Introduction

Endometriosis, defined as the presence of endometrium-like tissue outside the uterus, affects approximately 10% of women of reproductive age [1, 2•]. The origin of ectopic endometrium remains unresolved: some gynecologists believe that it originates from endometrial tissue in the backflow of menstrual bleeding, whereas others believe that it is a result of coelomic metaplasia [1]. These discrepancies yield continuous debates among gynecologists. Endometriosis affects many organs and structures, including the ovary, fallopian tube, pelvic serosa, rectum, retroperitoneal structures (e.g., the ureter), and more remote organs, including the lungs. The most frequently affected organ is the ovary. Ovarian endometriosis typically presents as an ovarian cyst containing old blood; usually called a chocolate cyst or an endometriotic cyst, these are diagnosed in about 17% to 44% of women with endometriosis [2•].

Although the diagnosis of endometriosis is sometimes difficult, especially during early-stage disease, the characteristic appearance of a typical ovarian endometriotic cyst can be easily detected with MRI. After a diagnosis of ovarian endometriotic cyst, there are several management options, including careful follow-up, medication, and surgical intervention. The efficacy of these options is different according to the purpose of the treatment; for instance, medication is more effective for relieving pain than for recovering fertility.

Endometriosis causes three major clinical disruptions: pain, infertility, and malignant transformation. The most common symptom in younger patients is endometriosis-associated pain including dysmenorrhea, which, if mistreated, may lead to endometriosis-associated infertility. Endometriosis-associated ovarian cancer has been recognized recently. It generally affects elderly women, especially postmenopausal women who are symptom-free and have no childbearing plans. Because the symptoms and problems in patients with endometriosis vary according to the woman’s age, the severity of the disease, and individual social requirements, the aim of treatment should be specific to each patient (Fig. 1). In this review, we summarize the updated management of endometriotic cyst in several clinical situations.

Fig. 1
figure 1

The symptoms and problems in patients with endometriosis vary according to the age of the patient, the severity of the disease, and individual social requirements. Therefore, the aim of treatment should be specific to each patient

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Diagnosis of Endometriotic Cyst

The most useful diagnostic imaging modalities for endometriotic cyst are ultrasonography (US) and MRI.

Exploratory Examination

Although plentiful information can be obtained from imaging analyses, the importance of a physical examination, especially an internal examination, should not be overlooked. With the aid of transvaginal US, careful internal examination by the experienced physician can identify the site causing pelvic pain and estimate the presence or absence of adhesions. Posttherapeutic improvement in pelvic tenderness detected by examination is as informative as improvement detected by imaging analysis.

Ultrasonography

US is used mainly in outpatient clinics for the screening of an adnexal mass, following exploratory examination. Typically, an ovarian endometriotic cyst presents with a diffuse, low-echoic appearance with occasional hyperechoic foci in the wall of unilocular or multilocular cysts 3 to 6 cm in diameter [3, 4] (Fig. 2).

Fig. 2
figure 2

Typical images of an endometriotic cyst. a Ultrasonography (US), showing a unilocular cyst with a diffuse and low-level echo within it. b–d On MRI scans, the contents of the cyst show high intensity in both T1-weighted and T2-weighted images, reflecting the blood element

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Differential diagnosis includes a mature cystic teratoma (or so-called dermoid cyst), which generally shows a more echogenic internal structure with an acoustic shadow reflecting hairballs and calcifications. Other differential diagnoses include functional cysts, such as a lutein cyst or a hemorrhagic follicular cyst, a tubo-ovarian abscess, and ovarian cancer [3]. Usually, differentiating an endometriotic cyst from other ovarian cysts is not difficult, using a precise evaluation of structural features and careful short-term follow-up. However, it is occasionally difficult to exclude other possibilities, especially when the cyst contains a solid portion or shows a wall irregularity. This finding most often represents a hemorrhagic clot, but it is difficult to exclude malignancy (Fig. 3). Color Doppler US may be useful for the differential diagnosis, but its effectiveness remains uncertain [5]. In such cases, further examination with MRI should be considered [3].

