Suspected Ovarian Masses in Pre & post-menopausal Women

INTRODUCTION

Ovarian cysts are common in postmenopausal women – most found incidentally
Exact prevalence in postmenopausal women is unknown (5-17%)
Ovarian cysts considered significant, if they are ≥1cm in size in postmenopausal women and ≥3 cm in premenopausal women
Symptomatic ovarian cyst in a premenopausal female being malignant is approximately 1:1000 increasing to 3:1000 at the age of 50.
10% of suspected ovarian masses à found to be non-ovarian in origin

The underlying management rationale is to minimise patient morbidity by:
- Conservative management where possible
- Use of laparoscopic techniques where appropriate
- Referral to a gynaecological oncologist where appropriate.
Functional / simple cysts < 5 cm (thin-walled cysts without internal structures) usually resolve in 2-3 menstrual cycles without need for intervention in premenopausal women
Benign ovarian masses – laparoscopic approach is gold standard & cost-effective.
On rare occasions – laparoscopy contraindication
Mini-laparotomy may be considered – very large cysts of benign appearance.
Borderline ovarian tumours
- Histological diagnosis
- Preoperative diagnosis can be difficult
- Serum markers – relatively insensitive
- Majority have suspicious USS finding & up to 20% of appear as simple cysts
Suspicious of malignancy need proper staging laparotomy

AIM – DIFFERENTIATE BENIGN FROM MALIGNANT

PRESENTATION IN PREMENOPAUSAL WOMEN

Acute pain (torsion or rupture of a cyst) requiring immediate evaluation
Features of endometriosis
Abdomino-pelvic lump / Non-specific symptoms (LOA / LOW)
Found incidentally- while investigating for other conditions
Identified during gynaecological investigations

PRESENTATION IN POSTMENOPAUSAL WOMEN

Most found incidentally- while investigating for non-gynaecological conditions
Identified during gynaecological investigations (PMB)
Acute pain (torsion or rupture of a cyst) requiring immediate evaluation

HISTORY

Symptoms suggesting of ovarian malignancy (vague abdominal symptoms)
- persistent abdominal distension
- feeling full
- appetite change (loss of appetite)
- increased satiety
- pelvic or abdominal pain
- increased urinary urgency and/or frequency
Symptoms suggestive of endometriosis
Acute presentation (torsion, rupture, haemorrhage).
Risk factors or protective factors for ovarian malignancy
Family history of ovarian or breast cancer

FAMILY HISTORY CRITERIA OF HIGH RISK FOR DEVELOPING OC

Considered high risk if, she has a first-degree relative (mother, father, sister, brother, daughter or son) affected by cancer within a family with

≥ 2 individuals with ovarian CA, who are first-degree relatives of each other
One individual with ovarian CA at any age & one with breast CA diagnosed under age 50 years who are first-degree relatives of each other
One relative with ovarian CA at any age & two with breast CA diagnosed under age 60 years who are connected by first-degree relationships
≥ 3 family members with colon CA, or two with colon CA & one with stomach, ovarian, endometrial, urinary tract or small bowel CA in two generations. One of these cancers must be diagnosed under age 50 years and affected relatives should be first-degree relatives of each other
One individual with both breast and ovarian CA
Known carrier of relevant cancer gene mutations (BRCA1,2 & mismatch repair genes)
She is an untested first-degree relative of an individual with a relevant cancer gene mutation (e.g. BRCA1, BRCA2, mismatch repair genes)

She is an untested second-degree relative, through an unaffected man, of an individual with a relevant cancer gene mutation (e.g. BRCA1, BRCA2, mismatch repair genes.

