MALIGNANT DISORDERS OF THE OVARIES

Ovarian cancer account for 3 – 4 % of cancers in women

1. AETIOLOGY
Incessant ovulation thought to play an important role.
- Repeated disruption and repair of germinal epithelium may
provide opportunity for somatic gene deletions and mutations
which can contribute to tumour initiation and progression.
- Found protective
 Multiparity
 Oral contraceptives
 History of breastfeeding
- Increased risk
 Nulliparity
 Infertility
 Diets with high animal fat saturation
 High body mass index (BMI) especially for the
endometroid type
 Genetic preponderance in 10 – 12 % of epithelial
ovarian cancer patients
 Turner’s syndrome (45 X0 ) for dysgerminoma and
gonadoblastoma.
 Carcinogenic substances in mullerian ductal system
(BTL shown to reduce incidence of ovarian cancer).
- Hereditary ovarian cancer occurs in two forms
a) As breast and ovarian cancer (BOC) syndromes
 Most often associated with germ line mutations in the
BRCAI gene located on chromosome 17
 Less commonly with BRCA 2 mutations on
chromosome 13.

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  Women with BRCA 1 mutations from high risk families
have a lifelong risk of 44% of BRCA 2 upto 27%
 Autosomal dorminant inheritance
b) Hereditary nonpolyposis colorectal cancer (HNPCC)
syndrome- Lynch 11 syndrome
 Comprises familial colon cancer (lynch 1 syndrome)
and high rate of ovarian, endometrial, GIT and
genitourinary malignancies.
 Genes involved include DNA mismatch repair genes
like MLH 1, MSH 2, MSH 3, MSH 6, PMS 1 and PMS
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 A female member in affected family has a live long risk
of ovarian cancer at approximately 12%.
- A number of molecular mechanisms related to pathogenesis
have been described eg:
 Allelic loss and mutations of the P53 tumour suppressor
gene in about 59% of cancers
 Decreased expression of CDK(cyclic- dependent
kinase) inhibitors
 p16 deletions.

2. HISTOPATHOLOGICAL TYPES
a) Epithelial
 Serous cystadenocarcinoma
 Mucinous cystadenocarcinoma
 Endometroid
 Clear cell carcinoma
 Brenner – (Transitional cell) carcinoma
 Undiffferentiated
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b) Germ cell
 Dysgerminoma
 Endodermal sinus tumour
 Teratoma (immature, mature, specialized)
 Embryonal carcinoma
 Choriocarcinoma
 Gonadoblastoma
 Mixed germ cell
 Polyembryonal
c) Sex cord and stromal
 Granulosa cell tumour
 Fibroma
 Thecoma
 Sertoli-Leydig cell
 Gynandroblastoma
d) Neoplasms metastatic to the ovary
 Breast
 Colon
 Stomach
 Endometrium
 Lymphoma

a) Epithelial nesplasms
Derived from ovarian surface mesothelial cells

Serous cystadenocarcinoma
 Histologically like endosalpix
 Commonest ovarian tumour
 Account for 75 – 80% of all epithelia cancers

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 40 – 60% bilateral
 85% associated with extra ovarian spread at the time of
diagnosis
 More than 50% exceed 15cm diameter
 shows areas of hemorrhage, necrosis ,cyst wall invasion and
adhesions to adjacent structures
 Unilocular or multilocular cysts often with coarse papillae
projecting in cystic lumen
 Psammoma bodies (irregular lamellar calcifications)
 Degree of Differentiation based on degree of preservation of
papillary architecture
 Most are poorly differentiated
 Predominantly in premenopausal women
 Associated with good prognosis

Mucinous neoplasms
 10% of all epithelial tumours
 Bilateral in less than 10% of cases
 Large sized median size 18 – 20cm
 Multilocular cysts filled with viscous mucin
 Histologically resemble endocrinal epithelium
 Differentiation related to preservation of gland like
architecture of the tumour
 Should be differentiated from metastatic mucinous tumours
originating from colon, rectum, appendix, endocervix and
pancreas
 Pseudomyxoma peritonei may occur

