OVARIAN CANCER

Presenter: Wanda Harriet Yvonne

:Nabuuma Shamim
Tutor: Dr Birungi Juliet
 OUTLINE
• Introduction and anatomy
• Epidemiology
• Risk factors
• classification
• Pathogenesis
• Clinical presentation
• Diagnosis
• Staging
• Management
 GROSS ANATOMY OF THE OVARY
• The ovary lies on the lateral wall of the true pelvis.
• It is held in place by:
• the peritoneum of the broad ligament,
• its attachment to the body of the uterus,
• the ovarian ligament,
• and to some extent by connective tissue which runs to the lateral wall of the pelvis,
• the suspensory ligament of the ovary.

• The peritoneum of the broad ligament stops at the mesovarium and does not cover
the ovary itself.
• The ovary is covered by a layer of germinal epithelium (which does not produce
ova), below which lies a tough fibrous coat, the tunica albuginea.
• In young women the ovary is about 4cm long and 2cm in diameter. In post-
menopausal women the ovary becomes flattened and shrunk.
 GROSS ANATOMY - OVARY
Blood supply
• The blood supply to the ovary arises, as for the testes, from the abdominal
aorta at the level of the renal arteries.
• Venous drainage: on the right side the ovarian vein drains into the inferior
vena cava, and on the left side into the left renal vein. The veins follow the
route taken by the arteries.

Lymph drainage
• The lymphatic drainage of the ovary reflects its origin. The lymphatics drain
upwards along the ovarian vessels to aortic lymph nodes.

Innervation
• The innervation of the ovary is entirely by the autonomic nervous system
through the aortic plexus related to the T10 spinal cord segment.
The blood supply, nerve supply and lymphatics all reach the ovary along the
suspensory ligament.
 ANATOMY OF THE OVARY

Uterus and right broad ligament, seen from

behind. The broad ligament has been spread out
and the ovary drawn downward
 EPIDEMIOLOGY
• Third most common cancer of the female reproductive system in
developing countries, after cervical and breast cancers
• Ovarian cancer is the second most common gynecologic malignancy,
after endometrial cancer but it is the Leading cause of death from
gynaecological malignancies.
• 75% present with stage III or IV disease
• According to WHO Global Cancer Registry 2018, Uganda had 596
new cases that year, 497 deaths and 1058 5-year prevalence in all ages
of ovarian cancer.
• Due to absence of specific symptoms and signs and lack of
trustworthy screening for early detection of ovarian malignancies,
about 60-65% of women are diagnosed when the cancer is beyond the
confines of the ovary
 RISK FACTORS
• Family history

• Ethnicity

• Reproduction

• Others
 FAMILY HISTORY
• The strongest risk factor
• A woman with a single first degree relative with ov.Ca has a relative risk of
approximately 3.6 for developing ov. Ca compared with general population.
• 5- 10% of ov Ca are linked to identifiable, inherited mutations in certain genes.
Families in which 3 or more first degree relatives have ovarian or ovarian plus
breast cancer are likely to have a cancer susceptibility genetic mutation that is
transmitted in an autosomal dominant inheritance pattern.
Three familial ovarian cancer syndromes include;
1. The site specific ov.Ca syndrome.
• Only ov.Ca is seen and accounts for 10- 15% of hereditary ov.Ca.
2. The hereditary breast/ovarian cancer syndrome.
• Its associated with 65- 75% of hereditary ov.Ca.
3. The hereditary nonpolyposis colorectal cancer syndrome(HNNPC), affected
individuals may have colon, endometrial, breast, ovarian or other cancers.
 RISK FACTORS CONT’D
Ethnicity
• Higher in white women
• Higher in north America and northern Europe than japan.
• BRCA1 and BRCA2 genes are more common among white women of
Ashkenazi descent.
Reproduction
• Nulliparity
• First childbirth after the age 35 years
• Involuntary infertility
• Late menopause and early menarche
• Prolonged period or uninterrupted ovulation
 OTHERS
• Exogenous hormones; hormonal replacement therapy
• Dietary factors; diets high in saturated animal fats seem to confer an
increased risk by unknown mechanisms.
• Environmental; Talc, asbestos, alcohol, tobacco/cigarette smoking.
 PROTECTIVE FACTORS
• Multiparity; first pregnancy before age of 30
• Oral contraceptives; 5 years of use cuts the risk nearly in half
• Tubal ligation
• Hysterectomy
• Bilateral oophorectomy
• Lactation
• Epidemiologic and laboratory evidence suggests a potential role for
retinoids, vitamin D, NSAIDs as preventive agents for ovarian cancer.
 CLASSIFICATION
• Ovarian cancer can be divided into 3 major categories based on the
cell type of origin.

