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 Ovary - Epithelial Carcinoma

1.1 Predisposing Factors & Screening

Risk Factors:

Ovarian cancer is the fifth most common malignancy in British Columbia women with a crude incidence rate of 17.1 per 100,000. The majority of the cases (about 90%) are of epithelial origin. The incidence rate has remained relatively stable over the past 30 years as has the 5-year relative survival, which is about 35% (Weiss et al, 1996).

Established risk factors for epithelial malignancies are reproductive and genetic in nature; an excellent review is given by Kelsey and Whittemore (1994). Higher risks have been observed in women with no children or with low numbers of live births. An increased risk of developing ovarian cancer has been seen with the use of fertility drugs, although not all studies have found this. A family history of breast cancer or ovarian cancer is also a risk factor. In addition, a diet with high levels of saturated fat may increase risk. There is also evidence that exposure to asbestos increases risk of ovarian cancer.

There appears to be an inverse relationship between the use of oral contraceptives and risk of ovarian cancer, even after controlling for parity. Women with tubal ligation or hysterectomy (without oophorectomy) may also have lower risk.

Prevention:

At present time, most risk factors for ovarian cancer are not well enough understood so that primary prevention approaches can be considered. Although screening approaches have been proposed, including ultrasound and serum CA125, their benefits for population screening have not been demonstrated.

References:

  1. Weiss NS, Cook,LS, Farrow DC, Rosenblatt KA. Ovarian cancer. In Schottenfeld D, Fraumeni JF Jr. (Eds) Cancer Epidemiology and Prevention 2nd Ed. 1996. Oxford University Press, Oxford. Pp1040-1057.

  2. Kelsey JL, Whittemore AS. Epidemiology and primary prevention of cancers of the breast, endometrium and ovary: a brief overview. Ann Epidemiol 1994;4:89-95.

Screening/ Early Detection

As yet there is no effective screening program. The studies performed using a combination of pelvic examination, CA125 and ultrasound have found an unacceptably high rate of false positives.

1.2 Diagnosis

​ 1) Clinico-pathologic Considerations

Pre-Operative Assessment:

  • Complete history and physical, including pelvic and pelvirectal examinations.
  • CBC, BUN, Cr
  • CA 125 and CEA in all patients
  • AFP, HCG, LDH in patients under 40 (To rule out germ cell tumours, see 9.1)
  • Chest X-ray
  • Barium or Hypaque Enema in patients with possible bowel involvement
  • IVP or Renal Ultrasound to rule out obvious ureteric compression
  • Neither Pelvic Ultrasound nor CT of the abdomen and pelvis are essential investigations

Surgery provides prognostic information and is therapeutic in its own right.

A review of the prognostic factors influencing outcome of epithelial ovarian carcinoma identified stage, tumour grade and the presence or absence of visible residual disease at the conclusion of initial laparotomy as the three major independent prognostic variables.

Successful treatment of epithelial carcinoma of the ovary is initiated by accurate and aggressive initial surgical management. Optimal surgical debulking has been shown to be the cornerstone of successful ovarian cancer management. As a result of that, it is highly recommended that patients presenting with apparent advanced staged ovarian cancer should be referred to sub-specialist care (Gynecologic Oncologists).

In apparent early stage ovarian cancer, complete staging with multiple biopsies and possibly lymphadenectomy is key to ruling out microscopically advanced disease.

2) Classification Criteria Surface Epithelial-Stromal Tumours

Serous Tumours:

  1. Benign
    1. cystadenoma and papillary cystadenoma
    2. surface papilloma
    3. adenofibroma and cystadenofibroma
  2. Of borderline malignancy (carcinomas of low malignant potential)
    1. cystic tumour and papillary cystic tumour
    2. surface papillary tumour
    3. adenofibroma and cystadenofibroma
  3. Malignant
    1. adenocarcinoma, papillary adenocarcinoma, and papillary cystadenofibroma
    2. surface papillary adenocarcinoma
    3. adenocarcinofibroma and cystadenocarcinofibroma (malignant adenofibroma and cystadenofibroma)

Mucinous Tumours, Endocervical-like and Intestinal-type

  1. Benign
    1. cystadenoma
    2. adenofibroma and cystadenofibroma
  2. Of borderline malignancy (carcinomas of low malignant potential)
    1. cystic tumour
    2. adenofibroma and cystadenofibroma
  3. Malignant
    1. adenocarcinoma and cystadenocarcinoma
    2. adenocarcinofibroma and cystadenocarcinofibroma (malignant adenofibroma and cystadenofibroma)