Endometroid neoplasms
 10% of epithelial tumours

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  Resemble endometrial adenocarcinoma
 Bilateral in 30 – 50% of cases
 Rarely (less than 10%) arise in foci of endometriosis
 Degree of differentiation based on exent to which glandular
architecture retained
 May co-exist (30%) with primary endometrial carcinoma

Clear cell carcinoma

 Also referred to as mesonephrid carcinoma
 Histology includes “clear cells” as in renal carcinomas
 Account for less than 1% of epithelial tumours
 Biologically aggressive and can be associated with
hypercalcaemia and hyperpyrexia
 Show both cystic and solid areas
 Cell – types are clear cell and “Hobnail cell”
 Can be difficult to differentiate from mucinous but acid
Schiff reaction strongly positive in mucinous tumours

Transitional cell (Brenner) Carcinoma

 Less than 1% of epithelial cancers
 Cells resemble low-grade transitional cell carcinoma of
urinary bladder
 Present in advanced stage and exhibit poor prognosis when
compared with other epithelial cancers

Undifferentiated carcinoma
 Less than 10% of epithelial neoplasms
 No characteristic histological features
b) Germ cell Neoplasms
 From germ cell elements of the ovary
 Tend to occur in second and third decades of life
 As a group associated with better prognosis
 Many produce biological markers
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 Neoplasm x – fetal protein hCG
(AFP)
Dysgerminoma * +/-
Endodermal sinus tumour + -
Immature teratoma +/- -
Mixed germ cell tumour +/- +/-
Choriocarcinoma - +
Embryonal carcinoma +/- +

* - AFP borderline

Dysgerminoma
 Female counterpart of male seminoma
 Primarily in young females
 Approximately 30 – 40% 0f germ cell tumours
 Unilateral in 85 – 90% of cases
 Solid but may have degeneration soft areas
 Mimics pattern seen in primitive gonad
 Lymphocytic infiltration considered a favorable prognostic
indicator

Endodermal sinus tumour

 Formally called yolk sac tumour
 Third commonest germ cell neoplasm
 Nearly 100% bilateral
 Most rapidly growing neoplasm that occurs at any site
 Friable, focally necrotic and haemorrhagic
 Common presentation is acute abdomen
 Comprises primitive epithelial cell architecture similar to
primitive gut and liver
 Schiller – Duval body pathognomonic
- - a single papilla lined by tumour cells with a central blood
vessel
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 Commonly contains cells that produce alpha - foetal
protein (useful in following response to therapy).

Immature teratomas
 Malignant counterpart of mature cystic teratoma
 Second most common germ cell malignancy
 Mostly in patients less than 20 years
 Bilateral in less than 5% but contralateral ovary may have
dermoid
 Serum AFP usually elevated
 Has tissues derived from the three germ layers with some
components having an immature embryonic appearance
 Immature elements commonly neuroectodermal tissue;
stage not increased and prognosis not diminished
 Graded from 1 – 3 based on amount of immature neural
tissues they contain
 If metastatic implants entirely of nature neuroectodemal
tissue, stage not increased and prognosis not diminished

Mature teratomas
 Primarily ages 20 – 30 years
 Most common neoplasm diagnosed during pregnancy
 Less than 1% of all teratomas are malignant

Embryonal carcinoma
 Very rare with mean age 15 years
 Highly aggressive growth with early extensive spread
 hCG and AFP usually elevated
 Estrogens may be produced

Choriocarcinoma
 Rare and unrelated to pregnancy
 Associated with somewhat lower hCG levels when
compared to pregnancy related.

