Adekunle A.O. 1

MALIGNANT TUMOURS OF THE OVARY

Professor Adeyemi O. Adekunle

Department of Obstetrics and Gynaecology

College of Medicine, University of Ibadan

University College Hospital,

Ibadan, Nigeria.

Adekunle A.O. 2

MALIGNANT TUMOURS OF THE OVARY

ENABLING OBJECTIVES

Mention the incidence of malignant ovarian tumours, and aetiology including genetic factors;

Classify ovarian tumours;

Describe the essential features of each type;

Discuss the clinical staging of ovarian tumours;

Discuss the diagnosis and management of malignant ovarian tumours.

Adekunle A.O. 3

Malignant Tumours of the Ovary The incidence of carcinoma of the ovary is

increasing steadily.

It is a leading cause of cancer deaths in women being surpassed only by cancer of the breast, cervix, lungs, colon and rectum.

Ca ovary is unusual before the age of 20, but it increases steadily thereafter.

The average age at which it is diagnosed is about 50.

It occurs somewhat more often in whites than un blacks.

Adekunle A.O. 4

Malignant Tumours of the Ovary The lesions are far advanced and impossible to

cure when the patient first seeks treatment.

She may have had a mild GIT disturbance, which she attributes to “indigestion,” and perhaps a slight increase in girth but no other symptom.

She often presents only after she feels a mass in the abdomen or has an attack of pain.

Less than 25% of women with ovarian cancer are alive after 5 years.

Adekunle A.O. 5

Aetiological Factors Epithelial tumours are most frequently

associated with: Nulliparity Early menarche Late age at menopause A long estimated number of years of ovulation

Oral contraceptive use reduces the risk four-fold.

Even without oral contraceptives, increasing age at first birth reduces the risk of ovarian cancer.

This and other anomalies cast doubt upon the “incessant ovulation” theory.

Adekunle A.O. 6

Aetiological Factors - Genetic There is family history in between 5 and 10% of

women with epithelial ovarian cancers – usually serous adenocarcinomas.

A woman with one affected relative has a lifetime risk of 2.5%, which is twice the risk in the general population.

With two affected relatives, the lifetime risk increases to 30 – 40 per cent.

Most of these families also have cases of breast or colorectal cancer in the family.

The defective gene in the breast/ovary families is most commonly the tumour suppressor gene BRCA1 (81%).

BRCA2 is defective in about 14 per cent.

Adekunle A.O. 7

Classification of Ovarian Tumours

Ovarian tumours may be: Solid or Cystic

They may be: Benign Malignant, and in addition, Borderline – i.e., those while having some

features of malignancy, lack any evidence of stromal invasion.

Adekunle A.O. 8

Classification of Ovarian Tumours

Primary ovarian tumours are divided into:

Epithelial type Implying an origin from surface epithelium

Sex gonadal type Also known as sex cord stromal type, or

Sex cord mesenchymal type Originating from sex cord mesencymal

elements.

Germ cell type

Metastatic tumours

Adekunle A.O. 9

Simplified Histological Classification of Ovarian Tumours

A. Common Epithelial Tumours (Benign, boderline or malignant)

Serous tumour Mucinous tumour Endometroid

tumour Clear cell

(mesonephroid) tumour

Brenner tumour Undifferentiated

carcinomas

B. Sex Cord Stromal Tumours

Granulosa stroma cell tumour

Androblastoma: Sertoli-Leydig cell tumour

Gynandroblastoma

Adekunle A.O. 10

Histological Classification of Ovarian Tumours (Contd.)

C. Germ Cell Tumours

Dysgeminoma Endodermal sinus

tumour (yolk sac tumour)

Embryonal cell tumour

Choriocarcinoma Teratoma Mixed tumours

D. Metastatic Tmours

Adekunle A.O. 11

Pathology of Epithelial Tumours

Well-differentiated epithelial ca. tend to be more often associated with early stage disease, but the degree of differentiation does not correlate with survival (except in most advanced stages).

Diploid tumours tend to be associated with earlier stage disease and a better prognosis.

Cell type is not itself prognostically significant;

There is no difference in survival between different epithelial types although mucinous and endometrial lesions are likely to be associated with earlier stage and lower grade than serous cystadenocarcinoma.

Adekunle A.O. 12

Serous Carcinoma Most have both solid and cystic elements but

some may be mainly cystic;

They often affect both ovaries;

Well-differentiated tumours have a papillary pattern with stromal invasion.