• The ovary may also be the site of metastatic disease by primary cancer
from another organ site.

• Unlike carcinomas of the cervix and endometrium, precursor lesions

of ovarian carcinoma have not been defined.
 CONT’D
Major histopathologic categories of ovarian cancer
1. Epithelial
• Serous, Mucinous, Endometrioid, Clear cell, Transitional cell
(Brenner).
2. Germ cell
• Dysgerminoma, endodermal sinus tumor, teratoma (immature, mature
and specialized), embryonal carcinoma, choriocarcinoma,
gonadoblastoma, mixed germ cell and polyembryoma.
3. Sex cord and stromal
• Granulosa cell, thecoma, fibroma, sertoli-leydig cell and
gynandroblastoma.
 SECONDARY TUMORS

• Malignant tumors that metastasize to the ovary.

• Krukenberg tumor; metastaic mucinous/ signet ring cell

adenocarcinoma of the ovaries that typically originates from primary
tumors of the intestinal tract, characteristically the stomach. Ovarian
mets represent late disseminated stage with other hematogemous mets.
 PATHOGENESIS

Three tumorigenic pathways

1. Accumulation of genetic malignant transformation of benign cysts to LMP
tumors and ultimate progression to invasive ovarian carcinoma.

2. Inherited predisposition especially the high grade serous tumors. BRCA

and p53 mutations.

3. Carcinomas appear to originate denovo from ovarian epithelial surface cells

that are sequestered in cortical inclusion cysts(CICs) within the ovarian
stroma. Repetitive ovulation requires abundant cellular proliferation.
Replicative stress and DNA damage transforms the entrapped surface
epithelial cells within the CICS into any histologic ovarian cancer variant.
( incessant ovulation + inflammation theory)
 PATTERNS OF SPREAD
1. EOC predominantly metastasize by exfoliation.
Malignant cells are first released into the peritoneal cavity when the tumor
penetrates through the ovarian capsule. Following normal circulation of peritoneal
fluid, cells may develop into implants anywhere in the abdomen.

2. Lymphatic dissemination; malignant cells move through channels following

the ovarian blood supply along the infundibulo-pelvic ligament which terminate in
the para aortic nodes.

3. Direct extension of a progressively enlarging ovarian cancer may create

involvement of pelvic peritoneum and adjacent structures including uterus, recto-
sigmoid colon and fallopian tubes.

4. Hematogenous spread is atypical. Mets to the liver, lung parenchyma, brain or

 EPITHELIAL OVARIAN CANCER
• Accounts for 90% of ovarian cancers.

• ¼ of the patients will have stage 1 disease while 2/3 will have
advanced disease due to absence of effective screening tests for
ovarian cancer.

• 80% of patients develop relapse that eventually leads to disease

progression and death.
 WHO CLASSIFICATION OF EOC
• Serous adenocarcinoma; 50% of EOC
• Endometrioid adenocarcinoma; compose 15-20%. In 15-20% cases,
uterine endometrial carcinoma co exists.
• Mucinous adenocarcinomas; 5-10%. Resemble mucin secreting
adenocarcinomas of intestinal and endocervical origin.
• Clear cell adenocarcinoma; 5-10%. Frequently associated with
pelvic endometriosis.
• Malignant Brenner tumor/ transition cell; account for <5% and
resembles carcinomas arising from the urinary tract often with
squamous differentiation.
• Other histologic types include; Mixed epithelial/ mesenchmal,
Squamous cell carcinoma, Mixed carcinoma, Undifferentiated
carcinoma, Small cell carcinoma.
PRIMARY PERITONEAL CARCINOMA

• 15% of typical epithelial ovarian cancers are primary peritoneal

carcinomas that develop DE novo from the lining of the pelvis and
abdomen.

