Download ACOG Practice Bulletin No 174, Nov 2016

‫به نام خداوند بخشنده و مهربان‬
Adnexal Mass
Observation vs Intervention
M.Mohit
Gynecologist Oncologist
NAIGO, Bahman 1395
Ovarian Cancer
• Ovarian Cancer is a Major Women's Health Problem
• 7th most common cancer in women in US: 3% of all female
malignancies
• About 1/3 of invasive female genital organ cancers
• Deadly disease with High morbidity and mortality
• 4th cause of women cancer mortality (6%) : 1/ 44 min
• Leading cause of death of gyn malignancies: 53% death of
gyn cancers
Epidemiology of ovarian cancer
• Highest fatality/case ratio of all the gynecologic malignancies
• fatality /case:
- Ovarian ca:
15520 /21650 ≈ 80/100
- Cervical ca:
3710 /10500 ≈ 37/100
- Endometrial cancer:
7310 /40800 ≈ 16/100
Epidemiology of ovarian cancer
- Age
• Peak incidence: 56-60 y/o, rises from 20-80 ,then decline
• Ovarian mass: Age < 40 : 1/10 invasive or borderline
Age > 40 : 1/3 invasive or borderline
- Postmenopause: 30% of neoplasms are malignant
- Premenopause: 7% of epithelial neoplasms are malignant
• Epithelial cancers: the most common ovarian cancer
• Ovarian ca before age 20: 1% epithelial, 2/3 germ cell
Ovarian Cancer
• Greatest clinical challenge in all gynecologic cancers
• Usually asymptomatic until advanced disease: >2/3 at diagnosis
• Major surgical challenge, requires intensive & often complex
therapies, extreme demand in pt's psychological & physical energy
• Appropriate diagnosis & optimal treatment can improves survival:
- Early stage diagnosis
- Optimal surgery ( gyn oncologist, High volume surgeons & centers)
- Suitable chemotherapy
Survival Rates for Ovarian Cancer Need to be Improved
Ovarian Cancer 5-yr Survival Rate by Stage
Stage Distribution
at Diagnosis
Survival Rate
Stage I
20-27%
73-93%
Stage II
5-10%
45-70%
Stage III
52-58%
21-37%
Stage IV
11-17%
11-25%
stage
Heintz APM, et al. FIGO Annual Report on the Results of Treatment in Gynecologic Cancers. 2000; 24 :107-138.
Holschneider CH, Berek JS. Semin Surg Oncol. 2000;19:3-10.
Surgery can Impact Survival
• Surgery by gynecologic oncologist:12 month survival advantage
• Complete surgical staging / Cytoreductive surgery
• Complete surgical staging: to Define extent of disease, Determine the
need for adjuvant treatment, Provide prognosis, Outline a plan of care
• Optimal surgical debulking: remove all tumor in advanced tumor by
Hysterectomy, removal of ovaries, omentectomy, bowel resection if
needed, peritoneal stripping, diaphragmatic stripping, l.n. debulking, …
Oncology Specialist Most Likely to
Perform Comprehensive Surgery
*Ovarian Cancer Surgery by: Surgeon
Surgeon Specialty
Rate of Comprehensive
Surgery
Gynecologic oncologist
75.7%
Obstetrician gynecologist
37.3%
General surgeon
38.5%
* South Carolina admissions
Goff BA et al. Cancer. 2007;109(10):2031-2042.
High Volume Surgeons Most Likely to
Perform Comprehensive Surgery
Ovarian Cancer Surgery by: Surgeon
Surgery Volume
Very Low
1 case/year
Low / Medium
2-9 cases/year
High
≥ 10 cases/year
Goff BA et al. Cancer. 2007;109(10):2031-2042.
Percentage
of Cases
Rate of
Comprehensive
Surgery
25.2%
55.2%
22.7%
65.1%
52.1%
75.2%
Less than Half of US Ovarian Cancer
Surgery is at High Volume Hospital
Ovarian Cancer Surgery by: Hospital
Surgery Volume
Low
1-9 cases/year
Medium
10-19 cases/year
High
≥ 20 cases/year
Goff BA et al. Cancer. 2007;109(10):2031-2042.