EXAMINATION (poor sensitivity of 15–51%)

General
- BMI
- Local lymphadenopathy
Abdominal
- Palpable mass
- Mass tenderness
- Mobility
- Nodularity
- Ascites
Vaginal examination
Rectal examination

(Features most consistently associated with carcinoma include a mass that is irregular, has a solid consistency, is fixed, nodular, or bilateral, or is associated with ascites)

INVESTIGATIONS (To triage women and guide further management)

Blood tests
YOUNG WOMEN (<40 YEARS WITH A COMPLEX OVARIAN MASS)
LDH, α-FP & hCG (possibility of germ cell tumours)
CA-125
1. No need if simple ovarian cyst
1. Unreliable in differentiating benign from malignant
If CA-125 is raised
1. Serial monitoring – rapidly rising levels more favour malignancy than high levels which remain static
1. < 200 units/ml àmay need further investigation to exclude/treat the common differential diagnoses
1. > 200 units/ml à discussion with a gynaecological oncologist

PERI, POST-MENOPAUSAL WOMEN
CA125
- Only serum tumour marker used for primary evaluation as it allows the RMI calculation in postmenopausal women
- Should not be used in isolation to determine if a cyst is malignant
- Very high value may assist; a normal value does not exclude the diagnosis of ovarian cancer due to the nonspecific nature of the test.
- Widely distributed in adult tissues.
- Raised in over 80% of epithelial ovarian cancer cases, but not in most primary mucinous ovarian cancers
- Cut-off value of 35 iu/ml (sensitivity and specificity of 78%)
- Lower levels (20 iu/ml) found in healthy postmenopausal women
- Raised in numerous conditions

Lower level
- Caffeine intake / Hysterectomy / Smoking
Primarily a marker for EOC and is only raised in 50% of early stage disease
- Other tumour markers
  - There is currently not enough evidence to support the routine clinical use of other tumour markers, such as human epididymis protein 4 (HE4), carcinoembryonic antigen (CEA), CDX2, cancer antigen 72-4 (CA72-4), cancer antigen 19-9 (CA19-9), AFP, LDH or β-hCG) to assess the risk of malignancy in postmenopausal ovarian cyst
  - HE4
    - Glycoprotein found in epididymal epithelium
    - Increase levels and expression of the HE4 gene occurs in
      - Ovarian cancer
      - Lung
      - Pancreas
      - Breast
      - Bladder/ureteral transitional cell
      - Endometrial cancers
    - Not increased in endometriosis
    - More sensitive & specific than CA125 in the diagnosis of ovarian CA
    - Combination of HE4 & CA125 is more specific but less sensitive than either marker in isolation
    - HE4 is not in routine clinical use currently
  - Inhibin
    - Use as a marker for mucinous and granulosa cell
Imaging
- Pelvic ultrasound
- TVS – preferable over TAS due to its increased sensitivity.
- TVS (sensitivity – 89% & specificity – 73%)
  - Single most effective way of evaluating ovarian cysts
- TAS
  - Should not be used in isolation.
  - Provide supplementary information to TVS particularly when an ovarian cyst is large or beyond the field of view of TVS
  - For extra-ovarian disease.

Mainly in post-menapausal wome

The morphological description & subjective assessment of the ultrasound features should be clearly documented to calculate RMI
- Features of ‘simple cyst’
  - Round or oval shape
  - Thin or imperceptible wall
  - Posterior acoustic enhancement
  - Anechoic fluid
  - Absence of septations or nodules.
- Ovarian cyst is defined as complex in the presence of one or more features
  - Complete septation (multilocular cyst-8% risk of malignancy)
  - Solid nodules (36-39% risk of malignancy)
  - Papillary projections.
- Premenopausal ovarian cysts with a solid component
Same like Postmenopausal ovarian cysts +
- Endometrioma
  - Torted & necrotic ovary
- Postmenopausal ovarian cysts with a solid component
  - Benign
    - Some teratomas
    - Cystadenomas
    - Cystadenofibromas
    - Torted ovary
  - Malignant
    - Primary
    - Metastatic
- USS features suggestive of malignancy
  - Size
  - Internal borders
  - Papillary projections
  - Echogenicity
  - Mural nodules / septations (especially with vascular flow)

If initial imaging modality was a CT scan, unless this clearly indicated ovarian malignancy and widespread intra-abdominal disease, an ultrasound scan should be obtained in order to calculate the Risk of Malignancy Index (RMI)

