Key points
-
Adnexal masses occurred in women of all age groups, and their etiology and frequency
vary age accordingly.
-
Most of the adnexal masses are benign, without symptoms diagnosed incidentally, and
can have expectant management.
-
Otherwise, ovarian cancer is an adnexal mass with poor prognosis and must be managed
quickly in an appropriate setting.
-
Correct differential diagnoses of benign and malignant mass matter.
-
Panels of biomarkers is not sufficient for the initial evaluation of an adnexal mass.
-
Transvaginal ultrasonography is the single most effective way of evaluating an ovarian
mass.
-
Ovarian cancer patients referred to a cancer center for further Management experience
the best outcomes.
Recommendations
-
Transvaginal ultrasonography is the single most effective way of evaluating an ovarian
mass. Computed tomography (CT), magnetic resonance imaging (MRI), and positron emission
tomography (PET) not recommended in the initial evaluation of adnexal masses.
-
The suspicious ovarian cysts should be initially assessed by measuring serum CA125
level and transvaginal ultrasound scan.
-
Spillage of cyst contents should be avoided preoperative and intraoperatively. Assessment
cannot preclude malignancy.
-
Frozen sections for the intraoperative diagnosis of a suspicious adnexal mass could
be useful when availability and patient preference allow.
-
Malignancy histology revealed during or after diagnostic laparoscopy; the comprehensive
surgical medical report belongs to the patient, and images should move to a cancer
center for further management.
-
Consider opportunistic salpingectomy as risk reduced surgery for ovarian cancer during
benign operation.
Background
Tumoral masses originating from the ovaries, fallopian tubes, and structures around
these organs are called adnexal masses, which occur in women of all ages, and their
etiology and frequency range age accordingly. The adnexal mass may come from functional
or physiological changes, inflammatory processes, endometriosis, benign and malignant
tumor. Moreover, the differential diagnosis from a non-gynecologic disorder has to
be done.[1] The actual incidence of adnexal masses in the general population is unknown since
most of these are asymptomatic and undiagnosed. Usually are detected on physical examination
or pelvic imaging screening. Less commonly, an adnexal mass may present with symptoms
of acute or intermittent pain.[1]
The incidence and mortality due to ovarian cancer have remained stable over the past
three decades and represent the leading cause of death from malignant neoplasm of
the female genital tract in developed countries.[2] The literature does not support routine screening for ovarian cancer in the general
population, and any professional society does not currently recommend it.[3]
The diagnosis of adnexal mass in women with pelvic symptoms or incidentally represents
a routine in gynecological practice and often presents diagnostic and management dilemmas.[1] The mainstream to management of adnexal masses is excluding malignancies. The characterization
of malignancy findings on the image (TVUS or MRI) is the key since women with ovarian
cancer should preferably be treated in oncological referral centers as soon as possible.
The false-negative rates are uncommon and benign adnexal masses can have expectant
management or undergo conservative surgery in general hospitals.[4]
How to differentiate benign from malignant disease?
How to differentiate benign from malignant disease?
Estimate the malignancy risk index is essential to assess an adnexal mass. The definition
based on image characteristics, in addition to age, oncologic personal and family
history, symptoms, findings on physical examination, and levels of tumor markers.[2] Thus, patients are classified as high or low risk for malignancies ([Chart 1]). Specific attention should be given to risk or protective factors for ovarian malignancy
revealed on medical history symptoms suggestive of ovarian malignancy, and a family
history of ovarian, bowel or breast cancer.[5]
[6] The complete physical examination, including performance status, body mass index,
palpable peripheric lymph nodes, and leg lymphedema evaluation, are useful to characterize
the patient. The clinical scan of the abdomen brings the most interpretive signs to
malignancy suspicion as ascites, abdominopelvic palpable mass, mobility, combined
to its anatomic relations with the uterus, bladder, rectum-sigmoid evaluated by vaginal
examination.[5] Imaging and laboratory testing may clarify the suspected etiology of a pelvic mass.