Fig. 3
figure 3

Images of a case of clear cell carcinoma, which arose in the same patient as Fig. 2 after an interval of 6 years. a ultrasonography (US), showing that the cyst contains a solid portion and the cyst is larger than it was 6 years ago. b–e On MRI scans, the cyst is unilocular and shows high intensity both in T2-weighted images (b, c) and T1-weighted images (d, e) with several nodular portions. These nodular portions show isointensity to high intensity in the T2-weighted image and low intensity in the T1-weighted images. e These portions also show positive contrast enhancement (CE)

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Because it is neither invasive nor expensive, US is also useful in the follow-up of endometriotic cyst. Regular check-ups every 6 months should be recommended. If any alteration in the US appearance is noticed, a closer follow-up or additional MRI examination is necessary.

Magnetic Resonance Imaging

MRI is one of the most powerful and informative diagnostic tools for an endometriotic cyst. Typically, an endometriotic cyst shows high intensity in both T1-weighted and T2-weighted images, reflecting the blood element in the cyst [3, 6] (Fig. 2). A “shading” or “shading sign” refers to a T2 shortening in the cyst, corresponding to a hyperintense portion on the T1 image, which is useful to distinguish endometriotic cyst from other blood-containing lesions, such as a hemorrhagic corpus luteum cyst [3, 4]. Although the hypointensity typically presents either as a focal/diffuse area or a layering with a hypointense fluid level, a significant proportion of cases show only a complete loss of signal intensity [7]. Lack of fat suppression helps to distinguish an endometriotic cyst from a dermoid cyst [4]. In cases of endometriotic cyst with a solid portion, contrast enhancement is mandatory to exclude malignancy, such as a clear cell carcinoma [3, 8].

Malignant transformation of endometriotic cyst is the most serious problem related to late-stage endometriosis. If US screening shows atypical findings such as a nodular portion, wall thickening, or a significant change in appearance during follow-up, MRI is helpful not only to rule out malignancies but also to estimate the histologic subtype of malignancies (Fig. 3). For this purpose, various parameters should be taken into account, such as maximum diameter, the presence of shading, and the size and the nature of the nodular portion. The most apparent risk factor is enhancement of the nodular portion, although a benign endometriotic cyst occasionally harbors an enhanced nodule. According to a study by Tanaka et al. [9•], the diameter of the cyst nodule is significantly correlated with a malignant phenotype. Lack of shading is also an important finding in the malignant transformation of endometriosis, especially when MRI scans are repeated in the same patient. Tanaka et al. [9•] reported that 81% of benign endometriotic cysts showed shading on T2-weighted images, but only 33% of malignant tumors showed shading. It is most likely that a nonhemorrhagic secretion by malignant cells may dilute the cyst’s contents, causing the loss of shading. One of the difficulties in diagnosing malignancy in endometriosis is a decidualized endometriosis during pregnancy, which presents as a rapidly growing nodular portion or wall thickening with abundant vascularity in the endometriotic cyst. This finding can be easily misdiagnosed as a malignancy [10–12]. In such cases, expectant management with careful serial follow-up is needed. MRI is also useful to estimate histologic subtypes of cancer arising in endometriosis. In cases of endometrioid cancer, MRI shows either a solid or cystic pattern without shading [13]. The nodular portions in the cyst tend to be multiple rather than single. In contrast, a clear cell carcinoma tends to be more cystic and unilocular, with one or several nodular portions [8].

One of the important roles of MRI in treating a patient with an endometriotic cyst is the diagnosis of coexisting extraovarian endometriosis, as it has similar symptoms, such as pain and infertility. Diagnosing it is also helpful to ensure adequate surgical intervention. Endometriotic lesions frequently involve the surface of the peritoneum and ovary. Fat-suppressed images are useful to identify the lesion, but a diagnosis is relatively difficult, resulting in poor diagnostic accuracy [5]. The characteristic MRI pattern of superficial endometriosis is either high T1 intensity with low T2 intensity or high intensity in both T1 and T2 imaging. Deep endometriosis, sometimes referred to as posterior endometriosis, often affects retroperitoneal organs, including the ureter and rectum. It frequently causes severe pelvic pain as a result of the involvement of the uterosacral ligament. The sensitivity of diagnosis of deep endometriosis by MRI is reported to be 76% to 86% [3]. Adhesions caused by endometriosis are also important as a cause of infertility and frequently make operation difficult. Using MRI, adhesions are typically identified by low-signal-intensity strands.

