Endometriosis: Pathogenesis and Treatment 2014 Ed.

25. Prevention of Recurrence After Surgery

Yutaka Osuga Yuri Takemura1Masashi Takamura1 and Kaori Koga1

(1)

Department of Obstetrics and Gynecology, School of Medicine, the University of Tokyo, Japan, 7-3-1 Hongo Bunkyo, Tokyo 113-8655, Japan

Yutaka Osuga

Email: yutakaos-tky@umin.ac.jp

Abstract

Recurrence of ovarian endometrioma after excision imposes profound encumbrance on the suffered women, with increasing pain, subfertility/infertility, and a risk of ovarian cancer. Postoperative recurrence is relatively common, the rate ranging from 11 to 32 % in 1–5 years. To date, a number of risk factors for the recurrence have been reported, i.e., younger age, larger cysts, high rASRM scores, previous medical treatment, previous surgery for endometriosis, and short-term postoperative medical treatment. In contrast, postoperative pregnancy reduces the risk. Several biomarkers are suggested to predict the recurrence but not yet validated in clinical practice. Postoperative OC use for a long period has been demonstrated to reduce the recurrence remarkably. Postoperative GnRH analogue use is also effective for the reduction of the recurrence. There still remain some issues on the duration and the drugs most suitable for the prevention.

Keywords

EndometriomaOral contraceptiveRecurrenceSurgery

25.1 Introduction

Endometriosis is a disease defined as the presence of endometrium-like lesions outside the uterus. Although the exact etiology has not yet been determined, it is widely accepted that endometrial cells in the retrograde menstruation attach, invade, and grow in the peritoneum to cause the disease. It occurs in women of reproductive age and deteriorates the quality of life of the affected women by inducing infertility/subfertility and intractable pain. Treatment of the disease is mainly conducted with drugs and/or surgery. A mainstream of medical treatment is hormonal treatment. However, hormonal drugs cannot be used for those who want to conceive since the drugs inhibit ovulation. In addition, some pain symptoms are occasionally resistant to medical treatment. Likewise, hormonal drugs are often not effective to eradicate developed lesions, such as endometrioma. On the other hand, surgical treatment is appropriate for removing developed lesions and often effective to mitigate drug-resistant pain. Widespread use of laparoscopic surgery makes it less invasive to treat endometriosis by surgery.

Surgical treatment for endometriosis, while having relatively effective outcome in the short term, has a problem in the long period after surgery. Hysterectomy with bilateral oophorectomy is radical enough to cure endometriosis, but the procedure is not acceptable for patients who want to maintain fertility. For these patients, excision of endometriosis lesions (conservative surgery) is a method of choice. This treatment often entails recurrence both in symptoms and in histology. Recently, the concern is gaining traction because more and more women need conservative surgery due to increasing tendency to childbearing in late reproductive ages.

This problem, however, is not so new. An incipient report that examined the recurrence after conservative surgery, while performed by open surgery in those days, indicated several noticeable findings. The authors followed 423 patients treated with conservative surgery and found 13.5 and 40.3 % cumulative recurrence rates in 3 and 5 years, respectively [1]. They found that severity of disease was not predictive of recurrence and pregnancy delayed recurrence.

There are a number of reports also in the era of laparoscopic surgery. When we read these papers, we notice the complexity of the problems regarding “recurrence.” Some papers examine recurrence of pain, while others examine recurrence of endometriosis lesions detected by laparoscopy or imaging. Some papers study recurrence of endometriosis in general while others study recurrence of a specific type of endometriosis, e.g., peritoneal lesion, ovarian endometrioma, and deep endometriosis at the cul-de-sac. The operation methods are either not uniform, including excision of the cyst (cystectomy) and coagulation or vaporization using electric devises or lasers. In this chapter, we focus on the recurrence of endometrioma, which can be easily detected by transvaginal ultrasound, after laparoscopic excision.

25.2 Recurrence of Endometrioma After Laparoscopic Excision

25.2.1 Recurrence Rate

Postoperative recurrence rate for endometrioma ranges from 11 to 32 % in 1–5 years [211]. The variation partly comes from the difference of the definition of recurrence; some define it by the presence of ovarian cysts greater than 3 cm [510] while others define it by the size at least 2 cm [68]. Instinctively, the time after surgery is related to the recurrence rate. However, unless patients are regularly followed up, as often with the case of asymptomatic patients, it is difficult to accurately quantify the time of recurrence. It is thus not obvious in which time period the patient is most susceptible to recurrence, or whether there is a specific period of time after which a patient is less likely to develop recurrence. According to Evers et al. the recurrence rate during the first 5 years gradually increases [12]. This might imply that endometriosis will eventually reappear in all patients who underwent complete removal of the lesions. In accordance with this notion, a longitudinal study by Liu et al. showed that the recurrence rates continued to increase with time, 7.8, 17.7, and 32.3 % at 1, 2, and 3 years, respectively [10]. In contrast, Kikuchi et al. drew a cumulative recurrence rate curve and demonstrated that the cumulative rate reaches a plateau at around 48 months after surgery [6]. Further studies with longer follow-up are needed to settle the issue.