Endometroid Tumours

  1. Benign
    1. cystadenoma
    2. cystadenoma with squamous differentiation
    3. adenofibroma and cystadenofibroma
    4. adenofibroma and cystadenofibroma with squamous differentiation
  2. Of borderline malignancy (carcinomas of low malignant potential)
    1. cystic tumour
    2. cystic tumour with squamous differentiation
    3. adenofibroma and cystadenofibroma
    4. adenofibroma and cystadenofibroma with squamous differentiation
  3. Malignant
    1. adenocarcinoma and cystadenocarcinoma
    2. adenocarcinoma and cystadenocarcinoma with squamous differentiation
    3. adenocarcinofibroma and cystadenocarcinofibroma (malignant adenofibroma and cystadenofibroma)
    4. adenocarcinofibroma and cystadenocarcinofibroma with squamous differentiation (malignant adenofibroma and cystadenofibroma with squamous differentiation)
  4. Epithelial-stromal and stromal
    1. adenosarcoma, homologous and heterologous
    2. mesodermal (mullerian) mixed tumour (carcinosarcoma), homologous and heterologous
    3. stromal sarcoma

Clear Cell Tumours

  1. Benign
    1. cystadenoma
    2. adenofibroma and cystadenofibroma
  2. Of borderline malignancy (carcinomas of low malignant potential)
    1. cystic tumour
    2. adenofibroma and cystadenofibroma
  3. Malignant
    1. adenocarcinoma
    2. adenocarcinofibroma and cystadenocarcinofibroma (malignant adenofibroma and cystadenofibroma)

Transitional Cell Tumours

  1. Brenner tumour
  2. Brenner tumour of borderline malignancy
  3. Malignant Brenner tumour
  4. Transitional cell carcinoma (non-Brenner type)

Squamous Cell Tumours

Mixed Epithelial Tumours (Specify Types)

  1. Benign
  2. Of borderline malignancy (of low malignant potential)
  3. Malignant

Undifferentiated Carcinoma

1.3 Staging

1. Classification Criteria (FIGO)

In order to promote consistency and uniformity a pathology review by a BC Cancer Agency tumour group pathologist is recommended in every case.

Stage Description
IGrowth limited to the ovaries
IaGrowth limited to one ovary; no ascites
No tumour on the external surface; capsule intact
IbGrowth limited to both ovaries; no ascites
No tumour on the external surface; capsule intact
Ic*Tumour either Stage Ia or Stage Ib, but with tumour on surface of one or both ovaries; or with capsule ruptures; or with ascites present containing malignant cells or with positive peritoneal washings
IIGrowth involving one or both ovaries with pelvic extension
IIaExtension and/or metastases to the uterus and/or tubes
IIbExtension to other pelvic tissues
IIc*Tumour either Stage IIa or Stage IIb, but with tumour on surface of one or both ovaries; or with capsule(s) ruptured; or with ascites present containing malignant cells or with positive peritoneal washings
IIITumour involving one or both ovaries with peritoneal implants outside the pelvis and/or positive retroperitoneal or inguinal nodes; superficial liver metastasis equals Stage III
IIIaTumour grossly limited to the true pelvis with negative nodes but with histologically confirmed microscopic seeding of abdominal peritoneal surfaces
IIIbTumour of one or both ovaries with histologically confirmed implants of abdominal peritoneal surfaces, none exceeding 2 cm in diameter; nodes are negative
IIIcAbdominal implants greater than 2 cm in diameter and/or positive retroperitoneal or inguinal nodes
IVGrowth 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 metastases equals Stage IV

*To evaluate the impact on prognosis of the different criteria for allotting cases to Stage Ic or IIc, it would be of value to know: (1) if rupture of the capsule was (a) spontaneous or (b) caused by the surgeon or (2) if the course of malignant cells detected was (a) peritoneal washings or (b) ascites.

2. Staging Diagram​

Click image for larger version





1.4 Management

​Updated 24 January 2014

A. Surgery for Presumed Ovarian Cancer

Clinical judgment plays a large role in surgical decision making. Nowhere is this more important than in the approach to the pelvic mass. In the past surgical options were limited to laparotomy or observation. Now with the explosion of laparoscopic surgical techniques there is an increasing tendency to disregard the surgical principles previously used for diagnosing and treating pelvic masses.

Those findings which raise the possibility of intrapelvic or intra-abdominal malignancy should dissuade the surgeon from an endoscopic approach. If a laparoscopic approach is contemplated for a pelvic mass, the operator should have the appropriate skill level to remove the mass intact. Clinical guidelines should be used to help one determine which pelvic or adnexal mass is likely to be malignant.