Management of Endometriotic Cyst According to the Symptoms

The treatment options for ovarian endometriotic cyst are either medical or surgical interventions. Observation is another choice in some situations. Medical therapy typically consists of androgens, progestogens, oral contraceptives (OCs), and gonadotropin-releasing hormone (GnRH) agonists. Surgical treatment for ovarian endometriotic cyst varies from hysterectomy with salpingo-oophorectomy (SO) to unilateral cystectomy with or without laparoscopy. Treatment recommendations differ according to the purpose of treatment and the symptoms of the patient.

Treatment of Endometriosis-Associated Pain

Although ovarian endometriotic cyst could be a cause of pelvic pain, it is rare that endometriotic cyst is the only cause of severe, chronic pain. Rather, accompanying extraovarian endometriosis or resulting adhesions or inflammation may be responsible [14]. Various drugs have been used to treat endometriosis-associated pain. A GnRH agonist is the most popular treatment choice, and a number of placebo-controlled randomized studies have shown that these are effective [15•]. Other drugs, such as danazol, OCs, and gestrinone have also been shown to be effective, with little difference from GnRH agonists [15•, 16, 17]. Dienogest, a selective progestin, was also as effective as GnRH agonists [18]. There are few published data, however, that indicate whether medical treatment effectively alleviates pain in women with symptomatic endometriotic cyst. Rana et al. reported that a GnRH agonist or danazol is effective in reducing the size of an endometriotic cyst and in controlling pelvic pain and dysmenorrhea [19].

Surgery is thought to be the first line of treatment for pain in women with endometriotic cyst [15•]. Surgical treatment to conserve bilateral ovaries includes drainage, sclerotherapy, diathermy, laser vaporization, and cystectomy [20–22]. Drainage guided by laparoscopy or transvaginal US has reportedly resulted in a high recurrence rate and is less effective for relieving symptoms [20]. In addition, it can cause pelvic infection or adhesions [20, 22]. Combining sclerotherapy using ethanol, tetracycline, and methotrexate with aspiration may reduce the rate of recurrence, although it can cause severe adhesions, which may affect future fertility [22, 23]. Ovarian cystectomy is a more definite treatment for endometriotic cyst. Although several studies found no difference among various surgical procedures, including drainage, ablation, and cystectomy, randomized trials indicated a lower cumulative postoperative rate of recurrence of dysmenorrhea, dyspareunia, and chronic pelvic pain in patients who underwent cystectomy compared with those who underwent drainage alone [21, 22]. Another obvious advantage of cystectomy is that histologic examination is available. Uterine nerve ablation (UNA) was reported to be effective in relieving pain in earlier studies [22], but in recent randomized controlled trials, its effectiveness in alleviating symptoms has been controversial. Several reports found no difference in symptoms at 3 years after surgery between the women who underwent laparoscopy alone and the women who underwent laparoscopy with UNA [24, 25]. Several authors reported modest clinical benefits of UNA [26, 27]. By contrast, many studies, including randomized trials, showed that presacral neurectomy (PSN) significantly improved symptoms [25, 27, 28], although some patients suffered adverse effects from the procedure, including constipation, bladder dysfunction, or intraoperative hemorrhage. Radical treatment options for women who do not require fertility include oophorectomy and hysterectomy with oophorectomy.

There are conflicting data on the role of postoperative medical treatment. Randomized studies in which a GnRH agonist or danazol was used postoperatively for 3 months did not show a difference in the recurrence of pain compared with a nontreated group [29, 30]. In contrast, treatment with a GnRH agonist, danazol, or medroxyprogesterone acetate (MPA) for 6 months after operation showed a significant advantage against the recurrence of pain in randomized controlled trials [31, 32]. These data suggest that postoperative medical treatment should be administered for at least 6 months and that treatment over a shorter period may not be beneficial [22].

