Discussion
Epidemiology
The ovarian cyst is defined as a structure that contains fluid and has more than 30 mm
in diameter.[1] A significant part of the ovarian cysts is asymptomatic, which can lead one to underestimate
the real incidence. It is estimated that, in the United States, 250 thousand women
per year are hospitalized due to adnexal masses.[7]
According to a population-based cohort with 11,595 patients from 1991 to 2014,[8] the incidence of ovarian cysts increases exponentially with age. There is an incidence
plateau around the age of 26, reaching 152 cases per 100 thousand women per year at
35 years old, which is maintained throughout the menacme.[8]
Just over a third of the benign masses were epithelial lesions (35.1%). Almost a third
were tumor like lesions (32.8%), being functional cysts and endometriotic cysts. 29.8%
were germ-cell tumors (almost entirely mature teratomas), and a small fraction of
2.3% were stromal tumors (mostly fibromas/tecomas). The exact proportions are shown
in [Fig. 1].
Fig. 1 Most common benign adnexal masses.
At menacme, most of the masses are benign, and the chance of developing malignancy
of the symptomatic cysts is around 1: 1 thousand.[1] The incidence of borderline malignancies and tumors follows the same behavior with
regard to the incidence plateau; however, it is of around 8 cases per 100 thousand
women per year. Therefore, the proportion of malignancies among all ovarian neoplasms
is of ∼ 3%.[8] In the pediatric range, the common symptoms are acute and chronic abdominal pain,
presence of abdominal mass, and abdominal distension. Germ-cell tumors are more common,
with teratomas being the main representatives. Physiological cysts in premenarchal
girls are rare, and it is estimated that the prevalence of malignancy does not exceed
15%.[9]
Diagnostics
We can conclude from the previous section that, in fact, the chance of facing malignant
adnexal pathologies is relatively low. Despite this, the identification of malignant
neoplasms is mandatory. The difficulty in establishing a reasonable means of screening
for ovarian malignancies is widely known. Most ovarian cancers are not diagnosed in
the early stages (15% in stage I), even in the menopausal period, when the incidence
of this type of malignancy increases.[10]
Many models have been proposed to screen patients for appropriate treatment, but none
of them was able to be unanimously accepted. The details of the various models are
beyond the scope of the present review, but they may include: the Risk of Malignancy
Index (RMI); the National Institute for Health and Care Excellence (NICE) Guidelines;
the Risk of Ovarian Malignancy Algorithm; Logistic Regression (LR); and methods based
on ultrasound criteria proposed by the International Ovarian Tumor Analysis (IOTA):
“Simple Rules” (SRs); Simple Rules Risk (SRR); and Assessment of Different Neoplasms
in the Adnexa (ADNEX).[11]
Despite some modifications over the years after the creation of the RMI, it remains
as the alternative with the best validation.[1] It consists of the product between the level of carcinoembryonic antigen 125 (CA-125),
hormonal status (M) and ultrasound scoring (U): RMI = CA-125 x M x U ([Table 1]).
Table 1
Risk of Malignancy Index (RMI)
|
RMI CRITERIA
|
SCORE
|
|
MENOPAUSAL STATUS (M)*
|
|
|
Premenopausal
|
1
|
|
Postmenopausal
|
3
|
|
ULTRASOUND IMAGING (U)
|
|
|
Multiloculated
|
1 (if 1 feature)
|
|
Solid areas
|
3 (if 2 or more features)
|
|
Bilaterality
|
|
|
Ascites
|
|
|
SERUM CA-125
|
Absolute value in IU/mL
|
In order to create an adequate screening workup, the use of a specific set of ultrasound
characteristics to predict malignancy of the adnexal masses named the “Simple Rules”
(SRs) was recently proposed.[12] The concept is based on the identification of basic benign and malignant echography
features ([Box 1]).