Surgical expertise does impact patient survival outcomes with epithelial ovarian cancers.  Ideally surgery, if malignancy is suspected, will be performed by gynecologic oncologists or by gynecologists who routinely perform such complex operations as the intent is optimal debulking. The following table outlines some of the important factors in preoperative decision making that predict for an unsuccessful attempt at optimal debulking.

Clinical:Imaging:Other:
“Older” physiologic age of patientHigh levels of CA 125 (> 500)
Fixed masses
AscitesAscites
ObesityUpper abdominal location

Additional Issues:

  1. In the reproductive age group extensive pelvic endometriosis can mimic the findings of pelvic malignancy and present a diagnostic challenge.
  2. Patients under 40 with suspected cancer are more likely to have germ cell cancers and initial conservative surgery only is needed (ie unilateral salpingo-oophorectomy).  Therefore preop HCG, aFP, LDH are of immense value. 
  3. It is a principle of oncology to try and remove tumour masses intact without rupture or spill to avoid the potential for spread of malignant cells. However, the medical literature is contradictory on the effect of rupture on prognosis. Most cancer treatment centres would advocate no additional treatment for patients with un-ruptured stage I cancers of non-serous histology. If leakage occurred, the patient may require further therapy as a result. If the tumor can be removed intact with the use of endobags, etc. by a skilled laparoscopic surgeon then this may be appropriate. Aspiration of pelvic masses is not recommended for diagnosis. The aspiration of intracystic fluid seldom gives the diagnosis and may compromise prognosis. Results reported by skilled laparoscopic surgeons in the world literature will not reflect the learning curve in clinical practice.
  4. In stage I ovarian cancer once the diagnosis of malignancy has been made, a thorough staging laparotomy should be performed. Multiple peritoneal biopsies, pelvic and para-aortic node assessment and sampling, diaphragmatic biopsy and omentectomy and washings are all important in ensuring that there is no subclinical extra-ovarian spread. Wedge biopsy of the contralateral ovary is not required if the ovary is clinically normal as this may further compromise fertility.
  5. The objective of surgery is to reduce the residual disease to the lowest possible amount.

Timing of Surgery

In a multinational phase III trial, interval debulking surgery for stage III/IV patients was shown to be as effective as primary debulking in terms of survival but with less morbidity and avoided the need for repeat debulking in those who could not be optimally debulked initially.

However, primary debulking/staging ie pre-chemotherapy is the goal whenever possible.  The exceptions to this are (1) proven stage IV disease, (2) stage III patients who are unlikely to be optimally debulked to < 1 cm eg, ECOG status = 2; clinically apparent or widespread ascites upon imaging; upper abdominal disease involving diaphragms, porta hepatis, liver capsule, perigastric/pancreatic areas, (3) if timely surgery (< 4 weeks) cannot be performed and (4) lack of surgical expertise.  If there are doubts/concerns about operative feasibility, contact with BCCA Gynecologic Oncology is recommended.  If interval debulking is planned, a tissue diagnosis is mandatory, preferably histologic ie core biopsy.  Cytology can be used if core biopsy is not possible. However, its diagnostic reliability is less.

B. Postoperative Therapy

[A] Type 1
NO TREATMENT
CHEMOTHERAPY
/XRT
CHEMOTHERAPY ALONE
clear cellIA or IB
IC (rupture only+ no sharp dissection)
**IC (non rupture); IC rupture
+ sharp dissection; II
III-IV
mucinousIA or IB and G1, G2I G3; IC (any); IIIII-IV
endometrioidIA or IB or IC rupture alone and
grade 1 or 2
I G3; **IC (not due to rupture); IIIII-IV
serous G1/G2IA or IB or IC rupture aloneIC (not due to rupture alone)
II
III-IV***
[B] Type 2
serous G3--Any stage
un-
differentiated
endometrioid G3
--Any stage
​MMMT--Any stage

Table 1. Stage specific Histology Driven Treatment Paradigm

** IC with presence of surface involvement and/or cytologic positivity

*** consider hormonal maneuver if ER positive

Epithelial ovarian cancer is no longer regarded as a single entity but instead as different subtypes with differing underlying genotypes, resultant histology, and differing outcomes.

Low Risk Patients (<10% risk relapse)

  • Fully staged stage IA, IB or IC (due to rupture alone) that are grade 1 or 2, any histology. 
    Exception mucinous IC based upon rupture (see Intermediate Risk)
  • Clear cell stage IA, IB or IC (with no use of sharp dissection and rupture alone leading to IC designation)

 Highly likely cured by surgery alone and require no further therapy.

 If surgical staging was inadequate then can either surgically re-stage (to potentially avoid adjuvant therapy) or treat as per Intermediate Risk.