• Tumors are indistinguishable from EOC clinically and histologically.

• May develop in a woman after years of undergoing BSO.

• Staging, treatment and prognosis are the same as for EOC.

 CLINICAL PRESENTATION
Ovarian cancers lack early signs and symptoms is a misconception
• Increased abdominal size
• Bloating
• Urinary urgency
• Pelvic pain
• Fatigue, indigestion, inability to eat normally, constipation and back
pain may also be noted.
• Vaginal bleeding is rare
 PHYSICAL FINDINGS
• A pelvic or abdominal mass is palpable on bimanual examination.
Malignant tumors tend to be solid, nodular and fixed. A huge mass
filling the pelvis and the abdomen are often benign or borderline.

• Presence of a fluid thrill or flank bulging suggest presence of ascites.

• In advanced disease, upper abdominal examination reveals a central

mass signifying omental caking.

• Chest auscultation in patients with malignant pleural effusions.

 DIAGNOSIS
Laboratory testing
• Routine complete blood count; thrombocytosis (PLT> 400x10^9) .
Malignant ovarian cells release cytokines which are believed to
increase PLT production.
• Hyponatremia (125-130mEq/L). Tumor secretes vasopressin like
substance that causes a clinical picture suggesting SIADH secretion.
Elevated serum Ca 125 levels. Elevated values may also be associated
with common benign conditions like PID, leiomyomas, endometriosis,
pregnancy, menstruation etc.
• Human epididymal protein 4(HE4) along with Ca 125 in the Risk of
Ovarian Malignancy Algorithm(ROMA) to determine likelihood of
finding malignancy at surgery in women with adnexal masses.
• When mucinous ovarian tumor is identified, Ca 19-9 and CEA are
better indicators.
 DIAGNOSIS CONT’D
Imaging
• Transvaginal sonography is the most useful to differentiate benign
tumors and early stage ovarian cancers. Malignant tumors are
multiloculated, solid, echogenic and large >5cm with areas of
nodularity.
• Chest radiography to detect pulmonary effusions and metastasis.
• CT scan for treatment planning for women with advanced ovarian
cancer. Implants in the liver, retroperitoneum, omentum are detected to
guide surgical cytoreduction.

Paracentesis and Cyst aspiration are AVOIDED as malignant cells

can spread via direct exfoliation.
 FIGO STAGING
STAGE 1; Limited to Ovaries
• 1a: one ovary, capsule intact
• 1b: both ovaries, capsule intact
• 1c; tumor limited to 1 or both ovaries with:
1c1: with a surgical spill
1c2: capsule rupture before surgery or tumor on ovarian surface.
1c3: malignant cells in ascites or peritoneal washings.

STAGE 2; Pelvic extension below the pelvic brim or primary peritoneal

cancer
• 2a: extension to uterus or fallopian tubes
 FIGO STAGING CONT’D
STAGE 3; Confirmed spread to the abdominal peritoneum
• 3a1: positive retroperitoneal lymph nodes only.
• 3a2: microscopic extrapelvic peritoneal involvement +/- positive
retroperitoneal nodes
• 3b: macroscopic extrapelvic peritoneal mets < 2cm, positive retroperitoneal
nodes, extension to capsule of liver and spleen
• 3c: macroscopic extrapelvic peritoneal mets > 2cm, positive retroperitoneal
nodes, extension to capsule of liver and spleen

STAGE 4; Distant metastatic disease excluding peritoneal mets

• 4a: pleural effusion with positive cytology
• 4b: hepatic or splenic parenchymal metastases, (extraabdominal) pulmonary
parenchymal metastases, mets to the supraclavicular nodes and skin
 MANAGEMENT
Early stage ovarian cancer
• If malignancy appears clinically confined to the ovary, surgical
removal and complete staging is performed.
• Extra fascial hysterectomy and BSO is performed.
• Fertility sparing surgery is done in women below 40 and if disease is
confined to 1 ovary. Post operative chemotherapy may be required.
• Women with stage 1a or 1b grade 1 or 2 EOC, observation is done
post surgery.
• For stage 1a or 1b grade 3 EOC and all other stages(1c) are treated
with carboplatin and paclitaxel chemotherapy.
 MANAGEMENT CONT’D
Surveillance; Done after treatment is complete.
• Every 2-4 months for the first 2 years then,
• Twice yearly for additional 3 years then,
• Annually.