Psammoma bodies (calcospherules) are often present.

Occassionally, glandular structures may be present to enable diagnosis of adenocarcinoma to be made.

Adekunle A.O. 13

Mucinous Carcinoma

Malignant mucinous tumours account for 10% of the malignant tumours of the ovary.

Usually multioccular, thin-walled cysts with a smooth external surface containing mucinous fluid.

They are amongst the largest tumours of the ovary and may reach enormous dimensions;

A cyst diameter of 25 cm is quite common.

Adekunle A.O. 14

Endometroid Carcinoma These are ovarian tumours that resemble

endometrial carcinomas.

Most are cystic, often unilocular, and contain turbid brown fluid;

Five to 10% are seen in continuity with recognizable endometriosis;

15% are associated with endometrial ca. in the body of the uterus. In most cases, these are 2 separate primary tumours.

Ovarian adenoacanthoma account for 50% of some series of endometroid tumours.

Adekunle A.O. 15

Clear Cell carcinoma (Mesonephroid) Least common of the malignant epithelial

tumours of the ovary; Accounts for 5 – 10% of ovarian ca. The appearance from which the tumour derives

its name is the clear cell pattern; However, some areas show a tubulo-cystic

pattern with the characteristic ‘hob-nail’ appearance of the lining epithelium.

There is very strong association between clear cell tumours of the ovary and ovarian endometriosis and they often co-exist.

Therefore, it has been suggested that clear cell tumour may be a variant of endometrial tumour.

Adekunle A.O. 16

Borderline Epithelial Tumours Ten percent of all epithelial tumours of the ovary

are of borderline malignancy;

These show: Varying degrees of nuclear atypia; An increase in mitotic activity; Multilayering of neoplastic cells; Formation of cellular buds, but no invasion of

the stroma

Most borderline tumours remain confined to the ovaries and this may account for their much better prognosis.

Adekunle A.O. 17

Metastatic Spread – Direct and Lymphatic Spread

The peritoneum and other pelvic organs become involved by direct spread;

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

The omentum and the liver, Peritoneal surface of small and large bowels, The parietal peritoneal surface throughout the

abdominal cavity and on the surface of the diaphragm.

Metastasis on the undersurface of the diaphragm may be found in what otherwise seems to be stage I – II disease.

Adekunle A.O. 18

Metastatic Spread – Lymphatic and Haematogenic Spread (Contd.)

Lymphatic spread commonly involves the:

Pelvic and para-aortic nodes;

May also occur to the nodes in the neck or inguinal region.

HAEMATOGENIC SPREAD

Usually occurs late in the course of the disease.

The main areas involved are: Liver and lungs Bone and brain (sometimes)

Adekunle A.O. 19

CLINICAL STAGING – FIGO staging for primary ovarian carcinoma

STAGE I Growth limited to the ovaries Stage Ia:

Growth limited to one ovary; No ascites; No tumours on external

surfaces Capsule intact

Stage Ib Growth limited to both

ovaries No ascites; No tumours on external

surfaces; Capsule intact

Stage Ic Tumour either

Stage 1a or 1b but tumour on the surface of one or both ovaries; or with ascites present containing malignant cells.

STAGE 2 Growth involving

one or both ovaries with pelvic extension

Adekunle A.O. 20

CLINICAL STAGING – FIGO staging for primary ovarian carcinoma (Contd.)

STAGE III

Growth involving one or both ovaries with peritoneal implants in the pelvis or positive retroperitoneal or inguinal nodes.

Superficial liver metastases equals Stage III

STAGE IV

Growth involving one or both ovaries with distant metastases

If pleural effusion is present, there must be positive cytology to allot a case to Stage IV;

Parenchymal liver metastasis equals Stage IV.

Adekunle A.O. 21

CLINICAL STAGING – FIGO staging for primary ovarian carcinoma (Contd.)

Note that:

Clinical staging is an important prognostic indicator;

Peritoneal deposits on the surface of the liver do not make the patient Stage IV, the parenchyma must be involved;

Similarly, the presence of a pleural effusion is insufficient to put the patient in Stage IV status unless malignant cells are found on cytological examination of the pleural fluid.

Adekunle A.O. 22

DIAGNOSIS Abdominal pain or

discomfort – commonest presenting complaint

Distension or Feeling a lump – next most frequent

Other complaints: Indigestion Urinary frequency Weight loss Abnormal menses or

postmenopausal bleeding - rarely

ON EXAMINATION

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

A fixed, hard, irregular pelvic mass is usually felt best by combined vaginal and rectal examination.

