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Early recurrence of early stage endometrioid endometrial carcinoma: Possible etiologic pathways and management options
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Review
Early recurrence of early stage endometrioid endometrial carcinoma: Possible etiologic pathways and management options Christos Iavazzo a , Ioannis D. Gkegkes b,∗ , Nikolaos Vrachnis c a b c
Gynaecological Oncology Department, Christie Hospital, Manchester, United Kingdom 1st Department of Surgery, General Hospital of Attica “KAT”, Athens, Greece 2nd Department of Obstetrics and Gynecology, University of Athens Medical School, Aretaieio Hospital, Athens, Greece
a r t i c l e
i n f o
Article history: Received 9 February 2014 Received in revised form 8 April 2014 Accepted 8 April 2014 Available online xxx Keywords: Early endometrial cancer Recurrence Etiology Management
a b s t r a c t The majority of endometrial cancers is early stage and of the endometrioid histological type, as the symptoms (mainly vaginal bleeding) of the disease lead to an early diagnosis. Close follow-up is nevertheless essential in such cancers staged early on, in which the rate of recurrence is relatively low. We retrieved the studies included in our narrative review after performing a systematic electronic search in the PubMed, Scopus and Cochrane databases. The incidence or recurrence of disease in such patients could be up to 2.6%, with the main sites of recurrence being the vaginal vault or metastases in distant parts of the body. Genetic factors such as p53 overexpression, inactivation of 14-3-3-sigma, KRAS amplification and KRAS mRNA expression, microsatellite instability and Lynch syndrome genes could be associated with such a recurrence. Black race is also correlated, as well as lymphovascular space involvement, lower uterine segment involvement and DNA aneuploidy. Longer hysteroscopy duration was not found to be associated. Close follow-up is suggested for early detection of recurrences, while surgical excision of isolated disease or exenteration of local disease as well as radiotherapy and chemotherapy are the main treatment options. This narrative review investigated the possible mechanisms of early recurrence in patients with endometrioid endometrial cancer as well as the further management of them. © 2014 Published by Elsevier Ireland Ltd.
Contents 1. 2. 3. 4. 5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Competing interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Provenance and peer review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Endometrial cancer is the most common gynecological malignancy, especially in postmenopausal women. Because of the early
∗ Corresponding author at: 141 Oropou Str., Nea Ionia, Athens 14232, Greece. Tel.: +30 6993671843. E-mail address: [email protected] (I.D. Gkegkes).
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signs of vaginal bleeding, up to 75% of endometrial cancer cases are tumors detected at an early stage and confined to the uterus [1]. The management of early stage endometrial cancer consists of total abdominal, laparoscopic or robotic assisted hysterectomy and bilateral salpingo-oophorectomy plus surgical staging. Adjuvant therapy is given postoperatively in cases characterized by poor differentiation, deep myometrial invasion, lymphovascular space involvement or nonendometrioid histological type. Meanwhile,
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the role of chemotherapy is not as yet well clarified for early stage disease. Usually, stage Ia grade 1 or 2 endometrioid endometrial carcinomas have an excellent prognosis and early cases of recurrence are rare. The aim of this review is to clarify the incidence of patients with stage Ia endometrial cancer who may develop early recurrence, as well as to discuss the possible etiologic mechanisms and management of such cases. 2. Methods We retrieved the studies included our narrative review after performing a systematic electronic search in PubMed (08/10/2013) and Scopus (08/10/2013). Both the PubMed and Scopus search strategy included the combination of the key words: early recurrence AND endometrioid endometrial cancer AND early stage. The Cochrane database (08/10/2013) was also searched in order to look for any reviews on this topic. The references of included articles were also hand-searched for additional studies. Studies written only in the English language were included. The reporting data on the incidence, prognostic factors, pathogenetic pathways and management of patients with early recurrence of early stage endometrial cancer after surgical treatment were included in our review. Our analysis included only patients with endometrioid endometrial carcinoma at stage I, according to the FIGO 1988 classification [2]. Regarding the definition of early recurrence, due to the great variability in the definition, we adopted the one used by the authors of the selected studies. Conference papers, abstracts, editorials, review articles, animal studies as well as commentaries were not eligible for this review. 