• On each visit, complete physical and pelvic examination is performed.

Serum Ca 125 levels are measured. Ca 125 elevations or new
symptoms , recurrent disease must be confirmed with imaging. CT
scan is initially the most helpful in identifying intra peritoneal disease.
 MANAGEMENT CONT’D
Advanced ovarian cancer
• 2/3 of the patients will have stage 3 disease thus sequenced
multimodality therapy offers the most successful outcomes.

• Surgical cytoreduction is initially performed to remove all gross

disease followed by 6 courses of platinum based chemotherapy.

• Patients who are not appropriate candidates for primary surgery due to
medical conditions or unresectable tumor, may undergo chemotherapy
initially followed by interval debulking surgery.

• Radiation therapy is rarely used due to unproven benefit and fears of

excessive toxicity.
 MANAGEMENT CONT’D
Recurrent ovarian cancer
• Ca 125 is the first sign of relapse.
• Tamoxifene is given when there is only biochemical evidence of disease
progression.
• Patient may also be started on conventional cytotoxic chemotherapy or
observed until clinical symptoms arise (obvious within 2-6 months if
untreated)
Platinum refractory; pt progresses during primary chemotherapy. Salvage
chemotherapy is done.
Platinum resistant; relapse within 6 months of therapy. Pts are treated with
palliative single agent non platinum chemo. Conventional cytotoxic drugs
like paclitaxel, pegylated liposomal doxorubicin, topotecan or gemcitabine.
Platinum sensitive; relapse after more than 6-12 months of primary therapy
completion. Usually treated with platinum based combination. Carboplatin
 MANAGEMENT CONT’D
Palliation of end stage ovarian cancer
• Episodes of partial small and large bowel obstruction are common
during treatment. A colostomy, ileostomy or intestinal bypass will
often relieve these symptoms.

• Patients with refractory bowel obstruction due to progressive disease

despite multiple lines of chemotherapy, best approach is placement of
a palliative gastrostomy tube, iv hydration and hospice care.
 PROGNOSIS
Prognostic factors include;
• 5 year survival rate appx 45%
• BRCA mutation carries better prognosis due to increased platinum
sensitivity.
• Younger age
• Good performance status
• Cell type other than mucinous and clear cell
• Well differentiated tumor
• Smaller disease volume prior to surgical debulking
• No ascites
• Smaller residual tumor after primary cytoreductive surgery.
 OVARIAN GERM CELL TUMORS
• Arise from the germinal elements of the ovary.

• Malignant ovarian germ cell tumors are the most common ovarian
malignancies diagnosed during childhood and adolescence.

• 95% of germ cell tumors are clinically benign with the cystic teratoma
being the most common subtype.

• Most of the patients have stage 1 disease at diagnosis.

 MODIFIED WHO CLASSIFICATION OF
OVARIAN GERM CELL TUMORS
• Dysgerminoma: accounts for 1/3 of all malignant ovarian germ cell tumors. Most common ovarian
malignancy detected during pregnancy. Have a significant rate of bilateral involvement. 5% of pts have
elevated hCG levels. Serum LDH are useful in monitoring disease recurrence.
• Yolk sac tumor: accounts for 10-20%. Previously known as endodermal sinus tumors. Bilateral
involvement is rare and are the deadliest malignant ovarian germ cell tumor type thus chemo given
regardless of the stage. AFP is commonly produced.
• Embryonal carcinoma: occur in younger patients with a mean age of 14 years. Typically produce hCG
and 75% secrete AFP.
• Non gestational choriocarcinoma: produce high levels of hCG and have a poor prognosis.
• Teratoma:
Mature teratoma: benign and contains mature forms of the 3 germ cell layers
Immature teratoma: most common variant that accounts for 40-50% of all malignant germ cell tumors.
Rare bilateral ovarian involvement. Consists of immature elements with neuroectodermal tissue
predominating.
• Mixed germ cell tumor: have a mixed pattern of cellular differentiation. Dysgerminoma is the most
 CLINICAL PRESENTATION
Most of the signs and symptoms originate from tumor growth and
hormones produced.
• Subacute abdominal pain is the most common presenting symptom in
85% due to large growth of a unilateral tumor undergoing capsular
distension, hemorrhage or necrosis.
• Cysts rupture, torsion or intra peritoneal hemorrhage leads to acute
abdomen.
• Due to hormonal changes, menses can become heavy or irregular
• ¼ of the patients are asymptomatic and a pelvic mass is noted
unexpectedly during physical or sonographic examination.
• Vague pelvic symptoms are common during adolescence due to
initiation of ovulation and menstrual cramping.
 DIAGNOSIS
Laboratory testing
• CBC, LFTs are done before treatment.
• AFP and hCG tumor markers
TUMOR AFP hCG