Examine the neck and groin for enlarged nodes.

Adekunle A.O. 23

DIAGNOSIS (Contd.) HAEMATOLOGICAL INVESTIGATIONS Full Blood Count Urea and electrolytes Liver function tests

RADIOLOGICAL A chest x-ray is essential Sometimes, it is advisable to carry out a barium

enema or colonoscopy to Differentiate between an ovarian and colonic

tumour and To assess bowel involvement from the ovarian

tumour itself An IVP (Intravenous urogram) is occasionally

useful.

Adekunle A.O. 24

DIAGNOSIS (Contd.)ULTRASONOGRAPHY

May help to confirm the presence of a pelvic mass and detect ascites before it is clinically apparent.

In conjunction with Ca125 estimation- may be used to calculate a “risk of malignancy score”

LAPAROTOMY Most women are diagnosed at laparotomy –

undertaken on the basis that there is a large mass that needs to be removed regardless of its nature.

Adekunle A.O. 25

MARKERS FOR EPITHELIAL TUMOURS Ca125 is the only marker in common clinical

use but can also be raised in benign conditions such as endometriosis.

It is useful for monitoring women receiving chemotherapy to assess response: A persistent rise in Ca125 may precede

clinical evidence of recurrent diseases, in some cases, by several months.

However, the values can be normal even in the presence of small tumour deposits.

Adekunle A.O. 26

SCREENING FOR OVARIAN CANCERS

Most patients present with advanced disease because Ca. ovary tend to be asymptomatic in the early stages.

As yet, no tumour marker has become available which is truly specific and suitable for early detection of epithelial tumours.

Ultrasound is not suitable as a primary screening tool because it is too expensive and has a high false-positive rate

The most promising approach is a combination of Ca125 with ultrasound for those women with persistent raised values.

At this moment, screening the general population is neither useful or safe.

Adekunle A.O. 27

TREATMENT - SURGERY Surgery is the mainstay of both diagnosis and

the treatment of ovarian cancer. A vertical incision is required for an adequate

exploration of the upper abdomen. The therapeutic objective of surgery is the

removal of all tumours. While this is achieved in the majority of Stage I

and Stage II cases, it is usually impossible in the more advanced diseases.

A sample of ascitic fluid or peritoneal washings with normal saline should be taken for cytology.

The pelvis and abdomen are explored carefully to identify metastatic disease.

Adekunle A.O. 28

SURGERY FOR EPITHELIAL OVARIAN CANCER (1)

PRIMARY SURGERY

To determine diagnosis and remove tumour.

Requires: total hysterectomy, bilateral salpingo-oophorectmy, and infracolic omentectomy

Adekunle A.O. 29

SURGERY FOR EPITHELIAL OVARIAN CANCER (2)

CONSERVATIVE SURGERY(In young, nulliparous women with Stage Ia disease and no ascites)

Unilateral salpingo-oophorectomy may be justifiable after: Careful exploration to exclude metastatic

disease and Curettage of the uterine cavity to exclude a

synchronous endometrial tumour. If the tumour is subsequently found to be

poorly differentiated or if the washings are positive, a second operation to clear the pelvis will be necessary.

Adekunle A.O. 30

SURGERY FOR EPITHELIAL OVARIAN CANCER (3)

INTERVAL DEBULKING SURGERY

When bulky disease remains after initial surgery, a second laparotomy may be performed on those who respond after 2 to 4 courses of chemotherapy.

The chemotherapy is then resumed as soon as possible after the second operation.

This is called “Interval debulking.”

May improve the survival at 3 years from 10 to 20 per cent.

Adekunle A.O. 31

SURGERY FOR EPITHELIAL OVARIAN CANCER (4)

SECOND-LOOK SURGERY Defined as a planned laparotomy at the end of

chemotherapy. The objectives are:

To determine the response to previous therapy in order to document accurately its efficacy and to plan subsequent management, and

To excise any residual disease. Evidence suggests that neither the surgical

resection nor the opportunity to change treatment has any effect on patient’s survival.

Therefore, second-look procedures have no place outside clinical trials at the present time.

Adekunle A.O. 32

SURGERY FOR EPITHELIAL OVARIAN CANCER (5)

BODERLINE TUMOURS

Usually presents as Stage Ia tumour confined to one ovary.

It is often not recognized as malignant.

Ovarian cystectomy or oophorectomy is adequate in young women.