3. Results In total, 98 and 103 studies in the PubMed and Scopus search were retrieved, respectively, among which 9 studies met the inclusion criteria for our review (10, 224-31). No further studies were retrieved from the Cochrane database. No additional studies were found through hand-searching of references. The applied search strategy is depicted in Fig. 1 (flow diagram). The principle characteristics of the studies included in our review (demographics, publication type, stage of neoplasia, type of treatment, time lapse until recurrence, follow-up, outcome) are presented in Table 1. The present study included seven retrospective studies, one prospective study and one case report. The total number of patients included was 1955. The median age of the included patients ranged from 45 to 65 years old. The number of patients at stage Ia, Ib and Ic was 1040, 476 and 159, respectively. The initial treatment of endometrioid endometrial carcinoma comprised total abdominal hysterectomy and bilateral salpingo-oophorectomy in 1403 patients and pelvic lymphadenectomy in 63 patients, while adjuvant therapy (chemotherapy/pelvic radiation) was administered in 388 patients. The median period to recurrence ranged from 7 to 53.6 months, while the follow-up period ranged from 7 to 156 months. The survival rate after treatment for the recurrences was mentioned in only three studies, in which it had been extended by 33 to 100 percent. 4. Discussion A recent study showed that the overall recurrence rate in patients with endometrial cancer is 14.2%, with age, grade, mitotic activity, myometrial invasion, lymphovascular space invasion, microscopic vaginal metastases, adnexal involvement and nodal disease being the main prognostic factors [3]. Women with stage Ia
endometrial cancer have a low risk of recurrence (2.6%). The most common site of recurrence in patients with early stage endometrial cancer is the vaginal vault, but distant metastases (e.g. lung, muscle) are also described in the literature [4]. They are usually detected as isolated clinical findings and include vaginal vault recurrence, vaginal bleeding, abdominal pain or shortness of breath [5]. The possible pathogenetic pathways of early recurrence are still under investigation (Table 2). A population-based study suggested that recurrence-free survival may be shorter among black women with stage I endometrial cancer, especially in those women who used hormone replacement treatment postoperatively [6]. Although a query was raised regarding the role of preoperative low-pressure diagnostic hysteroscopy duration in early recurrences of stage I endometrial cancer, it was recently demonstrated that longer duration of hysteroscopy does not increase the risk of intraperitoneal transport of malignant cells or positive peritoneal cytology and so it is not an adverse prognostic factor for recurrence-free survival [7,8]. Lymphovascular space involvement in early stage well-differentiated endometrioid endometrial cancer could be a highly significant predisposing factor of recurrence and is associated with high mortality rates in such patients [9]. Lower uterine segment involvement could also be associated with an increased risk of recurrence [10]. Moreover, other authors recently sought to clarify the incidence and clinical significance of lymph node micrometastases determined by immunohistochemical staining in stage I lymph node-negative endometrial cancer, but no correlation was identified [11]. On the other hand, in a retrospective study of 217 patients, DNA aneuploidy was shown to be an independent prognostic factor in patients with stage Ia endometrial cancer and could distinguish high risk from low risk patients, as the recurrence rate was found to be 2.1% for diploid tumors and 12.5% for aneuploid tumors [12]. In another study, it was shown that patients with diploid, low-risk stage I endometrial cancers have a better prognosis, while patients with aneuploid tumors treated with adjuvant radiotherapy have the same risk of relapse as untreated patients with diploid tumors [13]. Furthermore, p53 expression in diploid tumors is associated with increased risk of recurrence, whereas Bcl-2 and ER could not be used as prognostic indicators [13]. Another possible explanation for early recurrence could be staging underestimation. More specifically, it has previously been shown that the preoperative prediction of grade was correct in 96% of the patients, while gross examination of myometrial invasion correctly differentiated between stage Ia, Ib and Ic disease in 89% of them. Moreover, the