Treatment of Endometriosis-Associated Infertility

Because endometriosis is primarily a disease encountered in women of reproductive age, infertility is one of its most important complications. The causal link between endometriosis and infertility is not clearly defined [33]. It is generally believed that endometriosis impairs fertility in multiple ways [33, 34•]. First, severe pelvic pain may interfere with regular sexual intercourse in couples who are trying to conceive. Second, endometriosis destroys the pelvic anatomy as it progresses, thereby disrupting the normal fertilization procedure. The most direct cause of infertility associated with endometriosis is tubal obstruction. Closure of the cul-de-sac, adhesions, and dislocation of the ovary or fallopian tube also interfere with natural conception. Third, in addition to these mechanical impairments, endometriosis affects fertility chemically and biologically. Inflammation caused by endometriosis alters the pelvic environment, with increases in inflammatory cytokines, growth factors, and angiogenic factors, which significantly disrupt fertility [34•]. For example, interleukins directly affect sperm motility, and tumor necrosis factor (TNF)-α causes DNA damage to the sperm [35–37]. These factors, along with reactive oxygen species (ROS) produced by endometriosis, also impede sperm capacitation, oocyte-sperm interaction, and oocyte quality [33, 34•].

Whether the presence of ovarian endometriotic cyst affects the normal ovarian function in terms of conception is unclear. It is suggested that endometriosis does not affect the quality of oocytes retained in the ovary. Rather, surgical intervention in the endometriotic cyst may damage ovarian function to some extent. In this view, which surgical procedure is favorable for reproductive ability is a matter of concern [38].

Treatment for endometriosis-associated infertility consists of medical and surgical approaches, just as for pain. However, because the purpose of treatment is different, the treatment strategy differs. The type of treatment may also be different for patients desiring natural conception and for those undergoing assisted reproductive technology (ART). Almost all medical treatments for endometriosis are based on the hormonal blockage of ovarian function and are thus contraceptive; therefore, medical treatment is usually not the chosen treatment for women pursuing spontaneous conception [34•]. Evidence suggests that there is no improvement in pregnancy rates with medical intervention for endometriosis [39].

Although removal of an ovarian endometriotic cyst is considered to be effective in correcting disrupted pelvic anatomy, it is still undetermined whether surgical intervention for endometriosis, especially endometriotic cyst, contributes to natural conception [34•]. The presence of endometriotic cyst may affect spontaneous ovulation [40]. Surgery for various degrees of endometriosis appears to improve the rate of natural conception, but determining the optimal operative procedure for endometriotic cyst is another issue. Several reports, including randomized controlled trials, indicate that ovarian cystectomy by way of laparoscopy is superior to drainage or vaporization in terms of higher pregnancy rates and lower recurrence rates [21, 41]. Yazbeck et al. [23] suggested that ethanol sclerotherapy may offer a better result because it causes less damage to the remaining ovarian function.

For patients who plan to undergo in vitro fertilization (IVF) after treatment for infertility associated with endometriosis, the management policy is different. It is estimated that 10–25% of patients undergoing IVF have accompanying endometriosis, and 17–44% of them have endometriotic cyst [38, 41]. The presence of endometriosis and its severity may negatively impact the outcomes of IVF, though the relationship is not definitively proven [42]. Medical treatment for endometriotic cyst prior to IVF reduces the size of the cyst, and several randomized controlled trials indicate that GnRH agonist treatment before IVF in women with endometriosis significantly increases pregnancy rates [43, 44].