Percentage
of Cases
Rate of
Comprehensive
Surgery
33.3%
57.4%
18.1%
69.5%
48.6%
73.7%
Significantly Higher Survival Rates
with Oncology Specialists
Type of Hospital
Impacts Survival Rates
1.0
1.0
0.8
0.8
Cumulative Survival
Cumulative Survival
Type of Surgeon
Impacts Survival Rates
0.6
0.4
0.2
0.6
0.4
0.2
0.0
TH: Teaching hospital
NTH: Nonteaching hospital
0.0
0
200
400
600
800
Survival in days
Paulsen T et al. Int J Gynecol Cancer. 2006;16(Suppl 1):11-17.
1000
0
200
400
600
Survival in days
800
1000
Adnexal mass
• Frequently found in both symptomatic and asymptomatic women
• Frequency: 7.8% in reproductive age, 2.5-18% in postmenopausal
• Usually detected by gynecologist, most incidentally in pelvic exam or imaging
and less commonly present with acute or intermittent pain
• Can have gynecologic or non-gynecologic etiologies
- Gynecologic: ovarian(benign or malignant), tubal(hydrosalpynx , EP, …),
paratubal, uterine( leiomyoma, anomalies, hemato or pyometra,…)
- Non-Gynecologic: GI, urologic, metastatic, retroperitoneal tumors ( LAP,
sarcoma, neurologic tumors),…
Adnexal mass
• The discrimination between benign and malignant adnexal masses is central to
clinical management and surgical planning in adnexal mass
• Characterizing ovarian pathology is fundamental to optimizing management in
both pre- and post-menopausal women:
- Inappropriate referral to oncology services
- Unnecessary surgery
- Overly radical interventions compromising fertility in young women
• For adnexal masses highly suspicious for cancer, women should be referred a
gynecologic oncologist and facility for optimal care.
• Failing to recognize cancer significantly impact on prognosis
Adnexal mass
• Main purpose of the diagnostic evaluation of adnexal tumors is to
exclude the possibility of malignancy
• Prediction of malignancy of an ovarian mass is critical for:
- Management ( surgery vs observation)
- Choice of surgeon
- Center and
- Surgical technique
• Accurate preoperative evaluations are pivotal for optimal managemen
Evaluation of adnexal mass:
How to predict the risk of malignancy in adnexal mass?
• Goal of our diagnostic evaluations on a pelvic mass?
prediction of it’s behavior/exclude malignancy
• How we can exclude malignancy?
• Is there any tool for definite diagnosis?
‫‬‫«در شناختن حق بیشتر خالف در میان خلق چنین است که‬
‫لکن‬
‫همه از وجهی راست گفته باشند و‬
‫بعضی را ببینند‪ ،‬پندارند که همه را بدیدند ومثال‬
‫ایشان چون گروهی نابینا باشد که‪».....‬‬
‫کیمیای سعادت امام محمد غزالی‬
‫پیل اندر خانه ای تاریک بود‪...‬‬
‫در کف هر یک اگر شمعی بدی‬
‫اختالف از گفتشان بیرون شدی‬
‫چشم حس همچون کف دست است و بس‬
‫نیست کف را بر همه او دسترس‬
Evaluation of pelvic masses
• Clinical evaluation of patient (patient’s characteristics, risk
factors, history and physical examination), imaging results
and serum markers help us to separate masses into the
categories of “probably benign”, “uncertain” and “likely
malignant” which can guide appropriate management.
Tools for Assessing Risk of Ovarian Cancer in a Mass
Tools as malignancy marker:
• Clinical:
- History: age , menopausal status, family history, Wt loss,..