same study disclosed that the combination of preoperative tumor grade and gross examination of myometrial invasion could lead to wrong clinical decisions and management in 11% of the patients [14]. Finally, the role of lymphadenectomy could be crucial. Our results showed that 63 (of 1955) patients underwent pelvic lymphadenectomy. Although the standard treatment today for endometrial cancer patients is pelvic lymphadenectomy, the included studies are older and some of them do not provide accurate information about the possible role of pelvic lymphadenectomy. For example, in the Robbins paper [24], since the patients included in the study may or may not have had lymph node dissection, it is indeterminate how many actually did undergo lymphadenectomy (pelvic or paraaortic). Genetic factors are associated with the pathogenesis. Although the role of microsatellite instability as an independent prognostic factor is questioned [6,15], rDNA methylation is correlated with early recurrence [16]. Mutant p53 overexpression, which is found three times more often in black women with stage I endometrial cancer, might explain this finding [17]. Possible correlation with Lynch syndrome could be another etiologic factor characterized by the presence of MSI or loss of MLH1 with lack of MLH1 methylation or loss of either MSH2 and/or MSH6 protein expression [18]. An inactivation of the 14-3-3-sigma gene has been shown to be
Please cite this article in press as: Iavazzo C, et al. Early recurrence of early stage endometrioid endometrial carcinoma: Possible etiologic pathways and management options. Maturitas (2014), http://dx.doi.org/10.1016/j.maturitas.2014.04.009
Publication type
Simpkins, 2013, USA [24]
Retrospective study
Lajer, 2012, Denmark [26]
Stage of neoplasiaa
Type of treatment (%)
Period to recurrence (in months) (%)
Follow-up (in months)
Survival (%)
131
Median (range): 67 (60–75)
Ib: 5/30 (16.6), Ic: 17/30 (56.6)
In 22/131 (16.8) Median (range): 16 (4–114)
Median (range): 51 (36–120)
NM
Prospective study
571
Median (range): 62.9 (28.3–87)
Ia: 572/572 (100)
In 23/571 (4) Median (range): 25 (1–152)
Median: 156
14/23 (60.8)
Ortac¸, 2012, Turkey [27]
Case report
1
45
Ia
7
7
1/1 (100)
Robbins, 2012, USA [25]
Retrospective study
57
Median (range): 65 (33–90)
In 43/57 (75.4) Median (range): 20.2 (8–174)
Median (range): 54.8 (8.4–184)
NMb
Esselen, 2011, USA [28]
Retrospective study Retrospective study
72
NM
Ia: 5/57 (8.7), Ib: 27/57 (47.3), Ic: 11/57 (19.3) I: 34/72 (47.2)
Total abdominal hysterectomy, bilateral salpingo-oophorectomy: 131/131 (100), adjuvant radiation: 86/131 (66) Total abdominal hysterectomy, bilateral salpingo-oophorectomy: 572/572 (100) Peritoneal washing, total abdominal hysterectomy, bilateral salpingo-oophorectomy, bilateral pelvic lymphadenectomy, partial omentectomy Abdominal hysterectomy: 57/57 (100), adjuvant radiation: 32/57 (56.1)c NM
NM
NM
NM
NM
In 36/481 (7.5) Median (range): 53.6 (0.2–165.3)
Median (range): 53.6 (0.2–165.3)
NM
Abdominal hysterectomy, bilateral salpingo-oophorectomy: 51/51 (100), Pelvic lymphadenectomy: 38/51 (74.5) Adjuvant therapy: 35/51 (68.6) Total abdominal hysterectomy: 513/513 (100), Adjuvant radiotherapy: 218/513 (42.5)
In 51/51 (100) Median (range): 12 (3–119)
NM
NM
In 67/513 (13.1) Median (range): locoregional: 14 (3–57), Distant: 18 (2–58) In 6/78 (7.7) Median (range): 19.5 (9–29)
Median (range): 28 (2–144)
NM
Median (range): 38 (9–98)
2/6 (33.3)
481
Median (range): 62 (22–92)
Ia: 112/481 (23.3), Ib: 222/481 (46.1), Ic: 95/481 (19.7) Ib: 6/51 (11.7), Ic: 11/51 (21.6)
Otsuka, 2010, Japan [29]
Retrospective study
51
Median (range): 64 (46–81)
Nofech-Mozes, 2008, Canada [30]
Retrospective study
513
Median (range): 63 (28–94)
Ia: 330/513 (64.3), Ib: 183/513 (35.7)
Papanikolaou, 2006, Greece [31]
Retrospective study
78
Median (range): 65 (35–80)
Ia: 20/78 (25.5), Ib: 33/78 (42.5), Ic: 25/78 (32)
Peritoneal cytology, total abdominal hysterectomy, bilateral salpingo-oophorectomy: 78/78 (100), Pelvic radiation: 17/78 (21.8), Pelvic lymphadenectomy: 24/78 (30.7)
Abbreviations: USA, United States of America; Nr, number; UK, United Kingdom; NM, not mentioned. a According to FIGO classification. b Median disease-specific survival: 26.3 months. c The author does not specify the stage of the 32 patients who were treated with radiation therapy.
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Age of patients (in years)
Kizer, 2011, USA [10]
Nr of patients
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Please cite this article in press as: Iavazzo C, et al. Early recurrence of early stage endometrioid endometrial carcinoma: Possible etiologic pathways and management options. Maturitas (2014), http://dx.doi.org/10.1016/j.maturitas.2014.04.009
Table 1 Published studies of early recurrence of early stage endometrioid endometrial carcinoma.
