OVARIAN CANCER

•	Epidemiology.
•	Pathology. 
•	Clinical presentation and investigations.
•	Management.

Epidemiology

1.	Second most common genital tract tumor. 

2.	Incidence in Singapore: 6 per 100,000 per year.

3.	Occurs most commonly between the ages of 40 – 69 with peak incidence at 55 years.

4.	Highest mortality rate among genital tract tumors as most are found in advanced Stage III with widespread intraperitoneal disease.

5.	Epidemiological factors:

a.	Nulliparity.

b.	Early menarche.

c.	Late age of menopause.

d.	Age.

e.	Family history: usually serous adenocarcinomas.

f.	Family history of breast or colorectal cancer: defective BRCA1 and BRCA2.

Pathology

1.	Classification:

Cell of origin	Derived tumors	Age 	Frequency	
Surface epithelium	Serous: 60%.
Mucinous: 15 –20%.
Endometrial: 15 – 20%.
Clear cell: 5%.
Undifferentiated: 10 – 15%	> 30	60 – 70%	
Specialized mesenchyme + stromal cells	Granulosa cell.
Theca cell tumor.
Sertoli-Leydig cell.	Any age.	5 – 10%	
Germ cells	Teratoma.
Dysgerminoma.
Choriocarcinoma.	15 – 25.	15 – 20%	
Non-specialized mesenchyme	Sarcoma.
Fibroma.
Myoma.
Fibrosarcoma.
Lymphoma.	> 40.	< 1%.	

2.	Epithelial tumors

a.	Serous carcinoma:

i.	most have both solid and cystic elements but some may be mainly cystic.

ii.	they often affect both ovaries.

iii.	well-differentiated tumors have a papillary pattern with stromal invasion.

iv.	Psammoma bodies are often present.

b.	Mucinous carcinoma:

i.	they are usually multi-locular, thin-walled cysts with smooth external surface containing mucinous fluid.

ii.	amongst the largest tumors of ovary: common diameter of 25cm.

c.	Endometroid carcinoma: most are cystic, often unilocular and contain turbid brown fluid. 

d.	Clear cell carcinoma: 

i.	least common.

ii.	associated with ovarian endometriosis.

3.	Granulosa and theca cell tumors:

a.	They often produce steroid hormones, e.g. estrogens, which can cause post-menopausal bleeding in older women and sexual precocity in prepubertal girls.

b.	Granulosa cell tumors usually secrete inhibin: this can be used to monitor the effects of treatment.

c.	Theca cell tumors are usually benign. 

d.	Granulosa cell tumors occur at all ages, but are found predominantly in postmenopausal women.

4.	Germ cell tumors:

a.	Dysgerminomas:

i.	nearly all occur in young women less than 30 years old.

ii.	they spread mainly by lymphatics.

iii.	all cases need a CXR and CT scan.

iv.	serum AFP and HCG must be assayed to exclude the presence of elements of choriocarcinoma, endodermal sinus tumor or teratoma.

v.	they are solid tumors that have a smooth, nodular, bosselated external surface and are soft or rubbery in consistency.

b.	Yolk sac tumors:

i.	may present as an acute abdomen due to rupture of tumor following necrosis and haemorrhage.

ii.	the tumor is usually well-encapsulated and solid. 

iii.	it often secretes AFP, which can be used to monitor treatment.

c.	Teratomas: most are benign, the most common being the cystic teratoma or dermoid cyst. 

5.	Natural history:

a.	Some two-thirds of patients with ovarian cancer present with disease that has spread beyond the pelvis.

b.	This is probably due to the insidious nature of the signs and symptoms of carcinoma of the ovary or due to a rapidly growing tumor.

c.	Due to the non-specific nature of most of these symptoms, a diagnosis of ovarian cancer is seldom considered until the disease is in an advanced stage. 

6.	Metastatic spread:

a.	The pelvic peritoneum and other pelvic organs are involved by direct spread.

b.	The peritoneal fluid, flowing to lymphatic channels on the undersurface of the diaphragm, carries malignant cells to the:

i.	omentum.

ii.	peritoneal surfaces of the small and large bowel.

iii.	liver.

iv.	peritoneal surface throughout the abdominal cavity.

v.	surface of the diaphragm.

c.	Lymphatic spread commonly involves the pelvic and the para-aortic nodes. 

d.	Haematogenous spread usually occurs late in the course of the disease and common sites are liver, lung, bone and brain.

7.	80% of all ovarian tumors are primary and 20% are of secondary metastases from elsewhere, the common primary sites being:

a.	Stomach (Krukenburg tumor).

b.	Large bowel.

c.	Liver.

d.	Gallbladder.

e.	Pancreas.

f.	Breast.

g.	Lungs.

Clinical presentation and investigations

1.	Classical presentation: ascites + ovarian mass + postmenopausal female = ovarian cancer unless proven otherwise.

2.	Asymptomatic:

a.	Early symptoms of ovarian cancer are rarely characteristic except for the results of excessive hormone production.

b.	Late presentation is usual.

3.	Abdominal pain or discomfort is the commonest presenting complaint and distension.

4.	A hard abdominal mass arising from the pelvis is highly suggestive, especially in the presence of ascites.

5.	Pressure symptoms:

a.	Urinary frequency.

b.	Indigestion.

c.	Sensation of pelvic heaviness.