Intermediate Risk Patients (10-40% risk relapse)

  • Stage IA, IB or IC, grade 3, endometrial or mucinous
  • Stage IC (surface positive and/or cytologically positive) endometrioid grade 1 and 2
  • Stage IC mucinous, any grade
  • Stage IC clear cell with any of:  surface positivity, positive washings or use of sharp dissection
  • "Under-staged" low risk patients and re-staging not carried out.
  • Stage II, any grade:  endometrioid, mucinous, clear cell

NB:  Clear cell is not grade 3 (no grading is applied)

Treat with 3 cycles of platin/taxane combination therapy (GOOVCATM; GOOVCATD; clear cell use GOOVIPCC or GOOVCATM and then pelvic XRT.  If XRT contraindicated, treat with 6 cycles of chemotherapy instead.

High Risk Patients (40-90% risk relapse)

  • Stage III or IV, any histology
  • Stages I and II, serous G3 or MMMT or undifferentiated

Standard therapy is debulking surgery (preferably primary but interval if optimal debulking (< 1 cm residual) is thought to be unlikely (see surgery section).

A variety of chemotherapy options based upon platin/taxane are available.  For those optimally debulked stage III patients (residual < 1 cm maximum size) at primary surgery or stage I/II grade 3 serous histology, two options are available: GOOVIPCC if can be treated at a centre providing intraperitoneal chemotherapy or dose-dense therapy (GOOVDDCAT). For those with residual > 1 cm recommend dose dense (GOOVDDCAT) but can use treatment every 3-4 weeks per GOOVCATX/GOOVCADX.  Standard number of cycles is 6 but more, usually with single agent carboplatin alone, are an option if there is still remaining cancer (upon imaging or tumor markers > ULN) and there has been no undue toxicity.

  • Dose dense (GOOVDDCAT) superior to standard "GOOVCATX" in a phase III study in women who were stage II-IV for high grade serous (no benefit seen for low grade (G1G2) and clear cell)
  • For those unable to tolerate such programs, single agent carboplatin is used (GOOVCARB)

C. Relapsed Ovarian Cancer

There are multiple options for treatment including surgery, radiotherapy and a variety of chemotherapies, including clinical trials or hormonal manipulation.  If patient is not already being followed at BCCA then referral to either a regional cancer centre or to a community, BCCA linked oncology centre is highly recommended.

D. Epithelial Tumours of Low Malignant Potential (Borderline)

Surgery is the cornerstone of therapy as per invasive ovarian cancer. For those desiring to maintain fertility unilateral salpingo-oophorectomy is adequate providing other ovary is clinically normal on abdominal exploration. We recommend a review of the pathology and assessment either in person or by review of operative reports, etc by the BCCA Gynecology Tumor Group at one of the regional centres. In this way we can identify the minority of such patients with biologically more aggressive tumours (those stage II or greater with invasive extra-ovarian implants) that could benefit from further therapy, eg chemotherapy or hormonal manipulation.

E. Estrogen Replacement Therapy: Site Specific Information

The relationship between estrogen and ovarian cancer is obscure. It is known that there are both estrogen and progesterone receptors present in many epithelial ovarian tumours. Unfortunately, the effects of exogenous hormones on these receptors are not well known. There is no convincing evidence that estrogen has either the potential to promote recurrence or to decrease the time to recurrence.

In the absence of scientific evidence to the contrary, it is not felt necessary to withhold estrogen replacement therapy from any symptomatic woman with ovarian malignancy regardless of risk category.

Recommendation:

In the absence of a uterus, estrogen alone.

With uterus in situ, continuous estrogen plus progesterone

            ***  consider hormonal maneuver if ER positive 

F. Intraperitoneal Chemotherapy

Intraperitoneal chemotherapy - pdf file

1.5 Follow-up

​Updated 24 January 2014

There are no data that prove the optimal follow-up durations or even the value of follow-up in an asymptomatic individual with regard to survival. As such the following are suggestions only.

Year 1 + 24 months
Year 3 + 56 months
Years 5+Annually

Note: follow-up consists of general exam and pelvi-rectal exam. Annual Pap smear screening is not required in women who have undergone a hysterectomy as part of their treatment. Women who have not had a hysterectomy should have cervical screening as per BCCA recommendations.

Other investigations, such as tumor markers, are not required other than for the satisfaction of research protocol and for specific indications when they arise or when the patient would like them done. NB: There is phase III evidence that early intervention with chemotherapy-based upon marker elevation alone does not increase quantity of life but does adversely impact quality.

SOURCE: Ovary - Epithelial Carcinoma ( )
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