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Fig. 1. Flow diagram of the detailed process of selection of articles for inclusion in the review.
correlated with more aggressive biological characteristics in early recurrence of endometrial cancer [19]. Recently, KRAS amplification and KRAS mRNA expression have both been correlated with endometrial cancer recurrence [20]. It is suggested in the literature that vaginal brachytherapy alone in early stage endometrial cancer can achieve 98.6% locoregional control and 96.8% disease-free survival [21]. However, it should be mentioned that it is not a common practice for stage Ia endometrioid endometrial cancer. Although the majority of isolated vaginal vault recurrences in early endometrial cancer can be salvaged via adjuvant radiotherapy, a multi-institutional study showed that it could be a common finding in patients with early stage endometrial cancer [22]. Endometrial cancer is known to be capable of behaving unpredictably for decades. The GOG study showed that the pelvic lymph nodes are positive in 3% of stage Ia grade 1 and in 5% of stage Ia grade 2 endometrioid endometrial cancers, respectively [23]. Moreover, endometrioid endometrial cancers detected early have a 92% longterm survival rate. The question raised is how we can identify women with early stage cancer but poor disease prognosis. Race, previous HRT use, presence of LVSI, lower uterine segment involvement, immunohistochemical determination of micrometastases, ploidy and genetic tests (either all or some of them) could be used in order to form a prognostic algorithm of possible early recurrence and could lead to a change in postoperative treatment options.
Table 2 Prognostic factors for early recurrence of early stage endometrioid endometrial carcinoma. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
Black race Hormone replacement therapy postoperatively Lymphovascular space involvement Lower uterine segment involvement Lynch syndrome DNA aneuploidy P53 expression rDNA methylation KRAS amplification and KRAS mRNA expression Microsatellite instability (?) Immunohistochemically detected lymph node micrometastasis (?) Longer duration of hysteroscopy (?) Staging underestimation
However, we understand that a question might be raised regarding the cost efficacy of all these “prognostic methods”. The management of endometrioid endometrial stage Ia cancer postoperatively and the early detection of a possible recurrence are based on close follow-up. The role of close follow-up (every 6 months for the first three years and then annually), clinical examination as well as counseling patients on symptoms of recurrence should be emphasized [5]. However, it should be mentioned that obtaining Papanicolaou smears routinely at each follow up has not proven to be beneficial and moreover it increases the cost [5]. Regarding treatment options after recurrence, these include surgical excision of isolated disease or exenteration of local disease, radiation therapy in women who have not been irradiated before, multiagent chemotherapy and, rarely, hormonal therapy. This review presents several limitations. The limited number of included studies as well as the small number of patients included reflects the fact that the treatment of recurrence of early stage endometrioid endometrial carcinoma needs to be more thoroughly investigated. Additionally, the methodological quality of the included studies renders difficult the extraction of any definitive conclusions. More specifically, an issue could be raised as to whether early stage patients who recurred may have had occult stage 3 disease (undiagnosed lymph node metastases), since not enough information could be identified in the included studies. Regarding the applied search strategy, it could be considered as limited due to the exclusion of the abovementioned types of articles. Last but not least, restriction to studies written only in the English language could also limit the range of the literature included. 5. Conclusions The possible mechanisms of early recurrence in patients with endometrioid endometrial cancer have been discussed, while the further management and follow-up of these patients have been presented. Contributors Christos Iavazzo, MD, PhD: study design, data analysis/interpretation, writing of the manuscript. Ioannis D.
Please cite this article in press as: Iavazzo C, et al. Early recurrence of early stage endometrioid endometrial carcinoma: Possible etiologic pathways and management options. Maturitas (2014), http://dx.doi.org/10.1016/j.maturitas.2014.04.009