Whether the recurrence of endometrioma occurs by de novo or the relapse of residual endometrioma is poorly understood as well as the origin of endometrioma per se. To address the issue, the recurrence rate was studied with analysis of the side in which endometrioma recurred, supposing that recurrence in the contralateral ovary should be de novo. Exacoustos et al. analyzed 62 patients with recurrent endometrioma and found that 12 patients had recurrence on the counter-lateral untreated ovary [13]. Kikuchi et al. also analyzed 26 cases with recurrence after hemilateral surgery and found that 11 cases had recurrence on the counter-lateral untreated ovary [6]. These findings suggest that the recurrence of endometrioma is not totally dependent on the presence of the residual endometrioma but in part on de novo occurrence. Of course, it cannot be denied that a lesion on the contralateral ovary undetected by the initial laparoscopy may have progressed after surgery. Although the difference between de novo and relapse is critical for optimal management of this disorder, it is impossible at the moment to discriminate clearly the origin by just looking at and following up the patents and the lesions. Further ingenious studies seem to be necessary to resolve the issue. Collectively, there is no doubt that the recurrence of endometrioma after laparoscopic excision is a common and serious problem, although the actual recurrence rate varies among studies.

25.2.2 Risk Factor and Biomarker of Recurrence

Since endometriosis has characteristics of a chronic disease, it would be useful if doctors are able to estimate the probability of recurrence before surgery. To this end, a number of studies have been conducted analyzing various factors which might associate with recurrence. We retrospectively studied a total of 224 patients who had undergone laparoscopic cystectomy of endometrioma [8]. The patients had a minimum of 2 years of postoperative follow-up after laparoscopic cystectomy. Recurrence was defined as the presence of endometrioma more than 2 cm in size, detected by ultrasonography within 2 years of surgery. We assumed that 14 variables (age, presence of infertility, pain, uterine myoma, adenomyosis, previous medical treatment of endometriosis, previous surgery for ovarian endometriosis, single or multiple cysts, the size of the largest cyst at laparoscopy, unilateral or bilateral involvement, coexistence of deep endometriosis, revised American Society for Reproductive Medicine (ASRM) score, postoperative medical treatment, and postoperative pregnancy) might associate with the recurrence and evaluated these variables to assess their independent effects on the recurrence using logistic regression analysis. As a result, the overall rate of recurrence was 30.4 % (68/224). Significant factors that were independently associated with higher recurrence were previous medical treatment of endometriosis [odds ratio (OR) = 2.324, 95 % confidence interval (95 % CI) = 1.232–4.383, P = 0.0092) and larger diameter of the largest cyst (OR = 1.182, 95 % CI = 1.004–1.391, P = 0.0442). As shown in Table 25.1, postoperative pregnancy was associated with lower recurrence (OR = 0.292, 95 % CI = 0.028–0.317, P = 0.0181). It seems intuitively reasonable that the larger cyst associates with the higher recurrence rate. In contrast, it appears to be difficult to construe the association between previous medical treatment and the higher recurrence risk. The finding may be explained by two possible mechanisms. The first is that the medication may mask endometriotic lesions and allow them to escape from removal at operations. Because more than half of the women who were categorized into previous medical treatment group had continued their medication until the time of operation, it may be possible that the medication might yield latent lesions that remain and recur after the operation. The other possible reason for a negative impact of medical treatment on endometrioma recurrence is that hormonal-suppressive therapy may alter some genomic characteristics of endometriotic lesions. As for malignant transformation of endometriosis, it is proposed that hormonal ablative treatments may cause negative selection, suppress the normal, eukaryotic cells more than aneuploid cells bearing chromosomal aberrations, and increase the rate of dyskaryotic cells in the endometriotic implants [14]. We conjecture that “negative selection” may also contribute to the recurrence of disease, making the lesion more active, progressive, and liable to recurrence. The association of postoperative pregnancy and lower rate of recurrence is an interesting finding but needs careful interpretation. A possible scenario is that subsequent pregnancy may have a protective effect on endometrioma recurrence. An absence of retrograde menstruation and formation of corpora lutea [15], both of which are known to cause endometriosis, and persistent exposure to progesterone are thought to contribute to the protective effect of pregnancy. Conversely, those who tended not to recur had more probability to be pregnant given that endometriosis causes infertility/subfertility.