Hysterectomy and bilateral salpingo-oophorectomy in older women who have no wish to have children.

Adekunle A.O. 33

ADJUVANT THERAPY FOR EPITHELIAL OVARIAN CANCER

Women with Stage Ia or Ib disease and well- or moderately differentiated tumours may not require further treatment.

The benefit of adjuvant therapy for women with Stage Ic remains uncertain, but many oncologists will recommend chemotherapy;

All other patients with invasive ovarian carcinoma require adjuvant therapy.

There is no evidence that adjuvant therapy affects the outcome in women with borderline tumours.

Adekunle A.O. 34

RADIOTHERAPY

Radiotherapy is now almost never used in the routine management of ovarian cancer.

A potential exception is radio-immunoassay in which radioactive Ytrium is linked to a monoclonal antibody which recognizes an antigen found on most ovarian cancers.

Given intraperitoneally.

Remains an experimental treatment.

Adekunle A.O. 35

CHEMOTHERAPY For Stages II to IV, and possibly Stage Ic.

Chemotherapy is given both to: Prolong clinical remission and survival, and For palliation in advanced and recurrent disease.

It is commenced as soon as possible after surgery and is usually given for five or six cycles at three- to four-weekly intervals.

The platinum drugs, cisplatin and its analogue, carboplatin, are considered to be the most effective drugs in general use for Rx of ovarian ca.

There are the most widely used cytotoxic drugs either alone or in combination.

Adekunle A.O. 36

CHEMOTHERAPY - Cisplatin Cisplatin and Carboplatin are heavy metal

compounds that cause cross-linkage of DNA strands in a similar fashion to alkylating agents.

Cisplatin is a very toxic drug.

Severe nausea and vomiting, sometimes lasting several days, were serious problems before the advent of 5HT antagonists (ganestron and ondasetron).

Permanent renal damage will occur unless cisplatin is given with adequate hydration with intravenous fluids.

Peripheral neuropathy and hearing loss are reported with increasing cumulative doses.

Adekunle A.O. 37

CHEMOTHERAPY - Carboplatin

As effective as cisplatin in the treatment of ovarian cancer;

Causes less nausea and vomiting;

Has no significant renal toxicity, therefore no need to give carbplatin with intravenous hydration.

Neurotoxicity is rare and hearing loss is subclinical.

The dose is calculated in relation to the glomerular filteration rate.

Adekunle A.O. 38

CHEMOTHERAPY – Paclitaxel (Taxol) Now considered to be part of the standard

treatment for ovarian ca. given in combination with cisplatin or carboplatin.

Paclitaxel is derived from the bark of the Pacific yew tree (taxus brevifolia) and has a mechanism of action which is unique among cytotoxic drugs.

Causes sensory neuropathy and neutropenia in high doses.

Loss of body hair is total, irrespective of dose schedule.

Nausea and vomiting is mild.

Adekunle A.O. 39

TREATMENT RESULTS – Borderline Epithelial Tumours

Those confined to the ovaries have a good long-term prognosis with very few women dying from their disease.

Even with extra-ovarian spread, the 15-year survival for serous borderline epithelial tumours is around 90 per cent.

For Stage III mucinous tumours, the 15-year survival rate is only 44 per cent.

Adekunle A.O. 40

TREATMENT RESULTS – Invasive Epithelial Ovarian Cancer

Survival for epithelial ovarian cancer is dependent on:

Stage Size of the tumour at the end of initial

surgery, and Grade of tumour

The 5-year survival rate ranges from 60 – 70 per cent for women with Stage I disease to 10% for Stages III – IV.

Adekunle A.O. 41

NON-EPITHELIAL TUMOURS Non-epithelial tumours constitute approximately

10 per cent of all ovarian cancers.

Because of their rarity and their sensitivity to intensive chemotherapy, it is especially appro-priate to refer these patients for specialist care.

They include: Sex cord stromal tumours

Granulosa and theca cell tumours Sertoli-Leydig cell tumours

Germ cell tumours Disgerminomas Yolk sac (endodermal sinus) tumours Teratomas

Adekunle A.O. 42

SEX CORD STROMAL TUMOURS – Granulosa and Theca Cell Tumours

The most common sex cord tumours are the granulosa and theca cell tumours.

They often produce steroid hormones, in particular estrogens, which can cause postmenopausal bleeding in older women and sexual precocity in prepubertal girls.

Granulosa cell tumours usually secrete inhibin. This can be used to monitor the effects of treatment.