- P/E : firm nodular adherent pelvic mass, evidences of advanced tumor
• Paraclinical:
- Imaging (Sono, CT and MRI): bilaterality, solid part, large tumor size(
>10cm), mural nodules and vegetation, thick wall and septation, detection of
omental or peritoneal nodularity and seeding, ascites, lymphadenopathy
- Serum tumor markers: CA125, …
• Combinations of markers
Clinical evaluation
Risk factors:
• Age: most important independent risk factor of ovarian cancer, about 70% >
55y/o
• Menopausal status: risk of malignancy is much greater than premenopausal
• Familial history of breast or ovarian cancer: most important personal risk factor
of ovarian cancer. Different from familial ovarian cancer syndrome
- lifetime probability of general population: 1.6%
- one affected family member: 5%
- woman with BRCA1 mutation: 41-46% by age 70
- woman with BRCA1 mutation: 10-27% by age 70
- woman with Lynch syndrome: 5-10% by age 70
ACOG Practice Bulletin No 174, Nov 2016
Clinical evaluation
• Detailed history and Symptoms:
• Patient may present history and symptoms that can refine the differential
diagnosis: genetic/familial high risk assessment, potential of pregnancy,
acute onset pain, intermittent acute pain, fever, chills, vaginal discharge,
secondary dysmenorrhea, dyspareunia, chronic pelvic pain, AUB, bloating,
early satiety, wt loss,…
• Physical examination: irregular, firm, nodular, bilateral mass or associated
with ascites are concerning for malignancy
ACOG Practice Bulletin No 174, Nov 2016
Imaging of mass
• Ultrasonography:
- TVS: most commonly used for evaluation of adnexal mass
- TAS: distorted pelvic structures, mass extended beyond the pelvis or
when TVS cannot be performed
• Color Doppler ultrasonography
• CT, MRI, PET: not recommended for initial evaluation of adnexal mass
TVS
• Transvaginal ultrasound has long been considered the imaging
modality of choice for the evaluation of adnexal masses:
- Available, high quality images, detailed descriptions of macroscopic
appearance of mass, and least expensive of all imaging modalities
currently available
• Advantage: widespread availability, good pt tolerability, cost
effectiveness
• Main limitation for distinguishing benign from malignant mass: low
specificity, low PPV especially in premenopausal women
Gray scale TVS
• Recommended modality for suspected adnexal mass
• No alternative imaging modality has sufficient superiority to TVS to
justify its routine use
- High frequency gray scale TVS: high resolution images of mass that
approximate it’s gross anatomic appearance
• Image quality is operator dependent
• High inter-observer agreement among experts
• In premenopause: expert sonography reached the highest
discriminative power with PPV of 0.45, and an NPV of 0.99.
MR Imaging
• MRI: limited data
• May have superior ability compared to TVS in correctly classifying
malignant masses at the expense of lower detection rate. Help
clarify malignant potential in patients in whom ultrasonography
may be unreliable, MRI is the most appropriate test
• Often helpful in differentiating the origin of pelvic masses that are
not of ovarian origin, specially leiomyoma
CT
• CT: best use of CT is not to detect or characterize pelvic masses
but to evaluate:
• In cases in which extra-ovarian disease and abdominal
metastasis suspected or needs to be ruled out, CT is the most
useful technique
• To evaluate an alternate primary cancer site when cancer is
suspected based on sono, P/E or serum markers
Doppler technology
• Doppler technology: Evaluation of an adnexal mass by Doppler technology
alone is not recommended. Doppler technology should be combined with a
morphology assessment
• Increase the specificity of two dimensional gray scale sonography
• Overlapping range of values of resistive index, pulsatility scale, max systolic
velocity between benign and malignant masses
• In attempt to overcome this overlap: Three dimensional ultrasound of
vasculature of mass, better discrimination than Doppler sono
What ultrasound finding suggest malignancy?
• Findings should raise concern regarding malignancy are:
- Size: greater than 10 cm
- Papillary or solid component
- Irregularity
- Ascites
- High color Doppler flow
• Many research on different various ultrasonographic scoring
systems to quantify cancer risk based on morphology
• Generally all evaluated scoring systems were found to have an
acceptable level of sensitivity and specificity
What ultrasound finding suggest benign disease?
• Characteristics of benign masses: simple appearance with
- Thin smooth walls
- Absence of septation, solid component
- Absence of internal blood flow in Doppler
• Highly likely (almost always) to be benign in any age group
regardless of menopausal status and often regress
• Malignancy rate in most series: 0-1%
Cutoff size of need for surgery of simple masses
• Cutoff size of need for surgery of simple masses:??
• Often ≥ 10 cm
• Large prospective study: 2763 postmenopause cystic < 10 cm 2/3
regress, no case of malignancy in 6.3 y mean f.u.
Obstet Gynecol 2003;102:594.