Box 1
International Ovarian Tumor Analysis (IOTA) “Simple Rules”
|
IOTA “SIMPLE RULES”
|
|
|
Benign (B)
|
Malign (M)
|
|
1- Unilocular cyst
|
1- Irregular solid tumor
|
|
2- Solid component, but < 7 mm
|
2- Ascites
|
|
3- Acoustic shadows
|
3- At least 4 papillary structures
|
|
4- Smooth multilocular tumor < 100 mm
|
4- Irregular multilocular tumor > 100 mm
|
|
5- No blood flow
|
5- Very strong flow
|
Eight years later, in 2016, a large multicenter cross-sectional study[13] involving 22 research centers with 4,848 patients aimed to evaluate the efficacy
of the SRs in the prediction of malignancy of adnexal masses. For the 1% risk cutoff,
the sensitivity was of 99.7%, the specificity was of 33.7%, the LR was + 1.5 and -0.010,
the positive predictive value (PPV) was of 44.8%, and the negative predictive value
(NPV) was of 98.9%. For the 30% risk cutoff, the sensitivity was of 89.0%, the specificity
was of 84.7%, the LR was + 5.8 and -0.13, the PPV was of 75.4%, and the NPV was of
93.9%.[13]
The use of SRs was subsequently validated considering their performance in the diagnosis
of early ovarian malignancies, even when compared with the other models proposed by
the IOTA. At this point, we highlight the high NPV (98.9%) of the SRs in scenarios
of low risk of malignancy.[13]
After the application of the screening methods, the patients whose initial evaluation
reveals high risk for malignancy should ideally be treated in specialized centers
with a multidisciplinary team, maximizing the oncological results and making it possible
to discuss options to preserve fertility.[14]
Ovarian Reserve
There is currently no ideal method to predict the ovarian reserve, and some important
aspects should be considered. Estimates of the ovarian reserve are performed mainly
by the measurement of the antimullerian hormone (AMH) and the antral follicle count
(AFC). The AMH is produced by granulosa cells from active follicles, and can be dosed
in the peripheral blood. The production of AMH is stable throughout the menstrual
cycle, and is the first to change with advancing age. The levels of AMH are related
to some outcomes of assisted reproductive technology (ART), such as the number and
the quality of yielded oocytes and the live-birth rate (LBR).[15]
[16] The diversity of laboratory kits available for AMH dosage generates distortions
and differences in reference values, which can cause bias in the interpretation of
results. In addition, since the AMH is produced by both ovaries simultaneously, the
actual impact of the surgical procedures may be underestimated in cases of unilateral
disease.[17]
The AFC consists of the sum of the 2- to 10-mm ovarian follicles found between the
2nd and 4th days of the menstrual cycle, and it is also related to ART outcomes.[17]
It has already been proposed that the association of methods (dosage of AMH and AFC)
may contribute to reduce the risk of misunderstandings. In the event that the levels
of AMH are higher than expected given an AFC, the presence of polycystic ovarian syndrome
should be considered. And levels of AMH lower than expected for a given AFC may be
an early sign of ovarian failure.[18]
Some of the studies mentioned in the present review also used other methods such as
the follicle-stimulating hormone (FSH), ovarian volume measurement and ovarian peak
systolic velocity (PSV), but they are less reliable.[19]
Treatment
Surveillance
A significant proportion of the benign ovarian masses will present spontaneous resolution.
Therefore, the expelling conduct may be of extreme validity, avoiding unnecessary
surgeries, and, consequently, additional damage to healthy ovarian tissue. Functional
cysts or simple ovarian cysts (anechogenic, thin-walled and smaller than 50 mm) usually
resolve after 3 menstrual cycles without the need for any intervention.[1]
Management of the Risk of Adnexal Torsion
After the decision regarding surveillance, the risk of adnexal torsion remains a concern.