Theca cell tumours are usually benign. Granulosa cell tumours occur at all ages, but are

found predominantly in postmenopausal women.

Adekunle A.O. 43

Granulosa and Theca Cell Tumours

Most present as Stage I. Bilateral tumours are present in only 5% of

cases.

PATHOLOGY Granulosa cell tumours are normally solid but

cystic spaces may develop when they become large.

Some are predominantly cystic. Like most tumours in this group, the cut surface

is often yellow because of neutral lipid related to sex steroid hormone production.

Areas of haemorrhage are also common.

Adekunle A.O. 44

Granulosa and Theca Cell Tumours - Treatment

The surgical treatment is the same as for epithelial tumours.

The effect of adjuvant therapy is difficult to assess as granulosa cell tumours can recur up to 20 years after the initial diagnosis.

Radiotherapy has been largely replaced by chemotherapy in advanced or recurrent cases.

The five-year survival is around 80% overall but recurrence is associated with a high mortality.

Adekunle A.O. 45

Sertoli-Leydig Cell Tumours (Androblastoma)

Rare tumour;

Half of these neoplasia produce male hormones which cause virilization.

Rarely, estrogens are secreted.

The prognosis for the majority with localized disease is good.

Treatment is the same as for granulosa cell tumours.

Adekunle A.O. 46

Germ Cell Tumours - Dysgerminomas

Disgerminomas account for 2 – 5% of all primary malignant ovarian tumours.

Nearly all occur in women less than 30 years old;

They spread by lymphatics.

PATHOLOGY They are solid tumours that have a smooth or

nodular, bosselated external surface. Soft or rubbery in consistency, depending on

the proportion of fibrous tissue contained in them.

Adekunle A.O. 47

Germ Cell Tumours – Dysgerminomas (Contd.)

They may reach a considerable size, the mean diameter is 15 cm.

Approx. 10% are bilateral; they are alone among malignant germ tumours in having a significant incidence of bilaterality.

Elements of immature teratoma, yolk sac tumour or choriocarcinoma are found in about 10% of dysgerminomas.

Presence of these more malignant cell elements indicates a worse prognosis.

Adekunle A.O. 48

Germ Cell Tumours: Dysgerminomas - Treatment

DIAGNOSIS Chest x-ray

Computerized Tomography (CT) scan

Serum alpha-fetoprotein (AFP) and βhCG must be assayed to exclude the omnious presence of elements of choriocarcinoma, endodermal sinus tumour or teratoma.

PROGNOSIS

Pure dysgerminomas have a good prognosis as they are normally Stage I tumours (75%), most being Stage Ia.

Adekunle A.O. 49

Germ Cell Tumours: Yolk Sac (endodermal sinus) Tumours

Second most common malignant germ cell tumour of the ovary, making up 10 – 15% over all and reaching a higher proportion in children.

May present as an acute abdomen due to rupture following necrosis and haemorrhage;

Usually well-encapsulated and solid.

Areas of necrosis and haemorrhage are often seen, as are small cystic spaces.

Its consistency varies from soft to firm and rubbery; cut surface slippery and mucoid.

Secretes AFP, which can be used to monitor treatment.

Adekunle A.O. 50

Germ Cell Tumours: Teratomas Mature teratomas are benign, the most

common being the cystic teratoma or dermoid cyst;

Found at all ages but particularly in the third and fourth decades;

Immature teratomas are composed of a variety of tissues and comprise about 1% of all ovarian teratomas.

They are unilateral in almost all cases and appear as solid masses that have smooth and bosselated surfaces.

Not all solid tumours are of immature type.

Adekunle A.O. 51

Teratomas – Treatment

Suspect a germ cell tumour prior to surgery if a young woman has what appears to be predominantly solid tumour on ultrasound examination.

Early disease is treated by surgery: Oophorectomy in young women Hysterectomy and BSO in older patients.

Women are suitable for conservative surgery if they have: Encapsulated tumour No ascites No evidence of abnormal lymph nodes at surgery Negative CT scan of the para-aortic nodes

Adekunle A.O. 52

Teratomas – Adjuvant Treatment Stage I malignant teratomas and

dysgerminomas may be followed up closely without further treatment.

For the remainder, chemotherapy has replaced radiotherapy, particularly when there is wish to preserve fertility;

Short courses of cisplatin chemotherapy given in combination with bleomycin and etoposide (BEP) is curative in 90% of patients without adverse features.

More intensive regimens are used for patients with adverse features.