• In 1148 unilocular cyst: 11, 0.96% were malignant (7/11 , sono did not
detect macroscopic papillary projection or solid part seen at surgery)
Ultrasound Obstet Gynecol 2013;41:80.
ACOG Practice Bulletin No 174, Nov 2016
Ultrasound finding suggest selected benign masses
• Some ultrasound findings may be specific for selected benign
masses (level II evidences, small descriptive studies):
- Endometrioma:
specificity 89%, sensitivity 83%, PPV 77%, NPV 92%
- Mature Teratoma:
98% accuracy in 155 case of dermoid
specificity 99%, sensitivity 58%
- Hydrosalpinx:
specificity 99%, sensitivity 93%,
Ultrasonography-based morphology scoring systems
• Generally various models all are able to distinguish benign from
malignant masses in most instances
• 2014 systematic review and meta-analysis compared various
morphologic (ultrasound scoring) malignancy prediction models.
Hum Reprod Update 2014;20:449-62
• Best performing models were:
- IOTA group logistic regression model 2(LR2):
patient age + 5 sono findings: sensitivity 92% , specificity 83%
- IOTA simple rules model:
including 10 ultrasound findings: sensitivity 93% , specificity 81%
ACOG Practice Bulletin No 174, Nov 2016
• Ultrasound based prediction model (LR2) developed by the
International Ovarian Tumor Analysis (IOTA) study offers better
diagnostic performance than CA125 alone.
Laboratory Testing
• To evaluate likelihood of malignancy and need for surgery of a mass
• CBC, pregnancy test, STD, U/A, stool-OB,...
• Serum markers: CA125, HE4, markers of less common ovarian
histopathology: BhCG, LDH, AFP, Inhibin,…
• CA125:
• Specificity and PPV are consistently higher in postmenopausal
• Cutoff : Premenopause: 30 U/ml
Postmenopause & hysterectomy: suggested 20 -26 U/ml
- Epithelial ovarian cancer: - 83% CA125 ≥ 35 IU/ml
- ↑ 50% in stage I
- ↑ 90% in more advanced stages
CA125
• Best known ovarian cancer serum tumor marker
• Biomarker in epithelial ovarian cancer
• Overall sensitivity in distinguishing malig: 61-90%, spec 71-93%
• PPV: 35-91, NPV 67-90%. wide variation
• Elevated only in ½ early stage, rarely elevated in germ cell,
stromal and mucinous
• Positive in many non malignant conditions: myoma, PID, ascites
of any etiology, endometriosis, IBD, SLE,…
CA125
• Limitations :
- Low specificity/ PPV in premenopausal years: Elevated levels in
benign gynecological diseases
- Low sensitivity/NPV: in Stage I ovarian cancer 50%.
CA 125 alone is not a sensitive marker for screening of pelvic mass
- Elevated level in some other cancers
- In premenopausal: Using > 35 U/mL as threshold 78% sensitivity
and 78% specificity
CA125
• In premenopause women:
• less value in prediction, extreme values increase suspicious and
concern for malignancy, even though benign conditions such as
endometrioma can have CA125 of 1000 or greater
• Threshold: ?, no evidence based threshold is currently available
• Prior ACOG guidance used ≥ 200 for referral of premenopause
• Gynecologist should integrate CA125 with other factors in
judging the need for referral
ACOG 2007 simple Guidelines for
referral of ovarian mass to GYN- Oncologist
• Premenopausal
• Postmenopausal
- CA125 > 200
- Ascites
- Evidence of metastasis
- Family history of breast
or ovarian cancer
- CA125 >35
- Ascites
- Fixed or nodular mass
- Evidence of metastasis
- Family history of breast
or ovarian cancer
ACOG Practice Bulletin. Obstet Gynecol. 2007;110:201-213.
