47)
	12q24-qter		10 (14/140)
	13q12-q21		18 (24/135)
	13q21-q32		12 (18/160)
	16p		13 (12/93)
	16q		23 (24/184)
	17p		20 (37/184)
	17q11.2-q32		23 (31/137)
		17q21-qter	6 (3/47)
		18p11.3	4 (1/27)
	18q12-qter		18 (33/184)
	19p		23 (10/44)
	19q		16 (11/69)
	21q		10 (12/116)
	22q		18 (17/93)
	Xp		19 (35/184)
	Xq		19 (9/47)
	Xq11.2-q21		13 (12/89)
	Xq21-qter		24 (16/68)
Primary epithelial ovarian cancer	4p15.2		18 (5/28)
	4q23-q24		18 (5/28)
	4q26-q27		18 (5/28)
	5q14		14 (4/28)
	5q15		14 (4/28)
	9p22-p24		11 (3/28)
	9q22-q31		18 (5/28)
	13q14		14 (4/28)
	13q31-q32		21 (6/28)
	14q24.3-q31		14 (4/28)
	15q21.1		25 (7/28)
	18q21		11 (3/28)
Ovarian Inherited (BRCA1 & BRCA2)		1q32-qter	10 (2/20)
		3q26.1	10 (2/20)
		5p	5 (1/20)
		6p22-p24	10 (2/20)
		6q21-q22	5 (1/20)
	6q25-qter		15 (3/20)
	8p23		40 (8/20)
		8q23-q24.1	30 (6/20)
		12p	5 (1/20)
		12q13-q21	5 (1/20)
	18p11.2-pter		15 (3/20)
	18q21-qter		20 (4/20)
		20p	5 (1/20)
	Xp		15 (3/20)
	Xq12-21		15 (3/20)
Ovarian cancer, sporadic & inherited	1p34-p36		25 (4/18)
	4q31.3-q35		19 (3/16)
	9q31-q34		40 (8/16)
	10q23-q26		25 (4/16)
	11q23-q25		19 (3/16)
	16p		19 (3/16)
	16q22-q24		38 (6/16)
	17p		19 (3/16)
	19		19 (3/16)
	22q12-q13		25 (4/16)
	Xp		19 (3/18)

Table 4 Recurrent amplifications and losses in epithelial ovarian tumours, including hereditary neoplasms (data taken from http://www.helsinki.fi/cmg/cgh_data.html)

Other studies have identified gain of chromosome 8 in 1/10 ovarian carcinomas.

A study of 31 primary ovarian carcinomas in Chinese women by CGH identified several non-random changes in copy number including gains of 3q (17 cases, 55%) with a minimum region of gain of 3q25-q26, 8q (16 cases, 52%), 19q (12 cases, 39%), Xq (11 cases, 35%), 1q (10 cases, 32%), 12p12-q13 (10 cases, 32%), 17q (10 cases, 32%) with a minimum region of gain at 17q21, and 20q (9 cases, 29%); together with losses of 16q (9 cases, 29%), 1p (7 cases, 23%), 18q (7 cases, 23%) and 22 (7 cases, 23%). High copy number amplifications were observed at 3q25-q26 (4 cases), 8q24 (3 cases) and 12p11.2-q12 (3 cases). The commonest imbalances detected by CGH of epithelial neoplasms were gain of 3q25-26, gain of 8q24, loss of 16q, and loss of 17pter-q21. 12p gains were seen in 8/44 cases, which has been reported previously in both ovarian and testicular germ cell tumours. Another study by Hauptmann et al., 2002 using CGH to analyse ovarian carcinomas identified frequent gains of 3q, 6p, 7, 8q and 20, together with losses of 4q, 6q, 12q, 13q and 16q, which have supported the available cytogenetic data.

CGH was used to screen a mucinous ovarian carcinoma and a Brenner tumour coexisting in different ovaries of the same female. Amplification of 12q14-q21 was identified in both tumours, in the presence of other copy number changes, 4 such changes in the Brenner tumour and 6 in the mucinous carcinoma.

Correlation of CGH data with Clinical data

In a large study of 106 primary ovarian carcinomas, the CGH findings were correlated with clinical parameters such as tumour grade of differentiation. 103 tumours displayed imbalances. Amplifications of 8q, 1q, 20q, 3q and 19p were frequent findings present in 69-53% of the tumours. Underrepresentations of 13q, 4q and 18q were also common, present in 54-50% of cases. Underrepresentation of 11p and 13q and overrepresentation of 8q and 7q correlated with undifferentiated ovarian carcinoma, whereas 12p underrepresentation and 18p overrepresentation were more commonly associated with well-differentiated and moderately differentiated tumours. These findings corroborate other CGH studies including.

A CGH study of a cohort of 12 ovarian clear cell carcinomas revealed similarities to the data of other subtypes of epithelial neoplasms, such as gains of 8q and 17q and losses of 19p. They also correlated their findings with disease status (i.e. disease free, recurrent disease, or death from disease). DNA copy number changes present in over 20% of cases included overrepresentation of 8q11-q13, 8q21-q22, 8q23, 8q24-qter, 17q25-qter, 20q13-qter and 21q22; and underrepresentation of 19p. Overrepresentation of 8q11-q13, 8q21-q22, 8q23, 8q24-qter was more common in disease-free patients than in those with recurrent disease or who had died. Conversely, overrepresentation of 17q25-qter, 20q13-qter was more frequent in patients with recurrent disease or non-survivors, than in disease-free patients. This data suggests ovarian clear cell carcinoma develop along 2 cytogenetic pathways.