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Gkegkes, MD: collection of data, data analysis/interpretation, writing of the manuscript. Nikolaos Vrachnis, MD, PhD: data analysis/interpretation, writing of the manuscript. Competing interest The authors declare no conflict of interest. Funding The authors have received no funding for this article. Provenance and peer review Not commissioned, externally peer reviewed. References [1] Tantravahi SK, Werner TL. Locally recurrent endometrial cancer: a case report. J Natl Compr Canc Netw 2012;10(April (4)):442–5. [2] Creasman WT. New gynecology cancer staging. Obstet Gynecol 1990;75(February (2)):287–8. [3] Ayhan A, Tuncer ZS, Tuncer R, Yüce K, Küc¸ükali T. Risk factors for recurrence in clinically early endometrial carcinoma: an analysis of 183 consecutive cases. Eur J Obstet Gynecol Reprod Biol 1994;57(December (3)):167–70. [4] Oaknin A, Barretina MP, Morilla I. Muscle metastasis of low-grade endometrial carcinoma seven years after diagnosis: a case report. Eur J Gynaecol Oncol 2010;31(1):114–6. [5] Salani R, Nagel CI, Drennen E, Bristow RE. Recurrence patterns and surveillance for patients with early stage endometrial cancer. Gynecol Oncol 2011;123(November (2)):205–7. [6] Maxwell GL, Tian C, Risinger JI, Hamilton CA, Barakat RR, Gynecologic Oncology Group Study. Racial disparities in recurrence among patients with early-stage endometrial cancer: is recurrence increased in black patients who receive estrogen replacement therapy? Cancer 2008;113(September (6)):1431–7. [7] Tempfer C, Froese G, Buerkle B, et al. Does duration of hysteroscopy increase the risk of disease recurrence in patients with endometrial cancer? A multi-centre trial. Exp Ther Med 2011;2(September (5)):991–5. [8] Ben-Arie A, Tamir S, Dubnik S, et al. Does hysteroscopy affect prognosis in apparent early-stage endometrial cancer? Int J Gynecol Cancer 2008;18(July–August (4)):813–9. [9] O‘Brien DJ, Flannelly G, Mooney EE, Foley M. Lymphovascular space involvement in early stage well-differentiated endometrial cancer is associated with increased mortality. BJOG 2009;116(June (7)):991–4. [10] Kizer NT, Gao F, Guntupalli S, et al. Lower uterine segment involvement is associated with poor outcomes in early-stage endometrioid endometrial carcinoma. Ann Surg Oncol 2011;18(May (5)):1419–24. [11] McCoy A, Finan MA, Boudreaux FT, et al. The incidence and clinical significance of lymph node micrometastases determined by immunohistochemical staining in stage I – lymph node negative endometrial cancer. Histol Histopathol 2012;27(February (2)):181–5. [12] Song T, Lee JW, Kim HJ, et al. Prognostic significance of DNA ploidy in stage I endometrial cancer. Gynecol Oncol 2011;122(July (1)):79–82. [13] Lim P, Aquino-Parsons CF, Wong F, et al. Low-risk endometrial carcinoma: assessment of a treatment policy based on tumor ploidy and identification of
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Review
Early recurrence of early stage endometrioid endometrial carcinoma: Possible etiologic pathways and management options Christos Iavazzo a , Ioannis D. Gkegkes b,∗ , Nikolaos Vrachnis c a b c
Gynaecological Oncology Department, Christie Hospital, Manchester, United Kingdom 1st Department of Surgery, General Hospital of Attica “KAT”, Athens, Greece 2nd Department of Obstetrics and Gynecology, University of Athens Medical School, Aretaieio Hospital, Athens, Greece
a r t i c l e
i n f o
Article history: Received 9 February 2014 Received in revised form 8 April 2014 Accepted 8 April 2014 Available online xxx Keywords: Early endometrial cancer Recurrence Etiology Management
a b s t r a c t The majority of endometrial cancers is early stage and of the endometrioid histological type, as the symptoms (mainly vaginal bleeding) of the disease lead to an early diagnosis. Close follow-up is nevertheless essential in such cancers staged early on, in which the rate of recurrence is relatively low. We retrieved the studies included in our narrative review after performing a systematic electronic search in the PubMed, Scopus and Cochrane databases. The incidence or recurrence of disease in such patients could be up to 2.6%, with the main sites of recurrence being the vaginal vault or metastases in distant parts of the body. Genetic factors such as p53 overexpression, inactivation of 14-3-3-sigma, KRAS amplification and KRAS mRNA expression, microsatellite instability and Lynch syndrome genes could be associated with such a recurrence. Black race is also correlated, as well as lymphovascular space involvement, lower uterine segment involvement and DNA aneuploidy. Longer hysteroscopy duration was not found to be associated. Close follow-up is suggested for early detection of recurrences, while surgical excision of isolated disease or exenteration of local disease as well as radiotherapy and chemotherapy are the main treatment options. This narrative review investigated the possible mechanisms of early recurrence in patients with endometrioid endometrial cancer as well as the further management of them. © 2014 Published by Elsevier Ireland Ltd.
Contents 1. 2. 3. 4. 5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Competing interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Provenance and peer review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Endometrial cancer is the most common gynecological malignancy, especially in postmenopausal women. Because of the early
∗ Corresponding author at: 141 Oropou Str., Nea Ionia, Athens 14232, Greece. Tel.: +30 6993671843. E-mail address: [email protected] (I.D. Gkegkes).