CA125
• In postmenopause:
• Both sensitivity and specificity of elevated CA125 for cancer diagnosis
in setting of pelvic mass is higher after menopause
• Elevated CA125 + pelvic mass in post menopause: highly suspicious to
malignancy & should be referred to Gyn Oncologist
• In post menopause: ↑ CA125 without ovarian ca is a risk factor of
death from other malignancies
• Combinations of expert sonography with CA-125 serum measurement
in postmenopause achieved the highest discriminative power:
• Combination of CA-125 & expert sono: PPV 0.89 and NPV of 0.97
Dual Marker: CA125+ HE4
• 1997: Maggino et al. examined sens and spec of CA125 at various
cutoffs
• At cutoff of 35: sensitivity of 78.3% , specificity 82%
• Increasing cutoff to 65: sensitivity decreased to 71.7% and specificity
increased to 92.5%
• 20% of EOC express little, if any, CA125
• In early stage ↑ to 50%
• So: not sufficient as single marker
Dual marker: CA125+HE4
• 2007: Moore et al. examined a panel of biomarkers.
• Dual marker of HE4 + CA125: highest sensitivity of various
combinations, increased sensitivity of CA125 alone
• HE4 is elevated in > 50% of tumors that do not express CA125
• Addition of HE4 to CA125 enables higher detection of
malignancies in:
1- Patients with tumor that do not express CA125 and will be
missed by algorithm CA125 alone
2- Early stage disease compared with CA125
• So it’s addition to CA125: ↑ sensitivity
Panels of Serum Tumor Markers
- Panels of biomarkers:
- FDA approved two panel for assessment of risk of malignancy
in adult women (>18) with pelvic mass that require surgery:
• MIA: Multivariate Index Assay (OVA1™: CA125 II+ transferrin+
transthyrenin+ apolipoprotein A1+ B2 microglobulin)
• ROMA: Risk Of Ovarian Malignancy Algorithm(CA125 + HE4+
menopausal status)
ACOG Practice Bulletin No 174, Nov 2016
Role of Serum biomarker panel testing
• Alternative to CA125 alone in determining the need for
referral or gyn oncology consult when a mass need surgery
• Note: not recommended for use in initial evaluation of mass
• CA125 alone: 65.7% predict ovarian malignancy in early stage
MIA
• Multivariate index assay:
- Correctly predict in 91.4%
- Abnl in 83.3% of malignancies which clinical impression was benign
- Abnl in 70.8% of malignancies with normal CA125
- Sens: 95.3%. more than clinical impression and CA125
- Add radiologic finding to MIA:
↑ Sens to 98% ( for TVS) and 97%(for CT)
↑ NPV to 99% ( for TVS) and 94%(for CT)
Note: Low risk imaging + low risk MIA: < 1-2% false negative
ROMA
• Risk of malignancy algorithm (ROMA):
• More sensitive and specific than CA125 alone
• In cohort of 531 women with epithelial ovarian cancer 93.8% of diagnosed as
high risk before surgery
• Pre-menopause: sens 92.3% , spec 75%
• Post-menopause: sens 76.5%, spec 74.8%
• ROMA compared with MIA, Prospective analysis of 146 cases of malignancy:
- MIA was more sensitive than ROMA (97% VS 87%)
- ROMA was more specific than MIA (83% VS 55%)
- NPV of both tests were similar(98 vs 96%)
ultrasound Obstet Gynecol 2013;42:218.
Combination of different markers
• Sonography + CA125:
• In postmenopausal with adnexal mass seems to improve
sensitivity and specificity of predicting adnexal malignancies. In
contrast
• In premenopausal women the consideration of CA-125 levels
with Doppler sono might confuse differential of ovarian masses
• As a standalone modality, serum cancer antigen 125 is not
recommended for distinguishing between benign and malignant
adnexal masses
•
Multimodal tests and diagnostic algorithms
• Incorporate serum markers, ultrasound findings and clinical
informations
• RMI = U x M x serum CA 125 level
• Imaging marker: ultrasound score( U = 0,1 or3) + Clinical marker:
menopausal status score ( M= 1 or 3) + Serum tumor marker:
CA125 level
• RMI I: recommended by NIH guideline for ovarian mass evaluation
• RMI > 200: systematic review, pooled estimated sensitivity 78%,
specificity 87%
Geomini et al.Obstet Gynecol 2009,113:384-94.