As regards surgical intervention, Tsoumpou et al. [41] performed a meta-analysis of five studies comparing surgical treatment versus no treatment for ovarian endometriotic cyst. The results showed no significant effect of treatment on IVF pregnancy rates and on ovarian response to stimulation, compared with no treatment. Nevertheless, the author mentioned that the decision regarding surgery for endometriotic cyst in asymptomatic women before IVF should take into account the anticipated difficulty in accessing the follicles and the risk of pelvic infection if inadvertent drainage of a large endometriotic cyst occurs at the time of retrieval. Expectant management of endometriotic cyst before IVF presents risks that include difficulty in monitoring follicular growth and spontaneous rupture and leakage, which may cause pelvic inflammation, infection, and adhesion. On the other hand, surgery may cause quantitative damage to ovarian reserves, as a decrease in the number of eggs has been observed after ovarian cystectomies, although the fertilization rates and the quality of the embryos did not differ [22].

Management of Endometriosis in Terms of Development of Ovarian Cancer

It is clinically evident that endometriosis gives rise to ovarian cancer with a relatively high frequency, and it has been shown that women with endometriosis have a higher risk of ovarian cancer. According to a survey in Japan, approximately 1% of cases of ovarian endometriosis transform into ovarian cancer [45]. Importantly, this rate significantly increases in elderly women. The risk of ovarian cancer in patients with endometriosis is reported to be significantly higher than in the general population (standardized incidence ratio [SIR], 1.4–1.9), and this risk increases in women with a longer history of endometriosis (SIR, 2.2–4.3) [46•]. It is also well known that ovarian cancers arising from endometriosis have a unique histology: most are of a clear cell or endometrioid subtype, relatively rare for ovarian cancer [47•].

Numerous pathologic and molecular biologic data suggest that endometriotic epithelium is actually a precursor of ovarian cancer [47•]. Continuation from morphologically benign endometriosis to cancer is frequently observed, and occasionally an intermediate lesion, such as atypical endometriosis, is found nearby [48]. The analysis of the loss of heterozygosity (LOH) and genetic mutations also indicates that endometriosis shares common genetic events with associated ovarian cancer [49]. These findings clearly show that ovarian cancer indeed develops from endometriosis, and that both conditions have common molecular pathways in their development. However, the precise mechanism involved in the development of cancer in endometriosis is still unclear. Various genetic events are implicated, as is the effect of the microenvironment, such as endometriotic fluid containing highly concentrated iron [50, 51].

Considering these facts, it is important to take the risk of cancer into account in managing endometriosis, especially in elderly women. There are few guidelines, however, on how to manage endometriosis as a precursor of ovarian cancer. This lack is partly because the risk factors for ovarian cancer among women with endometriosis are not fully defined. Especially in the case of endometrioid adenocarcinoma, and possibly in some cases of clear cell and mixed-type carcinomas, estrogen plays an important role not only in the growth and maintenance of endometriosis, a precursor lesion of these cancers, but also in the development of cancer [47•]. Mechanisms that may be implicated in these conditions include unopposed estrogen status, increased expression of estrogen α, progesterone resistance, and increased aromatase activity, but these should be further elucidated [46•]. In terms of clinical relevance, several authors reported that estrogen replacement therapy (ERT) increased the risk of ovarian cancer, especially of the endometrioid subtype [52]. Although it has not been directly shown that estrogen increases the risk of endometriosis-associated cancer, this possibility should be considered when introducing ERT in women who have a history of endometriosis, even after menopause [52]. There are several reports of endometrioid adenocarcinoma in patients who underwent a hysterectomy with bilateral oophorectomy for endometriosis with subsequent long-term estrogen use [53]. It is generally recommended to add a progestin if ERT is necessary after menopause or after a hysterectomy with oophorectomy for endometriosis [54].

Whether surgical intervention is indicated for cancer prevention in women with endometriosis is an important issue but is not clearly defined. It is unclear whether conservative surgery, such as ovarian cystectomy or vaporization, reduces the risk of malignant transformation of endometriosis [47•]. As previously mentioned, several surveys indicate that women who have a longstanding history of endometriosis have a greater risk of developing ovarian cancer [46•], which suggests that surgical intervention somehow may reduce the risk of malignant transformation. Interestingly, women who underwent a hysterectomy after a diagnosis of endometriosis did not show an increased risk of ovarian cancer, thus indicating that hysterectomy and possibly tubal ligation may have some protective role [46•]. For elderly women in whom endometriotic cyst has been diagnosed, early detection of cancer is clinically important. It is generally accepted that an endometriotic cyst growing after menopause should be resected. Kobayashi et al. [55] demonstrated that the risk factors for malignant transformation of endometriotic cyst are older age, postmenopausal status, and larger tumor size. They recommended considering surgery in postmenopausal women with an endometriotic cyst measuring 9 cm or larger.