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signs of vaginal bleeding, up to 75% of endometrial cancer cases are tumors detected at an early stage and confined to the uterus [1]. The management of early stage endometrial cancer consists of total abdominal, laparoscopic or robotic assisted hysterectomy and bilateral salpingo-oophorectomy plus surgical staging. Adjuvant therapy is given postoperatively in cases characterized by poor differentiation, deep myometrial invasion, lymphovascular space involvement or nonendometrioid histological type. Meanwhile,
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the role of chemotherapy is not as yet well clarified for early stage disease. Usually, stage Ia grade 1 or 2 endometrioid endometrial carcinomas have an excellent prognosis and early cases of recurrence are rare. The aim of this review is to clarify the incidence of patients with stage Ia endometrial cancer who may develop early recurrence, as well as to discuss the possible etiologic mechanisms and management of such cases. 2. Methods We retrieved the studies included our narrative review after performing a systematic electronic search in PubMed (08/10/2013) and Scopus (08/10/2013). Both the PubMed and Scopus search strategy included the combination of the key words: early recurrence AND endometrioid endometrial cancer AND early stage. The Cochrane database (08/10/2013) was also searched in order to look for any reviews on this topic. The references of included articles were also hand-searched for additional studies. Studies written only in the English language were included. The reporting data on the incidence, prognostic factors, pathogenetic pathways and management of patients with early recurrence of early stage endometrial cancer after surgical treatment were included in our review. Our analysis included only patients with endometrioid endometrial carcinoma at stage I, according to the FIGO 1988 classification [2]. Regarding the definition of early recurrence, due to the great variability in the definition, we adopted the one used by the authors of the selected studies. Conference papers, abstracts, editorials, review articles, animal studies as well as commentaries were not eligible for this review. 3. Results In total, 98 and 103 studies in the PubMed and Scopus search were retrieved, respectively, among which 9 studies met the inclusion criteria for our review (10, 224-31). No further studies were retrieved from the Cochrane database. No additional studies were found through hand-searching of references. The applied search strategy is depicted in Fig. 1 (flow diagram). The principle characteristics of the studies included in our review (demographics, publication type, stage of neoplasia, type of treatment, time lapse until recurrence, follow-up, outcome) are presented in Table 1. The present study included seven retrospective studies, one prospective study and one case report. The total number of patients included was 1955. The median age of the included patients ranged from 45 to 65 years old. The number of patients at stage Ia, Ib and Ic was 1040, 476 and 159, respectively. The initial treatment of endometrioid endometrial carcinoma comprised total abdominal hysterectomy and bilateral salpingo-oophorectomy in 1403 patients and pelvic lymphadenectomy in 63 patients, while adjuvant therapy (chemotherapy/pelvic radiation) was administered in 388 patients. The median period to recurrence ranged from 7 to 53.6 months, while the follow-up period ranged from 7 to 156 months. The survival rate after treatment for the recurrences was mentioned in only three studies, in which it had been extended by 33 to 100 percent. 4. Discussion A recent study showed that the overall recurrence rate in patients with endometrial cancer is 14.2%, with age, grade, mitotic activity, myometrial invasion, lymphovascular space invasion, microscopic vaginal metastases, adnexal involvement and nodal disease being the main prognostic factors [3]. Women with stage Ia
endometrial cancer have a low risk of recurrence (2.6%). The most common site of recurrence in patients with early stage endometrial cancer is the vaginal vault, but distant metastases (e.g. lung, muscle) are also described in the literature [4]. They are usually detected as isolated clinical findings and include vaginal vault recurrence, vaginal bleeding, abdominal pain or shortness of breath [5]. The possible pathogenetic pathways of early recurrence are still under investigation (Table 2). A population-based study suggested that recurrence-free survival may be shorter among black women with stage I endometrial cancer, especially in those women who used hormone replacement treatment postoperatively [6]. Although a query was raised regarding the role of preoperative low-pressure diagnostic hysteroscopy duration in early recurrences of stage I endometrial cancer, it was recently demonstrated that longer duration of hysteroscopy does not increase the risk of intraperitoneal transport of malignant cells or positive peritoneal cytology and so it is not an adverse prognostic factor for recurrence-free survival [7,8]. Lymphovascular space involvement in early stage well-differentiated endometrioid endometrial cancer could be a highly significant predisposing factor of recurrence and is associated with high mortality rates in such patients [9]. Lower uterine segment involvement could also be associated with an increased risk of recurrence [10]. Moreover, other authors recently sought to clarify the incidence and clinical significance of lymph node