In an international prospective cohort, among the patients selected for conservative
management and surveillance, the overall risk for torsion was of around 4%.[20]
A case series[21] with 360 patients showed that the main pathologies associated were dermoid cysts
(36%), follicular cysts (16.1%), corpus luteum cysts (9.9%), and serous cystadenoma
(9.9%), with an overall mass size ranging from 8 cm to 15 cm. Functional cysts were
successfully treated mainly with detorsion.[21]
An interesting proposal in the symptomatic pediatric/adolescent range is a composite
score of risk. It consists of identifying and scoring the presence of independent
risk factors: absence of vomiting (zero points) or presence of vomiting (2 points);
ovarian volume higher than 17 mL (pre-menarchal; 2 points) or 105 mL (menarchal; 2points);
adnexal ratio (volume of the affected ovary divided by the contralateral ovary) higher
than 21 (2 points). For scores ≥ 4, surgical treatment is recommended. Even with scores
between 2 and 3, until 10% of the patients presented with torsion.[22]
Regarding Endometriomas
A study[23] monitored 1,199 cycles of 244 patients with unilateral endometriomas, comparing
ovulation between the healthy and the affected ovaries. Documented ovulation did not
differ (49.7% versus 50.3% respectively), even with cysts with more than 6 cm in diameter.
In total, 43% of the patients conceived spontaneously during the study period of 4
years.[23] There is no relevant data on the literature that supports that systematic surgical
removal of cysts smaller than 4 cm prior to assisted reproduction procedures. Expectant
behavior is also justified in this scenario.[24] Other aspects regarding the management of endometriomas will be further discussed,
but surveillance seems to be the main approach.
Oral Contraceptives
A systematic review[7] that analyzed eight randomized trials concluded that, although widely used in the
clinical practice, the prescription of oral contraceptives does not influence the
resolution of functional cysts. The outcomes are the same for both spontaneous cysts
and those caused by ovulation-induction processes. Persistent cysts tend to be pathological
rather than physiological.[7]
Surgical Approach - Technical Considerations
The indication of surgery occurs when: there is uncertainty regarding the suspicion
of malignancy; the size of the adnexal mass increases the risk of pain and torsion
episodes; the augmentation of the mass might compromise the ovarian follicles; and,
in cases of endometriotic cysts, when there is a progressive increase in volume and
pelvic pain due to endometriosis.[25] Once the need for intervention is defined, one should consider several technical
details that can minimize the impact on the ovarian reserve and improve the overall
outcome of the surgery.
Laparoscopy
The body of evidence in favor of the laparoscopic approach is significant when there
is a need for surgery. Laparoscopic cystectomy is often the rule, to minimize potential
complications such as ruptures in malignant situations, and to optimize fertility
preservation. This technique is well established as the gold standard in this set
of pathologies.[1]
[25]
[26]
Comparison of Etiologies
Despite the fact that the multitude of etiologies of the ovarian masses and the surgical
practice demonstrate evident technical differences among the different types of cysts,
the damage to the ovary is evident and unavoidable in every situation.
The comparison of the levels of AMH, FSH, AFC, ovarian volume and vascularization
did not show significant differences when comparing the group with bilateral endometriomas
(n = 21), unilateral endometriomas (n = 29), other benign cysts (n = 20), and the control group without cysts (n = 20), when the laparoscopic surgery was performed with hemostatic sutures. The small
difference observed was in the first postoperative month, but did not remain after
12 months.[27]
Comparing the levels of AMH and the amount of remaining follicles in the surgical
specimen, no differences were found between patients with endometriomas (n = 68) and other benign cysts (n = 32). Bilaterality was the only risk factor associated with greater loss of ovarian
reserve.[28]
In a study[29] with 71 patients, the final volume was lower (2.41 mL versus 2.23 mL, p = 0.49), as compared with the non-operated ovary, as well as the AFC (3.45 versus
2.43, p = 0.11), regardless of the fact that there were endometriotic cysts or not. Ovarian
volume and CFA differences were not dependent on the size of the cysts.[29]
Contrasting this scenario, in a study[30] comparing the AMH levels of patients with endometriomas, other benign cysts and
patients with infertility of tubal cause, endometriomas show a different behavior
from the other benign cysts, since AMH levels may be lower than in the other conditions
(1.53 ng/mL, 2.20 ng/mL, and 2.82ng / ml respectively). Surgery significantly decreases
the levels of AMH in the case of endometriomas (worse if bilateral) compared with