Doppler and three-dimensional ultrasound

Colour flow Doppler – not significantly improve diagnostic accuracy and not essential for the routine initial assessment
- TVS with colour flow mapping and 3D imaging may improve sensitivity, particularly in complex cases
- 3D USS morphologic assessment not improve the diagnosis of complex ovarian cysts and its routine use is not recommended
- ‘Pattern recognition’ can produce sensitivity and specificity equivalent to logistic regression models, when performed by experienced clinicians
- Spectral and pulse Doppler indices should not be used routinely (resistive index, pulsatility index, peak systolic velocity, time-averaged maximum velocity) to differentiate benign from malignant ovarian cysts, as not having significant diagnostic accuracy over morphologic assessment by ultrasound scan [Malignant masses generally demonstrate neovascularity, These neovessels have lower resistance flow than native ovarian vessels]
- ultrasound assessment in the postmenstrual phase may be helpful in cases of doubt and endometrial views may contribute to diagnosis in cases of estrogen-secreting tumours
CT/MRI
- No further imaging beyond TVS in the presence of apparently benign
- May have a place in the evaluation of more complex lesions
- CT and MRI does not improve the sensitivity or specificity obtained by TVS in the detection of ovarian malignancy.
CT scan
- Should not be used routinely as the primary imaging
  - Low specificity
  - Limited assessment of ovarian internal morphology
  - Use of ionising radiation
- If, from the clinical picture, USS findings & tumour markers, malignant disease is suspected, a CT scan of the abdomen & pelvis should be arranged, with onward referral to a gynaecological oncology multidisciplinary team.
- Can detect omental metastases, peritoneal implants, pelvic or para-aortic lymph node enlargement, hepatic metastases, obstructive uropathy and possibly an alternate primary cancer site, including pancreas or colon
MRI
- Should not be used routinely as the primary imaging tool for the initial assessment
- Second-line imaging modality for the characterisation of indeterminate ovarian cysts when ultrasound is inconclusive
PET-CT scan
- Not support the routine use of PET-CT scanning in the initial assessment
- No clear advantage over TVS
- PET-CT may play a role in women with a known Hx of malignancy who present for evaluation of an adnexal mass to identify other sites of disease

SCREENING FOR OVARIAN CANCER

Due to the limitations of genetic testing at the present time, it is imperative that it is offered only to high-risk individuals (≥10% lifetime risk based on family Hx) may be offered screening
The best currently available modalities for screening are still these of pelvic ultrasound scan and the tumour marker CA 125

TRIALS:

PLCO cancer screening trial -screening for OC fails to decrease mortality but does increase unnecessary surgery rate
UKCTOCS – a large trial evaluating an algorithm (risk of ovarian cancer algorithm) which is based on changing levels of CA125 and a rigorous ultrasound protocol à No evidence to support screening for ovarian cancer in asymptomatic women
The ROCkeTS trial aims to identify the best tests and diagnostic pathways in pre and postmenopausal women with symptoms in primary and secondary care and wil report in 2018

POSTMENOPAUSAL WOMEN – INITIAL ASSESSMENT & ESTIMATION OF THE RISK OF CA

CLINICAL COURSE

Adnexal cysts 5 cm or smaller in postmenopausal women are rarely malignant
Asymptomatic postmenopausal women with simple cysts smaller than 5 cm,
- Disappear (53%)
- Remain static (28%)
- Enlarge (11%)
- Decrease (3%)
- Fluctuate in size (6%)

ESTIMATION THE RISK OF MALIGNANCY IN POSTMENOPAUSAL WOMEN

Simple models
- Discrete cut-off values of
  - CA-125
  - Pulsatility index
  - Resistance index
Intermediate models
- Morphology scoring systems – International Ovarian Tumor Analysis (IOTA)
- Risk of malignancy index (RMI)
Advanced models
- Artificial neural networks
- Multiple logistic regression models

RISK OF MALIGNANCY INDEX (RMI)

RMI is simple to use and reproducible
Its utility is negatively affected in the premenopausal woman
RMI I and RMI II have been sufficiently validated
RMI I is the most effective for women with suspected ovarian cancer
Is the product of three presurgical features:
CA-125 (CA-125)
Menopausal status (M)
Ultrasound score (U)

RMI = U x M x CA-125.