6.	Hormonal effects:

a.	Menstrual irregularities.

b.	Virilization due to androgen secreting tumor: breast atrophy, atrophy of genitalia, change in voice, alopecia, hirutism.

7.	Others:

a.	Dyspareunia and dysmenorrhoea in 10 – 20% of patients.

b.	Thromboembolism.

c.	Complication due to torsion, rupture, infection, haemorrhage and impaction.

8.	Signs:

a.	Small tumors are usually lateral and posterior to the uterus and identified to be separate from uterus by:

i.	mobility: does not move when cervix is moved.

ii.	separation: groove between tumor and cervix.

b.	Large tumor or tumors adherent to uterus:

i.	arises out of pelvis, usually in the midline.

ii.	can occupy the entire abdominal cavity.

iii.	on percussion, the centre is dull while the flanks are resonant. 

9.	Differentials:

a.	Distended bladder.

b.	Obesity.

c.	Ascites.

d.	Pelvic mass:

i.	uterine fibroid.

ii.	endometrial carcinoma.

iii.	endometriosis.

iv.	tubo-ovarian abscess.

v.	ectopic pregnancy.

e.	Abdominal masses:

i.	colon cancer.

ii.	diverticulitis.

iii.	appendiceal abscess.

iv.	enlarged lymph nodes.

v.	kidney masses: hydronephrosis.

10.	Investigations:

a.	Baseline:

i.	FBC.

ii.	U&E.

iii.	Urine FEME.

iv.	CXR.

v.	ECG.

vi.	barium enema / colonoscopy: differentiate between an ovarian and a colonic tumor and to assess bowel involvement.

vii.	IVP.

b.	Tumor markers:

i.	Ca125 is useful for monitoring women receiving chemotherapy to assess response. 

ii.	a persistent rise in Ca125 may precede clinical evidence of recurrent disease. 

c.	Ultrasound:

i.	confirm presence of a pelvic mass and detect ascites before it is clinically apparent.

ii.	small cyst < 5 – 8cm + no evidence of malignancy: follow-up patient with conservative management.

iii.	large cyst > 8cm: presumptive evidence of malignancy.

d.	Exploratory laparotomy: for staging and treatment.

11.	Indications for exploratory laparotomy:

a.	Two commonest clinical indications:

i.	enlarged asymptomatic ovarian masses.

ii.	pelvi-abdominal mass accompanied by abdominal pain, distension or ascites. 

b.	Any adnexal mass > 5cm in patients < 40 years.

c.	Any ovarian mass > 10cm.

d.	Any palpable adnexal or ovarian masses.

e.	Bilateral ovarian masses accompanied by nodularity, induration and nodules in the rectovaginal pocuh. 

12.	Procedure for staging laparotomy:

a.	Adequate midline incision.

b.	Peritoneal fluid: free fluid aspirated or peritoneal washing obtained and sent for cytology.

c.	Examine the ovarian masses for signs of malignancy: size, capsule integrity, haemorrhage, solid areas.

d.	Examine the other ovary.

e.	Examine the fallopian tubes.

f.	Evaluate the entire abdomen and its organs to rule out primary lesions from other sites.

g.	Inspect all peritoneal surfaces and biopsy any suspicious nodules for histology: omentum, subdiaphragm and bowel serosa.

h.	Palpate the pelvic and para-aortic nodes and excise enlarged nodes for biopsy.

i.	Perform a Pap smear.

j.	Staging of ovarian cancer.

Management

1.	Staging and treatment:

Stage	Treatment	5-year 
survival %	
I: confined to ovary.
IA: unilateral, capsule intact.

IB: bilateral, tumor excrescences.	
Cystectomy or unilateral oophorectomy with biopsy of other ovary.

THBSO and omentectomy with or without chemotherapy or intraperitoneal irradiation.	
60 – 90

60 – 90	
II: extension within pelvis.	THBSO with pelvic beam irradiation.	40	
III: extension to abdominal peritoneum.	THBSO and chemotherapy after surgery.	10	
IV: extension outside abdomen.	THBSO and chemotherapy.	1	

2.	Surgery:

a.	The resection of all visible tumor requires a:

i.	total abdominal hysterectomy.

ii.	bilateral salpingo-oophorectomy.

iii.	infracolic omentectomy.

b.	Total resection is possible in majority of stage I and II disease, but not likely in more advanced cases due to diffuse spread of microscopic deposits throughout the peritoneal cavity. 

c.	Conservative primary surgery:

i.	young, nulliparous women with Stage IA disease.

ii.	no evidence of synchronous endometrial cancer.

iii.	unilateral salpingo-oophorectomy. 

d.	Interval debulking surgery:

i.	women with bulky disease after primary surgery.

ii.	must respond after 2 – 4 courses of chemotherapy.

iii.	chemotherapy resume after surgery. 

3.	Chemotherapy:

a.	It is given to both to prolong clinical remission and survival and for palliation in advanced and recurrent disease.

b.	It is commenced as soon as possible after surgery and is usually given for 5 or 6 cycles at 3-to-4 weekly intervals for 6 – 9 months.

c.	After 6 – 9 months, do a laparotomy: if tumor persists, do debulking and combination chemotherapy.

d.	Single chemotherapy is used for stages I and II; combination chemotherapy comprising of carboplatin, cisplatin and taxol for stages III and IV.