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  May cause precocious puberty, uterine bleeding or
amenorrhea
 Has cytotrophablasts, intermediate trophablasts and
syncytiotrophoblasts

Gonadoblastoma
 Rare neoplasm
 Comprises nests of germ cells and sex cord derivatives
surrounded by connective tissue stroma.
 Commoner in right ovary
 Usually occurs during second decade of life
 Found in patients with abnormal gonadal development in the
presence of a Y chromosome

Mixed germ cell turmouos

 Approximately 10% of germ cell neoplasms
 Has two or more germ cell elements
 Dysgerminoma and endodermal sinus tumour occur together
most frequently
 Different components may require different chemotherapies

Polyembryomas
 Extremely rare
 Most commonly in premenarchal girls with signs of
pseudopuberty
 Secretes both AFP and hCG
 Composed of embroid bodies
 Mimics structures of the three somatic areas of early
embryonic differentiation.

c) Sex Cord- stromal tumours

 5 – 8% of all ovarian malignancies

Granulosa cell tumours

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  70% of all sex cord- stromal tumours
 Associated with hyperoestrogenism
 Associated with precocious puberty in young girls
 Associated with adenomatous hyperplasia and vaginal
bleeding in post menopausal women
 May show call-exner bodies
 Theca cells are present in varying amount

Thecomas
 Associated with hyperoestrogenism
 Mostly benign
 Lipid – laden stromal cells hence yellow appearance on
section

Fibroma
 Benign
 With ascites and pleural effusion makes Meig’s syndrome.

Sertoli – stromal cell tumours

 Rare
 Have testicular structures different stages of development
 Usually vilirizing
 Occur in third and fourth decade of life
 Average age of diagnosis 25 years
 Rarely bilateral

d) Neoplasms metastatic to the ovary

 Amounts for 5 – 6 % of all ovarian malignancies
 Most commonly from genital tract, breast and GIT
 May differ from primary tumour

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  Immunohistochemistry used to characterize the tumour
 Krukenberg tumours represent stomach metastases to the
ovary but commonly term used for all GIT tumours to ovary

3. Diagnosis
 Most produce few symptoms hence diagnosis late
a) History
 Non-specific GIT complaints e.g. nausea, dyspepsia, altered
bowel habits, early satiety and abdominal distention
 Sensation of pelvic weight or pressure in large tumours
 Acute abdomen if pelvic incarceration of tumour occurs
though rare
 Menstrual abnormalities (15% of reproduction age patients
with neoplasms)
 Abnormal vaginal bleeding as in endometrial hyperplasia or
metastatic tumour of the lower genital tract

b) Physical examination
Should be comprehensive
 Sister Mary Joseph’s nodule is metastatic implant in the
umbilicus
 Presence of ascites or large mass
 Enlarged supraclavicular and inguinal nodes
 Benign mass-mobile, cystic, smooth and unilateral
 If found unilateral in reproductive age, it is benign in up to
95%
 Possible malignancy if fixed, solid or firm, bilateral and
nodular

c) Investigations
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  Ultrasound - can detect majority but poor specificity
- Colour Doppler studies to improve
sensitivity and specificity
 CXR
 Computed tomography (CT) - information of both pelvic
and retroperitoneal structures
 Total blood count
 Urea and electrolytes
 hCG
 Serum AFP
 LFTS especially lactate dehydrogenase
 CA-125 serum immunoassay
 cancer antigen-125 is a glycoprotein in amniotic fluid
and coelomic epithel
 also elevated in cancers of the colon, breast, pancreas,
stomach, uterus and fallopian tube
 useful especially in postmenopausal women
4. Staging
Procedures in surgical staging
 Sample of ascites or peritoneal washing from the paracolic
gutters and pelvic and subdiaphragmatic surface for cytology
 Complete abdominal exploration
 Intact removal of tumour
 Hysterectomy
 Infracolic omentectomy
 Biopsies of peritoneal implants: if none, random biopsies
from peritonei of paracolic gutter, pelvis and right
subdiaphragmatic surface
 Pelvic and paraaortic lymph node biopsies
 Cytoreductive surgery to remove all visible disease
(debulking)
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 FIGO staging
Stage1 – Growth limited to the ovaries
1a – one ovary involved
1b – both ovaries involved
1c – 1a or 1b and ovarian surface tumour, ruptured capsule,
malignant ascites, or peritoneal cytology positive for
malignant cells