micrometastases determined by immunohistochemical staining in stage I lymph node-negative endometrial cancer, but no correlation was identified [11]. On the other hand, in a retrospective study of 217 patients, DNA aneuploidy was shown to be an independent prognostic factor in patients with stage Ia endometrial cancer and could distinguish high risk from low risk patients, as the recurrence rate was found to be 2.1% for diploid tumors and 12.5% for aneuploid tumors [12]. In another study, it was shown that patients with diploid, low-risk stage I endometrial cancers have a better prognosis, while patients with aneuploid tumors treated with adjuvant radiotherapy have the same risk of relapse as untreated patients with diploid tumors [13]. Furthermore, p53 expression in diploid tumors is associated with increased risk of recurrence, whereas Bcl-2 and ER could not be used as prognostic indicators [13]. Another possible explanation for early recurrence could be staging underestimation. More specifically, it has previously been shown that the preoperative prediction of grade was correct in 96% of the patients, while gross examination of myometrial invasion correctly differentiated between stage Ia, Ib and Ic disease in 89% of them. Moreover, the same study disclosed that the combination of preoperative tumor grade and gross examination of myometrial invasion could lead to wrong clinical decisions and management in 11% of the patients [14]. Finally, the role of lymphadenectomy could be crucial. Our results showed that 63 (of 1955) patients underwent pelvic lymphadenectomy. Although the standard treatment today for endometrial cancer patients is pelvic lymphadenectomy, the included studies are older and some of them do not provide accurate information about the possible role of pelvic lymphadenectomy. For example, in the Robbins paper [24], since the patients included in the study may or may not have had lymph node dissection, it is indeterminate how many actually did undergo lymphadenectomy (pelvic or paraaortic). Genetic factors are associated with the pathogenesis. Although the role of microsatellite instability as an independent prognostic factor is questioned [6,15], rDNA methylation is correlated with early recurrence [16]. Mutant p53 overexpression, which is found three times more often in black women with stage I endometrial cancer, might explain this finding [17]. Possible correlation with Lynch syndrome could be another etiologic factor characterized by the presence of MSI or loss of MLH1 with lack of MLH1 methylation or loss of either MSH2 and/or MSH6 protein expression [18]. An inactivation of the 14-3-3-sigma gene has been shown to be
Please cite this article in press as: Iavazzo C, et al. Early recurrence of early stage endometrioid endometrial carcinoma: Possible etiologic pathways and management options. Maturitas (2014), http://dx.doi.org/10.1016/j.maturitas.2014.04.009
Publication type
Simpkins, 2013, USA [24]
Retrospective study
Lajer, 2012, Denmark [26]
Stage of neoplasiaa
Type of treatment (%)
Period to recurrence (in months) (%)
Follow-up (in months)
Survival (%)
131
Median (range): 67 (60–75)
Ib: 5/30 (16.6), Ic: 17/30 (56.6)
In 22/131 (16.8) Median (range): 16 (4–114)
Median (range): 51 (36–120)
NM
Prospective study
571
Median (range): 62.9 (28.3–87)
Ia: 572/572 (100)
In 23/571 (4) Median (range): 25 (1–152)
Median: 156
14/23 (60.8)
Ortac¸, 2012, Turkey [27]
Case report
1
45
Ia
7
7
1/1 (100)
Robbins, 2012, USA [25]
Retrospective study
57
Median (range): 65 (33–90)
In 43/57 (75.4) Median (range): 20.2 (8–174)
Median (range): 54.8 (8.4–184)
NMb
Esselen, 2011, USA [28]
Retrospective study Retrospective study
72
NM
Ia: 5/57 (8.7), Ib: 27/57 (47.3), Ic: 11/57 (19.3) I: 34/72 (47.2)
Total abdominal hysterectomy, bilateral salpingo-oophorectomy: 131/131 (100), adjuvant radiation: 86/131 (66) Total abdominal hysterectomy, bilateral salpingo-oophorectomy: 572/572 (100) Peritoneal washing, total abdominal hysterectomy, bilateral salpingo-oophorectomy, bilateral pelvic lymphadenectomy, partial omentectomy Abdominal hysterectomy: 57/57 (100), adjuvant radiation: 32/57 (56.1)c NM
NM
NM
NM
NM
In 36/481 (7.5) Median (range): 53.6 (0.2–165.3)
Median (range): 53.6 (0.2–165.3)
NM
Abdominal hysterectomy, bilateral salpingo-oophorectomy: 51/51 (100), Pelvic lymphadenectomy: 38/51 (74.5) Adjuvant therapy: 35/51 (68.6) Total abdominal hysterectomy: 513/513 (100), Adjuvant radiotherapy: 218/513 (42.5)
In 51/51 (100) Median (range): 12 (3–119)
NM
NM
In 67/513 (13.1) Median (range): locoregional: 14 (3–57), Distant: 18 (2–58) In 6/78 (7.7) Median (range): 19.5 (9–29)
Median (range): 28 (2–144)
NM
Median (range): 38 (9–98)
2/6 (33.3)
481
Median (range): 62 (22–92)
Ia: 112/481 (23.3), Ib: 222/481 (46.1), Ic: 95/481 (19.7) Ib: 6/51 (11.7), Ic: 11/51 (21.6)
Otsuka, 2010, Japan [29]
Retrospective study
51
Median (range): 64 (46–81)
Nofech-Mozes, 2008, Canada [30]
Retrospective study
513
Median (range): 63 (28–94)
Ia: 330/513 (64.3), Ib: 183/513 (35.7)
Papanikolaou, 2006, Greece [31]
Retrospective study
78
Median (range): 65 (35–80)
Ia: 20/78 (25.5), Ib: 33/78 (42.5), Ic: 25/78 (32)
Peritoneal cytology, total abdominal hysterectomy, bilateral salpingo-oophorectomy: 78/78 (100), Pelvic radiation: 17/78 (21.8), Pelvic lymphadenectomy: 24/78 (30.7)
Abbreviations: USA, United States of America; Nr, number; UK, United Kingdom; NM, not mentioned. a According to FIGO classification. b Median disease-specific survival: 26.3 months. c The author does not specify the stage of the 32 patients who were treated with radiation therapy.