Pregnancy testing obtained in reproductive-aged women is mandatory.[1]
Chart 1
Risk stratification of adnexal masses
|
Characteristic
|
High-risk
|
Low-risk
|
|
Age
|
> 50 years
|
<50 years
|
|
Family history
|
Present
|
Absent
|
|
Symptoms
|
Persistent and multiple
|
Absent
|
|
Physical examination findings
|
Large, fixed, irregular mass, evidence of ascites or metastases
|
Not suggestive of high risk
|
|
Tumor markers
|
Elevated
|
Normal
|
|
Ultrasound findings
|
≥10 cm, thick, multilocular septation, increased and / or mixed echogenicity and /
or solid component, papillary growths present
|
<10 cm, absent or fine septum (1–2 mm), unilocular, homogeneous hypoechogenic, absent
papillary growths
|
Age
Age is a significant independent risk factor for ovarian malignancy in the general
population, with the incidence increasing sharply after the onset of menopause. The
frequency of ovarian cancer increases markedly with age, being relatively rare before
age 50.[2] The risk of malignancy is higher in postmenopausal than premenopausal women. However,
most adnexal masses in postmenopausal women are benign neoplasms, such as cystadenomas.
Simple cysts and hemorrhagic cysts in women of reproductive age are mostly physiologic.[7] The simple cysts in postmenopausal women are common too, and clinically inconsequential.[7] Appropriate tests should be carried out to exclude ovarian cancer in a postmenopausal
woman who developed nonspecific symptoms within the last 12 months that suggest irritable
bowel syndrome, unspecified gastric symptoms, unexplained weight loss, increased abdominal
volume. This is particularly true in women over 50 years of age or those with a significant
family history of ovarian, bowel, or breast cancer.[5]
Personal and family background
Personal and family background
Nulliparity, early menarche, late menopause, caucasian race, primary infertility,
and endometriosis are contributing factors for a higher risk for ovarian cancer.[1] Nevertheless, the most critical personal risk factor for ovarian cancer is a strong
personal or family history of breast or ovarian cancer, as they may be carriers of
deleterious mutations in genes related to these two types of cancer. Most gynecological
cancers are sporadic, but approximately 10–18% of OC has a hereditary pattern that
attributed to mutations in one of the BRCA genes.[8] BRCA1and BRCA2 mutations confer a lifetime risk for developing OC of 39–46 % and
11–27%, respectively.[9] Other genes besides BRCA1 and BRCA2 are also related to ovarian cancer.[10] Until their 70 years of age, women with Lynch syndrome have a 5–10% estimated risk
for ovarian cancer.[1] When the personal or family history suggests a high risk to hereditary ovarian-breast
cancer predisposition, a geneticist should be consulted.
Symptoms and physical examination
Symptoms and physical examination
Patients with symptomatic adnexal masses, especially climacteric, have a higher risk
of malignancy.[2] Ovarian cancer presents nonspecific symptoms within the last 12 months mimicking
irritable bowel syndrome, unspecified gastric symptoms, fatigue, and unexplained weight
loss. More specifically, infiltrative or compressive signs observed when increasing
abdominal volume leading to pelvic pain, bowel habits modification, abnormal uterine
bleeding, and a feeling of bladder fullness are noted. These symptoms appear quickly,
are recent and persistent.[10]
[11] Although the physical examination has low sensitivity for detecting adnexal masses,
it can provide some criteria for distinguishing between benign and malignant lesions
([Chart 2]).
Chart 2
Symptoms and findings on physical examination suggestive of malignancy
|
Symptoms
|
Physical examination findings
|
|
Pain (pelvic, abdominal, or back), bundling, increased abdominal volume, multiple
symptoms, the persistence of symptoms
|
Large adnexal mass, fixed mass, irregularity, ascites
|
Imaging
Transvaginal ultrasonography (TVUS) is the single most effective way of evaluating
an ovarian mass.[1]
[6] Computed tomography (CT), magnetic resonance imaging (MRI), and positron emission
tomography (PET) are not recommended in the initial evaluation of adnexal masses.