other pathologies.[30]
In a study[4] with 75 patients (33 teratomas, 25 endometriomas, 9 functional cysts, and 8 cystadenomas)
the reduction in the levels of AMH was different, depending on the histological diagnosis
of the mass. Patients with endometriomas had a faster and longer lasting reduction
in AMH levels: a 51-% mean reduction 6 months after surgery (p = 0.007). Patients with teratomas presented a 25-% reduction (p = 0.009). In the other patients, the reduction was of 34% (p = 0.059).[4]
In a study[31] with 22 patients, 12 with endometriomas and 10 with non-endometriotic cysts, there
was a reduction in the levels of AMH postsurgery (5.48 ng/mL before and 2.56ng/mL
after; p < 0.05), but without changes in the AFC, estradiol and ovarian volume. This decrease
occurred at the expense of the group of patients with endometriomas. A technique of
bipolar hemostasis associated with hemostatic suture was used.[31]
A retrospective study[3] of 97 patients aged between 20 and 39 years showed that AMH levels are lower in
patients with endometriomas compared with other benign cysts (4.12 ng/mL versus 6.02 ng/mL;
p < 0.001). The mean level of AMH was also lower the larger the diameter of the non-endometriotic
mass.[3]
In a case-control study[32] with 56 patients with endometriomas and 16 patients with other benign cysts, there
was a significant decrease in AMH levels after surgery (stripping cystectomy with
bipolar hemostasis) in the group with endometriosis (4.3 ng/mL versus 2.8 ng/mL; p < 0.001), but the same did not occur in the group of other benign cysts (5.6 ng/mL
versus 4.9 ng/mL; p = 0.251). This drop was also more significant in the group with endometriosis of
stages III to IV (4.26 ng/mL versus 2.62 ng/mL; p < 0.001) when compared with the group with endometriosis of stages I to II (4.38 ng/mL
versus 3.34 ng/mL; p = 0.66).[32]
Another retrospective study[33] with 138 women submitted to salpingectomy, 36 submitted to unilateral salpingo-oophorectomy,
40 who underwent excision of an endometrioma, and 41 who underwent cystectomy due
to other causes showed no difference in the levels of AMH (p = 0.33), AFC (p = 0.59) and FSH (p = 0.21) between the salpingectomy group and the group who did not undergo surgery.
The group submitted to unilateral salpingo-oophorectomy had lower levels of AMH (-54%;
p = 0.001). Women with endometrioma also had lower levels of AMH (-66%; p = 0.002), but this did not affect the AFC (p = 0.22) and FSH (p = 0.28).[33]
Recently, a study performed in patients[34] with endometriomas (n = 34) and other benign masses (n = 18) showed that, 6 months after surgery, the levels of AMH were reduced by 59.3%
(p < 0.12) when compared with baseline values in the group with endometriomas, and it
was reduced by 29.5% (p < 0.2) in the group with other benign masses. This reduction was not related to the
number of follicles inadvertently removed during the procedure (p < 0.669). It is very important to note that, in this study, all procedures were performed
by a single specialist surgeon, which indicates that postoperative damage to the levels
of AMH is evident, even for surgeons with extensive experience.[34]
In addition, a retrospective study[35] revealed that there are no differences in ovarian stimulation response (measured
through retrieved oocytes) in in vitro fertilization (IVF) cycles when there is an
evident ultrasound diagnosis of dermoid cyst.[35]
Endometriomas - Options of Surgical Techniques and Hemostasis
Several years ago, some advantages were associated with the excision of an endometriotic
cyst when compared with several types of ablative processes. There was an assumption
that the excision of the cyst capsule was associated with a lower recurrence of pain
symptoms (dysmenorrhea, dyspareunia and acyclic pelvic pain) and less need for further
surgeries. In addition, it was associated with a higher rate of spontaneous gestation
after the procedure. It was still unclear whether excision was superior to ablative
procedures for ART outcomes.[26]
In 2011, a randomized study[36] performed with 48 patients with bilateral endometriomas compared cystectomy and
coagulation and found, after cystectomy, a lower antral follicle count (3.67 versus
4.75; p = 0.001), lower ovarian volume (6.27 mL versus 9.87 mL; p = 0.005) and fewer oocytes collected after ovarian hyperstimulation (3.08 versus
3.86; p 0.01) compared with coagulation alone.[36]
In a study[37] with 25 patients with endometriomas, using only stripping, without coagulation,
there was no difference in presurgical AMH levels and 3 cycles after surgery (3.61 ng/mL
versus 3.00 ng/mL respectively; p = 0.62).[37]
In another study[38] with 99 patients who underwent surgery for endometriomas, the comparison between
cystectomy and bipolar vaporization showed a decrease of more than 50% in AMH levels
after surgery. There was no difference between the techniques.[38] It is imperative, however, to highlight some limitations of the mentioned study.