Ultrasound – scored 1 point for each of the following characteristics
- Multilocular cysts
- Solid areas
- Metastases
- Ascites
- Bilateral lesions
U = 0 (for an ultrasound score of 0)
U = 1 (for an ultrasound score of 1)
U = 3 (for an ultrasound score of 2–5)
The menopausal status
- 1 = premenopausal
- 3 = postmenopausal
- Postmenopausal – women who have had no period for more than one year or women over the age of 50 who have had a hysterectomy
Serum CA-125 is measured in IU/ml (Absolute value)

RMI I (score of 200) sensitivity 78%, specificity 87%

IOTA

Simple ultrasound rules – specific ultrasound morphological findings
Without CA-125 – have high sensitivity, specificity and likelihood ratios
Sensitivity – 95%, specificity – 91%, PLR – 10.37 and NLR – 0.06
Help to classify masses as benign (B-rules) or malignant (M-rules)
Women with any one of the M-rules USS findings should be referred to a gynae oncological service

ROMA

Quantitative test using CA125, HE4 level & menopausal status to calculate the risk of ovarian CA
Cut-off value of 2.27 representing a high risk of malignancy.
It must be interpreted in conjunction with an independent clinical and radiological assessment
Not intended to be a screening or a standalone diagnostic assay.
Sensitivity – 89% & specificity – 75%.
Distinguishing EOC from benign ovarian cysts (Not increases in endometriosis)

OVA1

A quantitative assay measuring five serum proteins CA125, transthyretin [prealbumin], apolipoprotein A1, beta-2-microglobulin and transferrin
A numerical score is calculated (range 0.0–10.0), with a value higher than 4.4 being indicative of a high risk of malignancy in postmenopausal women.
High sensitivity, lower specificity and positive predictive value than the RMI

MANAGEMENT IN PREMENOPAUSAL WOMEN

Ovarian cyst is ‘a fluid-containing structure of >3 cm in diameter
4% of women has ovarian cyst >3 cm in diameter in their luteal phase
Asymptomatic simple cysts 3-5 cm in diameter do not require follow-up, very likely to be physiological & almost always resolve within 3 menstrual cycles
Combined OCP does not promote the resolution of functional ovarian cysts.
Cyst 5-7 cm require follow-up with yearly ultrasound
Cysts > 7 cm should consider – further imaging (MRI) or surgical intervention

Persistent, asymptomatic ovarian cysts

Persist or increases in size are unlikely to be functional and may warrant surgical management after several cycles.
Mature cystic teratomas (dermoid cysts) have been shown to grow over time, increasing the risk of pain and ovarian accidents.
Surgical after preoperative assessment using RMI 1 or ultrasound rules (IOTA)

Laparoscopic approach VS laparotomy

Laparoscopy for elective surgical management of presumed benign ovarian masses
- Lower postoperative morbidity
- Shorter recovery time
- Reduced febrile morbidity
- Less postoperative pain
- Lower rates of postoperative complications
- Cost-effective – earlier discharge from hospital and return to work
Large masses with solid components (large dermoid cysts) laparotomy may be appropriate – Maximum cyst size above which laparotomy should be considered is controversial

Ovarian cyst aspiration

Aspiration of ovarian cysts, either vaginally or laparoscopically, is less effective
Resolution rates of simple ovarian cysts – similar to expectant management
Associated with a high rate of recurrence 53-84%
Aspiration may be an appropriate intervention in selected cases

Unplanned cyst rupture

Spillage should be avoided where possible
Preoperative & intraoperative assessment cannot absolutely preclude malignancy
Dermoid cyst rupture (<0.2%) – Chemical peritonitis
Endometrioma (> 3 cm) – histology should be obtained
- to confirm endometriosis
- to exclude rare cases of malignancy.
Any solid content should be removed using an appropriate bag
Meticulous peritoneal lavage of the peritoneal cavity (If cyst ruptured)
- Using large amounts of warmed fluid.
- Not to use of cold irrigation fluid
  - Cause hypothermia
  - Solidifying the fat-rich contents – make retrieval more challenging

Removal after laparoscopy

Various types of laparoscopic tissue retrieval bags
Where possible removal of benign ovarian masses should be via the umbilical port.
- Less postoperative pain
- A quicker retrieval time
Avoidance of extending accessory ports
- Beneficial in reducing postoperative pain
- Reducing incidence of incisional hernia
- Reducing incidence of epigastric vessel injury
- Improved cosmesis