Stage 11 – Extension of the neoplasm to the pelvis

11a – extension to uterus or fallopian tube
11b – extension to other pelvic tissues
11c – 11a or 11b and ovarian surface tumour, ruptured
capsule, malignant ascites or peritoneal cytology positive for
malignant cells

Stage 111 – Disease extension to the abdominal cavity

111a – abdominal peritoneal surface with microscopic
metastases
111b – tumour metastases < 2cm in size
111c – tumour metastases > 3cm in size or metastatic disease
in the pelvis, paraaortic or inguinal lymph nodes

Stage 1V – Distant metastatic disease

Malignant pleural effusion
Pulmonary parenchymal metastases
Liver or pelvic parenchymal metastases (not surface
implants)
Metastases to supraclavicular lymph nodes or skin

5. Management
a) Surgery
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  Hysterectomy because uterus is common tumour site and
endometrial carcinoma can co-exist.
 Also facilitates subsequent follow-up exams
 Infracolic omentectomy
- Common site of microscopic metastases
- Facilitates distribution of intraperitoneal agents
- May decrease post operative ascites accumulation rate
- Provides palliation in omental metastases
 Cytoreductive surgery (debulking)
- Often relieves GIT symptoms and improves overall
nutritional status
- Improves vascularization and oxygenation (Large tumours
poor vascularization and oxygenation hence more resistance
to chemo and radiotherapy)
- Reduces production of immunosuppressive factors that block
antitumour immune responses by inhibiting generation of
cytotoxic T- lymphocytes.

b) Chemotherapy - no need for stage 1a

i) Epithelial cancer
 Can use cisplatin and cyclophosphamide
 Paclitaxel and carboplatin more effective used for six cycles
at 3-week intervals
Carboplatin is second generation platinum
 Assessment of response
- Physical exam
- Changes in lesion size
- Reduction in CA – 125 (N < 35IU/mL).
ii) Germ cell Neoplasm
Dysgerminoma

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  Most radiation-sensitive neoplasm identified
 Cisplatin – containing therapies
- Good because can preserve future reproductive potential
Other tumours rare
 Regimens used
Vinblastine – bleomycin – cisplatin
Vinicristine – actinomyive D –cyctophosphamide
Bleomycin-etopiside-cisplatin

Chemotherapy-associated toxicities
Cisplatin – nephrotoxicity, neurotoxicity, ototoxicity.
Carboplatin – thrombocytopaenia, neutropaenia
Cyclophosphamide – haemorrhagic cystitis, pulmonary
fibrosis
Paclitaxel – myelosuppresion
Etoposide – myelosuppresion
Altretamine – peripheral neuropathy
Etoposide – myelosuppresion
Bleomycin – pulmonary fibrosis
Doxorubicin – cardiac toxicity
Vincristine – neuropathy
Ifosfamide – Hemorrhagic cystitis, central neurotoxicity.

c) Radiation therapy
 Limited role mainly became of damage to small bowel, liver
and kidneys
 Radioisotopes eg. intraperitoneal 32 P, benefit
- Stage ic
- Those with microscopically positive second look operations
- Useful in dysgerminoma
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 d) Alternative therapies
 Cytokines like interleukin -2 and interferon either alone or
with chemotherapy
 Monoclonal antibodies directed against ovarian cancer-
associated antigens eg
- CA – 125
- HMFG (human milk – fat globulin)
 Antibodies against vascular epithelial growth factor (VEGF)

6. Prognosis
Primary related to stage of disease but histology in each stage
Epithelial tumours 5- year survival rate
Stage 1 – 76% - 93% (depending on grade)
Stager 11 – 60 – 74%
Stage 111 – 23 – 41%
Stage IV – 5-11%
In general germ cell tumours associated with better 5- year survival
rate than epithelial.
Poor survival rate where secondaries exist.

DR D.K NGOTHO –SR. LECTURER, OB/GY

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