Dysgerminoma - +

Yolk sac tumor + -

Imm. teratoma +/- -

Choriocarcinoma - +

Embryonal carcinoma + +

Mixed germ cell tumor +/- +/-

Polyembryoma +/- +/-

 DIAGNOSIS CONT’D
Imaging
• Sonography
• Chest radiography for tumor metastases.

 specific immune staining to resolve equivocal cases.

Surgical resection for definitive tissue diagnosis, staging and

treatment.
 MANAGEMENT
Surgery
• Fertility sparing USO in women of reproductive age.
• Hysterectomy with BSO for those who have completed child birth.
• Cytoreductive surgery for advanced stage of malignant ovarian germ cell tumors and
adjuvant chemotherapy.

Chemotherapy
• Stage 1A dysgerminomas and stage 1A grade 1 immature teratomas do not require
additional chemotherapy.
• Standard regimen is a 5 day course of bleomycin, etoposide and cisplatin(BEP) given
every 3 weeks.
• Atleast 4 courses of BEP are used to treat recurrent ovarian germ cell tumors in women
who were initially managed by surgery alone.

Surgical salvage may benefit patients who do not achieve remission with BEP or those
 MANAGEMENT CONT’D
Management during pregnancy
• Dramatically elevated maternal serum AFP level as a presenting sign
of malignant germ cell tumor.
• Malignant germ cell tumors have the propensity to grow rapidly and
delaying treatment until delivery is potentially hazardous.
• Treatment with BEP appears to be safe during pregnancy though some
reports have speculated fetal complications( elit, 99, harbelt, 1994)
thus some advocate postponing treatment till puerperium.
• Patients with non dysgerminomatous tumors (yolk sac, imm.
Teratomas) and incompletely resected disease warrant strong
consideration of chemo during pregnancy.
 CONT’D
Surveillance
• Patients with malignant ovarian germ cell tumors are followed by
clinical, radiological and serological surveillance every 3 months for
the first 2 years.

Prognosis
• Have an excellent overall prognosis even with advanced disease due to
exquisite tumor chemo-sensitivity.
• Dysgerminomas have the best prognosis of all malignant ovarian germ
cell tumor variants.
OVARIAN SEX CORD- STROMAL TUMORS
• Rare and originate from the ovarian matrix.
• Account for 3-5% of ovarian malignancies and are twice likely to
develop in black women( unknown reasons).
• Ovarian SCSTs affect women of all ages.
• 90% of SCSTs are hormone producing tumors .
• Patients typically present with signs and symptoms of estrogen or
androgen excess.
• SCSTs have an indolent growth pattern and low malignancy potential
thus few patients require platinum based chemotherapy.
 MODIFIED WHO CLASSIFICATION OF
OVARIAN SCSTs
 Pure stromal tumors
• Fibroma / fibrosarcoma
• Thecoma
• Sclerosing stromal tumor
• Leydig cell tumor
• Steroid cell tumor

 Pure sex cord tumors

• Granulosa cell tumor
• Sertoli cell tumor
• Sex cord tumor with annular tubes

 Mixed sexcord – stromal tumors

• Sertoli-leydig cell tumors
 SCSTs
Granulosa cell tumors
• Further classified into adult and juvenile granulosa cell tumors.
 Adult form makes up 90% of cases while the juvenile type 5%.
• In the adult form, most women are diagnosed after 30 years and av. age appx
55 years. Inhibin B and A serum levels are elevated.
 Juvenile form, 90% are diagnosed at puberty with a mean age of 13 years at
diagnosis. May be associated with ollier disease or Maffucci
syndrome( xterised by endochondromas and hemangiomas).