Table 25.1

Univariate and logistic regression analysis of factors related to the recurrence of ovarian endometrioma

Factors

Univariate analysis

Logistic regression analysis

P values

P values

Odds ratio (95 % confidence interval)

Age (years)

NS

   

Infertility

NS

   

Pain

NS

   

Presence of uterine myoma

NS

   

Presence of adenomyosis

NS

   

Previous medical treatment of endometriosis

<0.05

<0.01

2.324 (1.232–4.383)

Previous surgery of ovarian endometrioma

NS

   

Multiple cysts

NS

   

Largest cyst diameter (cm)

<0.05

<0.05

1.182 (1.004–1.391)

Bilateral involvement

NS

   

Coexistence of deep endometriosis

NS

NS

0.456 (0.198–1.052)

Revised ASRM score

NS

NS

1.010 (1.000–1.021)

Postoperative medical treatment

NS

   

Postoperative pregnancy

<0.05

<0.05

0.292 (0.028–0.317)

ASRM American Society for Reproductive Medicine [8]

Several risk factors have been reported by others. In general, the more advanced the endometriosis, the more the disease recurs. Larger cysts [8] and high rASRM scores [67101617] are reported to be risk factors for recurrence. Factors that may correlate with the severity of endometriosis such as previous medical treatment [810], previous surgery for endometriosis [317], and short-term postoperative medical treatment [9] are also identified as risk factors. Younger age at surgery is reported as a risk factor by two studies [610]. A younger age at surgery would correlate with a younger age at onset and possibly a disease type that is more aggressive and prone to recurrence than the endometrioma associated with an older age of onset.

A few researches are trying to find out biomarkers for recurrence of ovarian endometriomas. Increased expression of progesterone receptor isoform B, nuclear factor kappa-B, SLIT/ROBO1, and cyclooxygenase-2 are shown to be associated with higher risk of recurrence [1820]. However, whether they are practically useful in predicting the recurrence awaits further studies.

25.2.3 Postoperative Medical Managements to Prevent Recurrence

Until recently, postoperative medical treatment that prevents recurrence has not been developed successfully. In the face of the fact that postoperative pregnancy decreases the risk of recurrence, as described above, we came up with the idea if postoperative oral contraceptives might decrease recurrence. We thus conducted a before and after study on postoperative OC treatment. In 2005, our clinic introduced the “OC recommendation,” that is, at the time of the operation, we provided each patient with information about OC and the known possible benefits and risks and let the patient decide whether or not to take OC. Women who chose to take OC were given a cyclic (21 days pills/7 days no pill), monophasic OC containing ethinyl estradiol (0.035 mg) and norethisterone (1.0 mg) (Ortho-M 21®, Mochida, Tokyo, Japan), in the first menstrual cycle after laparoscopy. We then conducted a historical study to compare the 2-year recurrence rate before and after the introduction of the “OC recommendation.” The overall recurrence rate in patients who underwent laparoscopy after the introduction of the “OC recommendation” was significantly lower than that in patients who received laparoscopy before the introduction (18.6 versus 33.1 %, relative risk 0.56, 95 % CI 0.32–0.97, P < 0.05) [21]. Figure 25.1 depicts the recurrence rate in those who used OC which was significantly lower than others (non-OC users plus those who quit OC) (2.9 versus 35.8 %, relative risk 0.08, 95 % CI 0.01–0.48, P < 0.001) [21]. This study indicated that postoperative OC use reduces the risk of ovarian endometrioma after laparoscopic excision.

A313895_1_En_25_Fig1_HTML.gif

Fig. 25.1

Recurrence after laparoscopic excision of endometrioma. Flowchart of the patients who underwent laparoscopic excision of endometrioma after May 2005, for the retrospective cohort study. A total of 87 patients were followed up for 24 months. Of the 87 patients, 48 started to take OCs, but 39 did not. Of the 48 patients who had started OC, 34 continued OC for the entire study period (24 months), whereas 14 discontinued

In addition to our study, there have been several studies that evaluate the role of postoperative OC on the recurrence of endometrioma. In contrast to the classical report showing OC had no effect on disease recurrence when used for up to 6 months [22], all studies that tested postoperative OC for 2 years or more demonstrated protective effect of OC on recurrence [112123]. The different outcomes between short-term and long-term studies indicate that the duration of treatment with OC affects recurrence. Indeed, Vercellini et al. compared cumulative recurrence according to the duration of postoperative OC use and found that women who used OC for less than 12 months were at higher risk of recurrence than women using OC for 12 months or more [11].

GnRH analogue also has an effect to mitigate recurrence. Jee et al. analyzed the influence of postoperative GnRH analogue according to the duration of the treatment and found that a 6-month treatment had a beneficial impact compared with a 3- and 4-month treatment and expectant management, although the differences did not reach statistical significance [24]. In another report, patients who received 3–6 months of GnRH analogue therapy alone and patients who received OC after GnRH analogue were compared. As a result, recurrent endometrioma after 60 months was significantly lower in OC plus GnRH analogue group than in GnRH analogue alone group (6.1 versus 43.3 %) [25]. It seems that GnRH analogue treatment longer than 6 months reduces the recurrence, and additional OC treatment may maintain the effect. However, the benefit of GnRH analogue should be weighed against the risk of adverse effects associated with estrogen deprivation.

25.3 Summary

Postoperative recurrence of endometrioma is a common event and prevention of the recurrence is needed to manage women with endometriosis successfully for a long period. Thanks to recent extensive studies, it has been established that long-term administration of OC after surgery is safe and tolerable and recommended for those who do not want to conceive immediately after the surgery. However, there still remain some issues regarding what kind of drugs are most suitable and how long the drug should be used. Further studies are warranted to improve strategies to prevent the recurrence.

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