The size and composition of the mass (cystic, solid, or mixed), its laterality, as
well as the presence or absence of septations, mural nodules, papillary excrescences,
or free fluid in the pelvis, should be assessed through TVUS. For the evaluation of
vascular features of lesions in the pelvis, spectral, color Doppler ultrasound can
be helpful.[1] The morphological aspects present on TVUS that suggest malignancy are (1) irregular
and thick walls and septa; (2) papillary projections; (3) solid injuries; (4) moderate
echogenicity at the ultrasound.
The big ovarian and the extra-ovarian masses should be evaluated using both transvaginal
and transabdominal ultrasonography approaches.[6] The Color Doppler findings improve the morphology assessment on ovarian cancer risk
instead of used alone to adnexal mass evaluation.[12] If one hand, computed tomography (CT), magnetic resonance imaging (MRI), and positron
emission tomography (PET) ) should be avoided on the first assessment of adnexal masses[1]
[6] in complex lesions, these new imaging approaches may be useful.[6] If ultrasonography is inconclusive to characterize indeterminate ovarian cysts,
MRI can be the second-line imaging option.[5]
[12] Computed tomography is the best approach for suspected extra ovarian disease or
when it has to be rule out.[12]
The IOTA group standardizes criteria for the classification of adnexal masses according
to characteristics of the ovarian surface, presence of septa, papillary vegetation,
cyst wall, and vascularization. The IOTA group proposed two systems for estimating
the risk of malignancy in adnexal masses. According to “The Ultrasound Simple Rules,”
masses are classified as benign, malignant, and inconclusive, and in the “ADNEX “,
is used a cutoff of 10% to predict malignancy.[13] The systems have a sensitivity of 92% and 96.5% and specificity of 96% and 71.3%,
respectively, for benign and malignant masses.[14] We highlight that none of those instruments should use for screening for ovarian
cancer, but only for referral to general hospitals or referral hospitals for treatment.[15]
Serum tumor markers
Tumor markers can be used alone or in combination with imaging tests and clinical
information for the differential diagnosis of adnexal masses. Serum marker testing
indicates the likelihood of malignancy and the need for surgery.[1]
The CA125 transmembrane glycoprotein is elevated in 80% of ovarian carcinomas, especially
in advanced tumors.[16] This tumor marker is the most used to differentiate benign and malignant adnexal
masses. The sensitivity rates of CA125 differentiating benign and malignant conditions
ranges from 61% to 90%. The specificity rates range from 71% to 93%. The positive
and negative predictive value range from 35% to 91%, and 67% to 90%, respectively.[17] CA125 is elevated in less than half of women with initial ovarian carcinoma and
may be elevated in women with benign premenopausal diseases, which include physiological
conditions, endometriosis, pregnancy and menstruation.[18] CA125 levels alone should not be used to determine the malignancy of adnexal mass.
While a very high value may assist in reaching the diagnosis, an average rate does
not exclude ovarian cancer due to the nonspecific nature of the test.[5]
A serum CA-125 assay does not need to be undertaken in all premenopausal women when
an ultrasonographic diagnosis of a simple ovarian cyst has been made.[6] If serum CA-125 assay more than 200 units/ml, discussion with a gynecologic oncologist
is recommended.[6]
HE4 (human epididymis protein 4) is a protein involved in sperm maturation that increases
in some types of ovarian malignancies and has been used in the differential diagnosis
of adnexal masses.[19] In addition to malignant neoplasms, different other factors influence serum concentrations
of HE4. Variations occur with age, smoking, chronic kidney disease, but not with the
menstrual cycle, contraceptives, and endometriosis, which makes this marker useful
in these situations.[20]
[21] Lactate dehydrogenase (LDH), α-fetoprotein (α-FP) and hCG should be measured in
all women under age 40 with a complex ovarian mass because of the possibility of germ
cell tumors.[6]
Multimodal tests
The effectiveness of using panels of biomarkers combined with clinical and radiologic
evaluation for the distinction between benign and malignant adnexal masses has been
studied.[1] In adnexal mass surgical cases, using serum biomarker panels can be an alternative
to the CA 125 level alone for assessing the need for referrals to gynecologic oncology.