Thecoma
• Relatively common and develop in post menopausal women in their mid 60s
• Are among the most hormonally active of the SCSTs and produce excess
estrogens. Clinically benign.
 SCSTs CONT’D
Fibroma / fibrosarcoma
• Fibromas are hormonally inactive
• Occur in perimenopausal and menopausal women
• Most are incidental findings on sonography while 1% present with
Meig’s syndrome triad consisting of (pleural effusion, ascites and
ovarian mass).
• 1% of pts with fibroma undergo malignant transformation into
fibrosarcoma.

Sertoli-leydig cell tumors

• Account for 5-10% of all SCSTs. Average age is 25 years and tumors
produce sex steroid hormones commonly androgens.
 CLINICAL PRESENTATION
• Isosexual precocious puberty is the presenting sign in 80% of
prepubertal girls.
• Adolescents report secondary amenorrhea
• Abdominal pain and distension are common
• In adult women, heavy irregular bleeding and post menopausal
bleeding are the most frequent symptoms.
• Mild hirsutism that rapidly progresses to frank virilization should
prompt evaluation to exclude these tumors.
 DIAGNOSIS
Laboratory testing
• Elevated circulating levels of testosterone or androstenedione strongly
suggest SCSTs in women with signs and symptoms of virilization.
Serum testosterone levels >150g/dl or dehydroepiandrosterone sulfate
levels > 8000g/L strongly suggest androgen secreting tumor and not
PCOS.

• Tumor markers are also done

Granulosa cell tumors; inhibin A and B.
Sertoli–leydig cell tumors; inhibin A and B. Occassionally AFP.
Steroid cell tumors not otherwise specified; steroid hormones are
elevated.
 DIAGNOSIS CONT’D
Imaging
• Sonography; gross appearance of SCSTs range from multicystic to
small solid masses.
• CT or MRI to clarify indeterminate sonograms.

Surgical resection for definitive tissue diagnosis, staging and

treatment.

SCSTs are distinguished histologically from germ cell tumors,

epithelial tumors by immune staining for inhibin.
 MANAGEMENT
Main stay treatment is complete surgical resection.
Relative insensitivity to adjuvant chemotherapy and radiotherapy
Chemotherapy is required if ;
• Large tumor size
• High mitotic index
• Incomplete staging
These are considered for platinum based chemotherapy . Stage 2-4
also warrant post operative chemotherapy. 5 day BEP regimen is
mostly used as first line.

Relapse; secondary surgical debulking is considered due to indolent

growth pattern. BEP is also given and paclitaxel can also be used.
CONT’D
Prognosis
• Overall prognosis is excellent primarily due to early stage disease at
diagnosis and curative surgery.

Differential diagnoses of ovarian tumors

• Ovarian (paraovaraian) cyst, Ovarian torsion
• Ectopic pregnancy, Hydro or Pyosalpinx, Tubo-ovarian abscess, Tubal
or Endometrial malignancy
• IO, Diverticulitis, Appendicular abscess, Intussusception, Gastric
malignancy.
• Peritoneal cyst, Psoas abscess.
• Hydronephrosis, Pelvic kidney/ Renal ectopy.
 REFERENCES
1. Williams Gynecology 3rd edition, chapter 35 and 36.
2. Cotran RS, Kumar V, Robbins SL: Robbins Pathologic Basis of
Disease. 5th ed. Philadelphia, W.B. Saunders, 1994,
3. http://ovariancancer.jhmi.edu/typesca.cfm
4. http://pathweb.uchc.edu/eAtlas/GYN/530.htm
5. http://www.med.mun.ca/anatomyts/repro/reproov.htm
THANK YOU.