It was not randomized, did not make a clear separation of the groups, and did not
present any follow-up data.
In yet another study,[39] 45 patients with unilateral endometriomas were treated with laparoscopy and cystectomy
with striping and hemostasis with a dual-wavelength laser (Biolitec Ceralas HPD, wavelength
of 980 nm and 1470 nm, model 120 W). The mean level of AMH before surgery was of 3.01 ng/mL;
4 to 6 weeks after surgery, it was of 2.41 ng/mL; and 6 to 9 months after, it was
of 2.7 ng/mL. The decrease was statistically significant (p < 0.05).[39] However, the technique was not compared with stripping alone or with other techniques.
The use of hemostatic sealants was compared with bipolar coagulation in a non-randomized
study.[40] The rate of decline in AMH levels was lower using the sealants (15.4%) compared
with bipolar coagulation (41.2%; p = 0.003).[40] The levels were measured in 129 patients, without randomization, a follow-up of
only 3 months, and other ovarian reserve parameters were not measured.
In a more recent study,[41] 207 patients who underwent excision of endometriomas were followed up for 12 months.
The levels of FSH, AMH, the AFC and the PSV were compared regarding 3 different hemostasis
techniques: bipolar cauterization (n = 69), ultrasonic scalpel (n = 69) and suture (n = 69). Throughout the period up to the 12th month, the levels of FSH were higher,
and the levels of AMH were lower, in the first 2 groups (p < 0.05). At the 12th month, the AFC and PSV were also lower in the first 2 groups
(p < 0.05). The authors concluded that bipolar cauterization and the use of ultrasonic
scalpel cause more damages to the ovaries when compared with hemostatic suture.[41]
Recently, the laparoscopic stripping of endometriotic cysts became the standard procedure,
since it favors a lower recurrence of symptoms and increases pregnancy rates.[42]
Despite this, one cannot deny that surgical damage to ovarian tissue is evident. The
histological analysis of the endometrioma capsules revealed the presence of normal
ovarian follicles, in a larger quantity the younger the patient and the smaller the
cyst diameter.[43]
Those analyses suggest that the intervention leads to the decrease in the ovarian
reserve, although the literature is controversial and heterogeneous, especially considering
the different methods of hemostasis.[44]
[45] The evidence points to a tendency to believe that suture is less harmful to the
ovarian reserve.
Additional Relevant Technical Details
Following cystectomy, removal of ovarian tissues from the abdomen should preferably
be performed through the umbilical portal and wrapped in a protective pouch. This
decreases the chance of eventual contamination of the abdominal cavity with the contents
of the cyst, and causes less postoperative pain and a shorter recovery time. Transverse
minilaparotomy should be considered for the cases of masses with a larger volume (higher
than 7 cm in diameter).[1]
The phase of the menstrual cycle for the surgery does not seem to influence the results
regarding blood loss and variations in AMH levels. In yet another study,[46] 84 patients in the follicular phase and 71 in the luteal phase were compared after
cystectomy for surgical blood loss (p = 0.984) and AMH levels before and 3 months after surgery (p = 0.945); no differences were found by the authors.[46]
During the surgical approach, one should take into consideration the anatomical position
of the vascularization of the ovary, aiming at the protection of the pelvic infundibulum
from surgical trauma. Interestingly, in a study,[47] the comparison between the excision of dermoid cysts with a mesial approach (33
patients) and an anti-mesial approach (34 patients) showed a higher maintenance of
the mean number of antral follicles, a larger mean ovarian diameter, and a higher
mean PSV in the ovaries of patients treated with the mesial approach.[47]
Fertility as the Endpoint
Interestingly, only one article[48] addressed the main objective of fertility, translated as the birth rates after ovarian
surgery. The follow-up of 60 women for 24 months after ovarian surgery demonstrated
a significant decrease in AMH levels (2.7 mcg/l to 1.1 mcg/l; p = 0.001). In total, 36 women tried to conceive, 18 became pregnant, and there were
12 live births. It was possible to determine the behavior of the AMH levels in 34
women who attempted to conceive, and it decreased in both groups (pregnant: 3.3 mg/l
to 1.0 mg/l; p = 0.057; not pregnant: 3.2 mg/l to 2.0 mg/l, p = 0.003), but this decrease was not different between the 2 groups (p = 0.112).[48]
Conclusion
We conducted a comprehensive review of the literature for the identification of relevant
factors regarding the practical recommendations for the treatment of benign adnexal
masses and the insights for fertility preservation. The discussion of the subject
is extensive, somewhat controversial, but with some points of convergence. In the
menacme, after the diagnosis of an adnexal mass, the incidence of cancer is not high,
and the use of magnetic resonance imaging (MRI) and SRs is satisfactory to predict
the risk of developing malignancy. Expectant management can be a valid alternative,
avoiding unnecessary procedures, surgical complications, and ovarian changes caused
by traumatic injuries. The use of anovulatory medications is, in most cases, unnecessary.