It is still unclear whether medical treatment for endometriosis reduces the risk of developing ovarian cancer. Oral contraceptives are known to reduce ovarian cancer risk partly by inhibiting ovulation, which is thought to be a major risk for ovarian cancer. Together with their therapeutic effect on endometriosis, OCs may reduce the risk of malignant transformation of endometriosis, but there is not yet any conclusive study on this issue. The use of a GnRH agonist may reduce or increase the risk of endometriosis-associated ovarian cancer because although postmenopausal status increases the risk of ovarian cancer, GnRH agonists suppress endometriosis itself. Newer drugs such as dienogest may be used more frequently for endometriosis, but no data are yet available on their effect on cancer prevention. Clinical studies are needed on the effect of medical care in preventing the development of endometriosis-associated cancer.

Minimally Invasive Surgery for Endometriotic Cyst

As mentioned above, various surgical procedures are used to manage various symptoms derived from endometriosis. Recently, minimally invasive surgery under laparoscopy is becoming the standard modality for the treatment of endometriosis, especially in conservative therapy.

Laparotomy Versus Laparoscopy for Endometriosis

Whether laparotomy or laparoscopic surgery is superior as a surgical management technique for endometriosis is an important issue. A number of reports, including controlled trials, indicate that pregnancy rates, monthly fecundity, and recurrence rates are comparable between laparotomy and laparoscopy [56, 57]. On the other hand, blood loss, length of hospitalization, and recovery time are usually decreased after laparoscopy [57]. It is generally thought that laparoscopy is technically difficult and has a greater risk of surgical complications than laparotomy, but a meta-analysis of prospective randomized trials showed that laparoscopy and laparotomy exposed patients equally to complications [58]. Therefore, except in cases with special indications, laparoscopic surgery is the first choice among surgical procedures for infertile woman with endometriotic cyst.

Laparotomy may be more applicable for women with severe pelvic endometriosis if curative surgery is planned. However, even in very radical operations, such as REHCR (radical en bloc hysterectomy and colorectal resection), laparoscopy is reported to be comparable or superior to laparotomy in terms of symptoms and improvement in quality of life [59].

Excision Versus Ablative Surgery for Ovarian Endometriosis

As previously mentioned, surgical procedures, including laparoscopic procedures, include salpingo-oophorectomy (with or without hysterectomy), ovarian cystectomy, ablation, and drainage. Randomized trials clearly show that laparoscopic excision of the cyst wall of an endometriotic cyst is superior to ablation in terms of reduced recurrence, relief of pain, and pregnancy rates [60]. Damage caused by the removal of normal ovarian tissue in an excisional procedure is usually minimal, but Donnez et al. [61] have recommended using laser vaporization for the portion close to the hilus.

Surgery for Recurrent Endometriotic Cyst

Vercellini et al. [62] reviewed the reports on the efficacy of repeat surgery for recurrent endometriosis. Among 313 patients who wanted to conceive after repeat surgery, 81 women became pregnant, with no significant difference between laparotomy and laparoscopy. However, the pregnancy rate after repeat surgery was significantly lower than the rate after primary surgery.

Conclusions

The roles of medical treatment with currently available drug regimens and of surgical interventions for treating endometriosis-associated pain and infertility in women with endometriotic cyst have been intensively investigated and are by and large clear. In contrast, the effect of medication and surgery on the development of cancer in women with endometriosis is poorly understood, and no standard management for endometriosis in terms of reducing malignant transformation has been proposed. High-quality clinical trials are needed to help in establishing a standard care for endometriotic cyst, especially after menopause.