ACOG Practice Bulletin No 174, Nov 2016
Serum biomarkers and multimodal test results
considered abnormal
Test
Premenopausal
Postmenopausal
CA125
♠
>35
MIA
>5
>4.4
ROMA
>1.31
>2.77
RMI
>200
>200
♠: No threshold in premenopausal women, should be integrated with other clinical factors in judging
the need for consultation. 2207 ACOGguideline recommended referral of >200 to gyn oncologist
ACOG Practice Bulletin No 174, Nov 2016
Serum markers of other ovarian tumors
- AFP: an oncofetal glycoprotein Ag. EST, mixed germ cell, immature teratoma
- Lactate dehydrogenase (LDH): dysgerminomas
- Human chorionic gonadotropin (hCG): GTT, PSTT, non gestational chorioca,
and embryonal ovarian ca
- Carcinoembryonic antigen (CEA): epithelial or germ cell tumors
- Inhibin and mullerian inhibiting substance (MIS): granulosa-theca cell
- Thrombocytosis: may be associated with ovarian malignancies in girls &
adolescents. Readily available, useful in emergency evaluation of ovarian
torsion suspicion for malignancy
When observation is recommended for a
pelvic mass?
Observation with repeat imaging is recommended when:
1- Morphology of ultrasonography suggests benign disease
2- Less certain morphology with compelling reason to avoid intervention
3- Asymptomatic women+ normal CA125 + no TVS finding suspicious for ca
4- Simple cysts < 10 cm, likely benign on TVS by expert ( rare exceptions)
5- Suspected endometrioma
6- Suspected mature teratoma
7- Suspected hydrosalpynx
8- Some women with substantial serious multiple comorbidities: repeat
imaging safer than immediate surgical intervention
ACOG Practice Bulletin No 174, Nov 2016
Adnexal mass in postmenopausal patient
• The adnexal mass in a postmenopausal patient poses an
important diagnostic and management dilemma for primary care
providers and gynecologists.
• Postmenopausal women are at a significantly increased risk of
gynecologic malignancy; yet even in this population the majority
of adnexal masses are benign.
• Evaluation and management of these lesions centers on the
identification of malignancy, while avoiding unnecessary
intervention in patients with benign lesions.
Repeat Imaging
• Is recommended when the diagnosis is uncertain and cancer remains
within the differential diagnosis
• Ideal interval and duration of ultra-sound follow: yet to be defined
• In one study all monitored masses eventually diagnosed as
malignancy: demonstrated growth by 7 m. (level II-III)
• Some experts recommend limit observation time to:(level III)
- Stable mass without solid component: 1y.
- Stable mass with solid component: 2y.
Such-Burgmann E, Hung YY, Kinney W. Am J Obstet Gynecol 2014;211:623
Such-Burgmann E, Kinney W. Am J Obstet Gynecol 2015;213:816
What type of surgical intervention
is appropriate?
• Presumed benign adnexal masses: minimally invasive procedures are the
preferred route of surgery
• Regardless of size and approach: fertility preservation should be priority in
adolescence and women who have not completed child bearing
• If suspicious of cancer during endoscopy: conversion to laparotomy 0-1.5%
• Rate of cyst rupture: equivalent in laparoscopy and laparotomy
• Shortened hospital stay, decreased pain, decreased convalescence time
• Conventional Vs robotic assisted: conventional is preferred , shorter
operative time
ACOG Practice Bulletin No 174, Nov 2016
Which patient may benefit from referral to a
Gynecologic Oncologist?
Consult or referral to Gyn oncologist
• Consultation or referral is recommended for women with one OR more
following criteria:
- Postmenopausal: masses with elevated CA125, ultrasound findings
suggestive of malignancy, ascites, nodular or fixed pelvic mass, evidence of
abdominal or distant metastasis
- Premenopausal: masses with elevated CA125, ultrasound findings
suggestive of malignancy, ascites, nodular or fixed pelvic mass, evidence of
abdominal or distant metastasis
- Pre or postmenopausal: masses with elevated score on a formal risk
assessment test such as RMI, ROMA,IOTA ultrasound-based scoring
systems
ACOG Practice Bulletin No 174, Nov 2016
ACOG Guidance for operation
• Proper staging + aggressive tumor debulking: improve survival
• Suspicious or persistent complex adnexal mass should be operated :
- By a physician trained to appropriately stage and debulking of
ovarian cancer
- In a hospital facility that has necessary support and consultation
services (eg. frozen)
• Discovered malignant tumor incidentally during operation: if
possible intraoperative consult to gyn oncologist
ACOG Practice Bulletin No 174, Nov 2016