In a study correlating CGH genomic imbalances with clinical endpoints in 60 ovarian carcinomas, the following associations were found:

Loss of chromosome 4 with high-grade tumours

Gains of 3q26-qter, 8q24-qter and 20q13-qter and low-grade and low-stage tumours

Deletion of 16q24 and >7 independent genomic imbalances and reduced survival times

Tumour grade correlated better with genomic progression than clinical stage.

CGH findings of Sporadic and Hereditary Ovarian Carcinoma

CGH profiles were compared from sporadic and hereditary (3 BRCA1 and 1 BRCA2 mutation carriers) ovarian cancers. The commonest imbalance included amplification of 8q22.1-qter (66.6%), 1q22-32.1 (41.1%), 3q (75%) and 10p (33.2 %), and deletion of 9q (41.6%) and 16q21-q24 (33.3%). Deletions of 9q were found in all 3 BRCA1 carriers and 2/8 sporadic tumours, and deletions of 19 were found in 2/3 BRCA1 carriers and none of the sporadic cases. These findings suggest preferential somatic losses of chromosome 9 and 19 in BRCA1 mutation carriers. In contrast, another study identified extensive similarity by CGH between sporadic and hereditary ovarian carcinomas, except for 2q24-q32. CGH analysis of a further 36 hereditary tumours found the majority of imbalances to be similar to that of sporadic tumours (Gains: 8q23-qter, 3q26.3-qter, 11q22, 2q31-32; losses: 8p21-pter, 16q22-qter, 22q13, 12q24, 15q11-15, 17p12-13, Xp21-22, 20q13, 15q24-25, 18q21). However some imbalances were identified that were specific to hereditary tumours, including deletions of 15q11-15, 15q24-25, 8p21-pter, 22q13 and 12q24, and gains of 11q22, 13q22 and 17q23-35. Deletions of 15q11-15 and 15q24-25 were found in 16/36 and 12/36 cases respectively which implicated hRAD51 and other tumour suppressor genes in these loci in the genesis of hereditary ovarian cancer.

INHERITED PREDISPOSITION

As mentioned in the Aetiology section, genetic factors are the most important risk factor for ovarian epithelial carcinoma. Having 1 or 2 first-degree relatives with ovarian cancer increases the lifetime risk to 3-5% and 39% respectively. Three hereditary syndromes in which familial aggregation of ovarian carcinoma occurs have been described:

Hereditary breast-ovarian cancer syndrome: clusters of breast and ovarian cancer among first- and second-degree relatives

Hereditary nonpolyposis colorectal cancer syndrome, HNPCC, or Lynch Cancer Family syndrome II): ovarian cancer develops in a proband whose close relatives have had cancers of the colon, breast, ovary, endometrium, urinary tract, uterine and other malignancies.

Site-specific ovarian cancer syndrome of unknown origin in which two or more first-degree relatives have ovarian cancer

All 3 patterns of familial ovarian cancer are consistent with autosomal-dominant transmission of one or more genes responsible for the development of >1 cancers, with incomplete penetrance and variable expression. The age of diagnosis of hereditary epithelial ovarian cancer is approximately 10 years earlier than its sporadic counterpart.

Breast-Ovarian Syndrome
Of the about 10% of ovarian epithelial cancers thought to have a hereditary component, 90% are associated with breast-ovarian syndrome. This syndrome is associated with two genes, BRCA1 at 17q21, and BRCA2 at 13q12.3 (see below), which are involved in DNA repair and transcription regulation. Mutations are distributed throughout the entire coding regions of BRCA1 and BRCA2, and most result in truncation of the protein. Germline mutations in BRCA1 account for about 80% of hereditary breast-ovarian cancers. Germline mutations of BRCA2 account for about 10-35% of familial ovarian cancers. BRCA1 is associated with a 26% cumulative risk for ovarian cancer for most mutation carriers, and a much higher risk, 85%, in a small subset. Women with a germline BRCA1 mutation have an about 40% risk of developing ovarian cancer by 70 years of age. BRCA2 increases susceptibility to a smaller degree. The lifetime risk for developing ovarian cancer in BRCA2 mutation carriers is 27%. However the risks of developing ovarian cancer associated with germline mutations of BRCA1 and BRCA2 vary according to the population studied. A study by revealed a lifetime risk of ovarian cancer of 40-60% for BRCA1 mutation carriers, whereas another one found a 25-30% risk for BRCA1 mutation carriers. Approximately 1/4000 in the general population has a mutation of BRCA1, although some populations have much higher incidences, for example the Ashkenazi Jews. Patients with breast cancer who had BRCA1 or BRCA2 mutations had a tenfold increased risk of developing ovarian cancer.

The variable penetrance of BRCA1 suggests that other genetic and non-genetic factors contribute to the pathogenesis in these individuals. One such modifier is a VNTR polymorphism, 1-kb downstream of HRAS. BRCA1 carriers with rare alleles of the VNTR had an 2.11 increased risk of developing ovarian cancer compared with the common alleles (p=0.015).

about 50% of familial ovarian cancers are not associated with germline BRCA1 or BRCA2 mutations. Linkage and LOH analysis has suggested a susceptibility gene for familial ovarian cancer at 3p22-p25. LOH of 3p33-p25 is higher (52%) in non-BRCA1/BRCA2 familial ovarian cancers than in the BRCA1 (29.7%) group.

HNPCC
Mutations of the mismatch repair genes (MMR) including MLH1, MSH2 and MSH6 are present in HNPCC syndrome (Lynch 2 Syndrome). This represents the second most common type of ovarian cancer with a hereditary component.

Site-Specific Ovarian Cancer Syndrome
The least common of the familial ovarian cancers is the site-specific ovarian cancer syndrome, in which ovarian cancer is the dominant cancer. It has been suggested that site-specific ovarian cancer is a variant of breast-ovarian syndrome attributable to mutation in either BRCA1 or BRCA2, and not a distinct clinical entity.

Early onset ovarian carcinoma (