Dermoid cysts are more associated with torsion, and masses ranging from 8 cm to 15 cm
are more common in this kind of complication. Detorsion is a valid option in cases
of functional cysts. The use of composite scores of risk factors in the pediatric/adolescent
scenario can aid in the decision for surveillance or surgical treatment. When surgery
is necessary, some technical aspects are somehow clearer. The use of videolaparoscopy
is well established, in which stripping cystectomy shows better results if we consider
all types of masses together. Surgery can be performed at any stage of the cycle.
Materials should be removed from the abdomen in protective pouches and, preferably,
through the umbilical scar incision. Minilaparotomy is acceptable for masses larger
than 7 cm. The mesial approach should be considered in cases of teratomas. The use
of bipolar electrocautery appears to have an even more negative impact on AMH levels
and the AFC after cystectomies, which may persist for 12 months after the surgical
procedure, and should be avoided. Suture is preferable. However, caution should be
exercised with such an assertion, given the heterogeneity of the available studies.
We emphasize the need for a precise standardization of future studies that involve
comparing new hemostasis techniques (when to apply them and if they are necessary
at all). Specifically in the case of endometriomas, the evidence is unclear, but,
apparently, there are no changes in the primary ovulatory function of the affected
ovaries, but they may be associated with decreased ovarian reserve caused by the disease
itself. In addition, the evidence regarding decreased ovarian reserve after the surgical
treatment is very strong. Moreover, in view of the recurrence of endometriomas, the
second surgery is even more harmful to the AFC. The precise indication and technical
quality of the first surgery is fundamental, and successive surgeries should be considered
with great caution. Now, there are no standardized protocols to address endometriomas,
especially considering the size as the mark of the decision. In regards to fertility,
surveillance seems to be the best alternative. Despite some proposals on this subject,
the need for future research is evident. Regarding the ovarian reserve, the current
difficulties of using markers that are more reliable are clear. Apparently, estimates
may be more accurate when counting the antral follicles (which show the direct impact
of the affected ovary) in relation to AMH levels (which reflect the pattern of the
two ovaries simultaneously). There is a lack of long-term follow-up studies that can
elucidate these differences more clearly. Nevertheless, despite the evidence of the
decrease in the parameters of evaluation of the ovarian reserve, the question remains:
what is the impact of the adnexal masses and their treatments on the real chances
of gestation? The data suggest that ovarian reserve evaluations purely based on AMH
levels or the AFC may not satisfactorily reflect the actual risks of infertility.
It has been suggested that, although objective assessments of the ovarian reserve
are of extreme value, it is necessary to prioritize the focus on long-term studies
that present the rate of live births as their endpoint. Therefore, we suggest great
caution and care when clarifying the best possible evidence for patients with adnexal
masses, revealing our limitations. In this way, we will be able to offer the necessary
data about the reproductive future and the adequate information for the correct decision
making regarding the patients who need treatment for adnexal pathologies.