Although these biomarker panels should not be used in the initial evaluation of adnexal
masses, they can help determine the patient that can benefit from referrals to gynecologic
oncology.[1] Currently, there is no strong enough evidence to recommend a particular test.
The risk of malignancy index (RMI) algorithm combines the value of CA 125 serum levels,
ultrasound, and menopausal status. It is used to assess the risk of malignancy and
calculated using the following formula RMI = U x M x CA 125 (U = score, M = menopausal
status, serum levels of CA 125).[22] When using the RMI 200 cutoff, the sensitivity and specificity of the method are
85% and 97%, respectively. Patients with values greater than 200 are at 42 times greater
risk of cancer than patients with an RMI of 0.15. A systematic review of diagnostic
studies concluded that the RMI I is the most effective for women with suspected ovarian
cancer.[6]
The most frequent use of HE4 is for the assessment of the risk of malignancy through
the ROMA (Risk of Ovarian Malignancy Algorithm) algorithm, which is a quantitative
test combining the concentration of CA 125, HE4 and menopausal status.[23] This test is calculated using two logistic regression formulas separately for peri
and postmenopausal women by considering the logarithm of CA 125 and HE4 concentration.[24]
[25] None of these tests; CA 125, HE4 alone, RMI and ROMA have specificity to differentiate
malignant from benign adnexal masses categorically. However, they are useful to assess
the risk, and together with clinical and imaging information, determine whether the
patient can have expectant management, investigation in general hospitals or referral
to oncologic centers is recommended because of high risk for malignant neoplasm. HE4
is useful in differentiating adnexal masses with elevated CA 125 and suggestive of
endometriosis, as it does not undergo major changes in the latter condition.[24]
Management of adnexal mass
Management of adnexal mass
Is the patient's age important to define the management?
The incidence of adnexal masses in childhood and adolescence is very low, higher in
the first year of life due to hormonal phenomena in utero, and rises again close to
menarche. The proportion of malignant neoplasms is higher in prepubertal women than
in menacme.[26] For these reasons, any adnexal mass with a solid component in this age group should
be investigated with the anatomopathological examination. The therapeutic approach
must include the differential diagnosis of malignancy and the hormonal and reproductive
aspects of the patient. Whenever possible, a minimally invasive procedure focused
on preserving the ovaries is recommended. Teratomas, the most common germ cell tumors,
can and should be removed without sacrificing the rest of the ovary. Even malignant
germ tumors allow conservative management.[27]
In menacme, benign adnexal masses are treated by cystectomies, oophorectomies or salpingo-oophorectomies
in more than a third of cases. In patients close to menopause, this number is close
to 50%. In borderline tumors, oophorectomies with or without salpingectomy are performed
in about 70% of cases in this age group.[28] However, in recent years, there has been a trend to preserve ovaries in benign ovarian
masses. This approach seems appropriate because even considering that the ovaries
are paired organs, preservation should always be attempted in the face of benign diseases
in young women. In women close to menopause, even with ovarian preservation, opportunistic
salpingectomy has been increasingly recommended because of new concepts related to
ovarian carcinogenesis.[29] High-grade serous carcinoma originates in the tubal epithelium.[30]
[31]
[32]
[33]
Most ovarian carcinomas occur in women over 50 years of age. It is recommended that
ovarian cysts in postmenopausal women should be initially assessed by measuring serum
CA125 level and transvaginal ultrasound scan.[5] Ovarian carcinomas should be treated in referral centers due to the high morbidity
and mortality of this disease. Approximately 25% of patients with high-grade ovarian
serous carcinoma die within the first ninety days, and 40% die before completing the
first year of diagnosis.[34] Patients treated in general hospitals who not adhere to strict protocols compared
to referral centers have an overall survival in five years of 11.4 versus 49.5 months,
respectively.[35] The centralization of the treatment of ovarian carcinoma in referral centers has
demonstrated a considerable increase in overall survival.[36]
Why adopt conservative management?