Oophorectomy

Possibility of removing an ovary should be discussed preoperatively
Pros and cons of electively removing an ovary should be discussed
- Pros
  - Avoid upgrading if malignant (to 1c)
- Cons
  - B/L Oophorectomy
    - Surgical menopause
  - U/L Oophorectomy
    - Reduction of ovarian follicular reserve (remaining ovary does compensate)
    - Overall effect on age at onset of menopause is small
Consideration the woman’s preference and the specific clinical scenario.

MANAGEMENT IN POSTMENOPAUSAL WOMEN

Aim – to differentiate benign cysts from malignant based on the clinical assessment & RMI

Low likelihood of malignancy can be managed conservatively
Selected cases of RMI < 200 can be managed laparoscopic salpingo-oophorectomy after discussion with the patient.
Likely to be malignant are best managed with further imaging in the form of a CT scan and referral to a gynaecological oncologist.

Asymptomatic, simple, unilateral, unilocular ovarian cysts, less than 5 cm in diameter, have a low risk of malignancy. With normal CA125 levels, can be managed conservatively, with a repeat evaluation in 4–6 months.
Discharge from follow-up after 1 year if the cyst remains unchanged/reduces in size, with normal CA125, taking into consideration a woman’s wishes & surgical fitness.
If a woman is symptomatic or a suspicious/persistent complex adnexal mass è Surgical evaluation

PROS AND CONS OF CONSERVATIVE VERSUS SURGICAL MANAGEMENT

Simple cysts did not increase the risk of subsequent invasive ovarian cancer
Risk of malignancy in simple cysts < 5 cm, unilateral, unilocular and echo-free with no solid parts or papillary formations is less than 1% and 50% of these simple cysts might resolve spontaneously within 3 months
It is reasonable to manage these simple cysts conservatively with the follow-up assessment of serum CA125 and a repeat ultrasound scan.
Ideal frequency of follow-up is yet to be determined.
A reasonable proposed interval is 4–6 months.
This depends on clinical assessment, surgical fitness & the views and symptoms of the woman.
Reasonable to discharge from follow-up after 1 year if the cyst remains unchanged or reduces in size, with normal CA125.
Surgical interventions are at substantial risk of perioperative morbidity and mortality.

SURGICAL OPTIONS

Not fit the criteria for conservative management should offer surgical treatment in the most suitable location & set-up and by the most suitable surgeon as determined by the RMI

Imaging-guided aspiration
- Aspiration is not recommended except for the purposes of symptom control in women with advanced malignancy who are unfit for surgery or further intervention
- No role in the management of asymptomatic ovarian cysts in PM women
- Diagnostic cytological examination of ovarian cyst fluid is poor at distinguishing between benign and malignant (sensitivity – 25%)
- Benign cyst
  - Is often not therapeutic (25% will recur within 1 year)
- Malignant cyst
  - May induce spillage and seeding of cancer cells into the peritoneal cavity, thereby adversely affecting the stage and prognosis (upgrade to 1c)
  - May recurring along the needle track through which aspiration was done
  - Strong evidence that spillage from a malignant cyst has an unfavourable impact on overall and disease-free survival of stage I cancer patients compared with patients from whom tumours have been removed intact
Laparoscopy
- Not eligible for conservative management but still have a relatively low risk of CA
- RMI I < 200 (low risk of malignancy)
- Should comprise bilateral salpingo-oophorectomy rather than cystectomy.
- Should be counselled preoperatively that a full staging laparotomy will be required if evidence of malignancy is revealed.
- Transvaginal extraction of specimen is also acceptable, if experienced surgeon
  - A safe, feasible, and applicable technique
  - Less of postoperative pain compared with transumbilical retrieval
Laparotomy
- Suspicious of malignancy require a full laparotomy and staging procedure
  - RMI I greater than or equal to 200
  - Suggestive CT findings
  - Clinical assessment suspicious of malignancy
  - Ovarian cancer is discovered during laparoscopic surgery or on histology