Ovarian cancer, while typically cystic, does not arise from these benign-appearing
cysts. In premenopausal women, after a good quality ultrasound in women of reproductive
age, don't recommend follow-up for a classic corpus luteum or simple cyst <5 cm in
greatest diameter. Use 1 cm as a threshold for simple cysts in postmenopausal women.[7] Women with small (less than 50 mm diameter) simple ovarian cysts generally do not
require follow-up as these cysts are very likely to be physiological and almost always
resolve within 3 menstrual cycles. Women with simple ovarian cysts of 50–70 mm in
diameter should have yearly ultrasound follow-up, and those with larger simple cysts
should be considered for either further imaging (MRI) or surgical intervention.[6] Ovarian cysts that persist or increase in size are unlikely to be functional and
may warrant surgical management.[6] Combining the oral contraceptive pill does not promote the resolution of functional
ovarian cysts.[6]
In postmenopausal women, asymptomatic, simple, unilateral, unilocular ovarian cysts,
less than 5 cm in diameter, have a low risk of malignancy. In the presence of normal
serum CA125 levels, these cysts can be managed conservatively, with a repeat evaluation
in 4–6 months. It is reasonable to discharge these women from follow-up after one
year if the cyst remains unchanged or reduces in size, with normal CA125, taking into
consideration the woman's wishes and surgical fitness.[5] If a woman is symptomatic, further surgical evaluation is necessary. A woman with
a suspicious or persistent complex adnexal mass needs surgical assessment.[5]
What is a better surgical approach?
The minimally invasive surgery (MIS) is a well-established route in propaedeutic and
treatment of benign adnexal masses and has been progressively indicated in oncology.
This approach has significant advantages, with careful selection of patients and not
to disseminate neoplastic cells.[37] In women undergoing surgery for benign ovarian tumors, laparoscopy was associated
with a reduction in fever, urinary tract infection, postoperative complications, postoperative
pain, hospitalization, and total cost.[38] Spillage of cyst contents should always be avoided, as pre and intraoperative assessment
cannot absolutely preclude malignancy.[6] The surgical specimen should be removed from abdominal cavity without intraperitoneal
spillage in the plastic retrieval bag through the umbilical port, small Pfannenstiel
incision, or transvaginally.[5] The rupture alters the staging in the event of malignancy and may indicate adjuvant
chemotherapy for this reason alone. Aspiration is not recommended for the management
of ovarian cysts in postmenopausal women except for the purposes of symptom control
in women with advanced malignancy who are unfit to undergo surgery or further intervention.[5] In the presence of large masses with solid components (for example large dermoid
cysts) laparotomy may be appropriate.[6]
Reasons for referrals to gynecologic oncology
When a patient with a suspicious or persistent complex adnexal mass requires surgical
evaluation, a physician trained to appropriately stage and debulk ovarian cancer,
such as a gynecologic oncologist, should perform the operation. Below are listed the
criteria (one or more should be met) of the American College of Obstetricians and
Gynecologists for referring women with an adnexal mass to gynecologic oncology:[1]
-
Postmenopausal, high level of CA 125, US characteristics of malignancy, ascites, nodular
or fixed pelvic mass, or evidence of abdominal or distant metastasis;
-
Premenopausal, high level of CA 125, US characteristics of malignancy, ascites, nodular
or fixed pelvic mass, or evidence of abdominal or distant metastasis;
-
Premenopausal or postmenopausal, risk assessment high score in formal tests such as
the multivariate index assay, risk of malignancy index, the Risk of Ovarian Malignancy
Algorithm, or one of the ultrasound-based scoring systems from the International Ovarian
Tumor Analysis group.
The National Comprehensive Cancer Network (NCCN) recommends an evaluation by a gynecologic
oncologist for all patients with suspected ovarian malignancies; published data demonstrate
that primary assessment and debulking by gynecologic oncologist result in a survival
advantage.[3]
What is the value of the frozen section intraoperative examination?
Frozen sections for the intraoperative diagnosis of a suspicious adnexal mass is recommended
in settings in which availability and patient preference allow.[12] This recommendation is based on a meta-analysis of frozen section diagnoses that
included 38 studies, involving 11,181 participants, and yielded an overall sensitivity
of 90.0% (95% confidence interval (CI) 87.6% to 92.0%); with most studies typically
reporting range of 71% to 100%), and average specificity was 99.5% (95% CI 99.2% to
99.7%; range 96% to 100%). If the frozen section showed a benign or invasive cancer,
the final diagnosis would remain the same in, on average, 94% and 99% of cases, respectively.
In cases where the frozen section diagnosis was a borderline tumor, on average 21%
of the final diagnoses would turn out to be invasive cancer.[39] In case of doubt and in order to preserve the ovary, it is reasonable to remove
only the adnexal mass without rupture or spread content in the peritoneal cavity.
Then, wait for the definitive paraffin exam result to define the nature of the disease
and to complete surgery if necessary.
What to do with the diagnosis of malignancy after non-cancer surgery?
Referrals to oncology specialists for additional treatment should occur when malignancy
is found during laparoscopy or after histology.[5] Stage II to IV cases with residual and unresectable disease should be evaluated
for interval debulking surgery before the fourth cycle of chemotherapy. The preference
is interval debulking surgery after 3 cycles of chemotherapy and it may be performed
after 4 to 6 cycles, depending on the clinical judgment of the gynecologic oncologist.
Postoperative chemotherapy may be advised after analysis of surgical results. All
stage II-IV patients with suspected residual and potentially resectable disease should
undergo tumor reduction surgery.[3]
Final considerations
Adnexal masses are anomalies that affect women of all ages, from the earliest childhood
to senility. They are more common in menacme, where the occurrence of benign diseases
is also greater. At the extremes of life, in pre-adolescence and postmenopause, diagnoses
of malignancy are more frequent. There are recommendations against routine screening
for ovarian cancer, including use of transvaginal ultrasonography, CA 125 level, and
screening pelvic examination. The differential diagnosis between benign adnexal masses
is made by clinical history, ultrasound, other imaging methods and tumor markers.
No method alone or in combination has sufficient sensitivity and specificity to formalize
the diagnosis of malignancy. However, they are useful to differentiate patients with
low probability of malignancy, who can be treated in general hospitals, from those
with a high probability of malignancy, who must be treated in referral centers with
multidisciplinary teams and high volume, within defined protocols. In benign adnexal
masses, minimally invasive surgery should be the route of choice. The systematic removal
of ovaries in benign ovarian diseases has given way to surgeries with conservation
of the gonads.
National Specialized Commission on Gynecologic Oncology of the Brazilian Federation
of Gynecology and Obstetrics Associations (FEBRASGO)
President:
Walquíria Quida Salles Pereira Primo
Members:
Angélica Nogueira Rodrigues
Caetano da Silva Cardial
Delzio Salgado Bicalho
Eduardo Batista Candido
Francisco José Cândido dos Reis
Jesus Paula Carvalho
Marcia Luiza Appel Binda
Renato Moretti Marques
Ricardo dos Reis
Sophie Françoise Mauricette Derchain
Suzana Arenhart Pessini