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Age of patients (in years)
Kizer, 2011, USA [10]
Nr of patients
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Please cite this article in press as: Iavazzo C, et al. Early recurrence of early stage endometrioid endometrial carcinoma: Possible etiologic pathways and management options. Maturitas (2014), http://dx.doi.org/10.1016/j.maturitas.2014.04.009
Table 1 Published studies of early recurrence of early stage endometrioid endometrial carcinoma.
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Fig. 1. Flow diagram of the detailed process of selection of articles for inclusion in the review.
correlated with more aggressive biological characteristics in early recurrence of endometrial cancer [19]. Recently, KRAS amplification and KRAS mRNA expression have both been correlated with endometrial cancer recurrence [20]. It is suggested in the literature that vaginal brachytherapy alone in early stage endometrial cancer can achieve 98.6% locoregional control and 96.8% disease-free survival [21]. However, it should be mentioned that it is not a common practice for stage Ia endometrioid endometrial cancer. Although the majority of isolated vaginal vault recurrences in early endometrial cancer can be salvaged via adjuvant radiotherapy, a multi-institutional study showed that it could be a common finding in patients with early stage endometrial cancer [22]. Endometrial cancer is known to be capable of behaving unpredictably for decades. The GOG study showed that the pelvic lymph nodes are positive in 3% of stage Ia grade 1 and in 5% of stage Ia grade 2 endometrioid endometrial cancers, respectively [23]. Moreover, endometrioid endometrial cancers detected early have a 92% longterm survival rate. The question raised is how we can identify women with early stage cancer but poor disease prognosis. Race, previous HRT use, presence of LVSI, lower uterine segment involvement, immunohistochemical determination of micrometastases, ploidy and genetic tests (either all or some of them) could be used in order to form a prognostic algorithm of possible early recurrence and could lead to a change in postoperative treatment options.
Table 2 Prognostic factors for early recurrence of early stage endometrioid endometrial carcinoma. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
Black race Hormone replacement therapy postoperatively Lymphovascular space involvement Lower uterine segment involvement Lynch syndrome DNA aneuploidy P53 expression rDNA methylation KRAS amplification and KRAS mRNA expression Microsatellite instability (?) Immunohistochemically detected lymph node micrometastasis (?) Longer duration of hysteroscopy (?) Staging underestimation
However, we understand that a question might be raised regarding the cost efficacy of all these “prognostic methods”. The management of endometrioid endometrial stage Ia cancer postoperatively and the early detection of a possible recurrence are based on close follow-up. The role of close follow-up (every 6 months for the first three years and then annually), clinical examination as well as counseling patients on symptoms of recurrence should be emphasized [5]. However, it should be mentioned that obtaining Papanicolaou smears routinely at each follow up has not proven to be beneficial and moreover it increases the cost [5]. Regarding treatment options after recurrence, these include surgical excision of isolated disease or exenteration of local disease, radiation therapy in women who have not been irradiated before, multiagent chemotherapy and, rarely, hormonal therapy. This review presents several limitations. The limited number of included studies as well as the small number of patients included reflects the fact that the treatment of recurrence of early stage endometrioid endometrial carcinoma needs to be more thoroughly investigated. Additionally, the methodological quality of the included studies renders difficult the extraction of any definitive conclusions. More specifically, an issue could be raised as to whether early stage patients who recurred may have had occult stage 3 disease (undiagnosed lymph node metastases), since not enough information could be identified in the included studies. Regarding the applied search strategy, it could be considered as limited due to the exclusion of the abovementioned types of articles. Last but not least, restriction to studies written only in the English language could also limit the range of the literature included. 5. Conclusions The possible mechanisms of early recurrence in patients with endometrioid endometrial cancer have been discussed, while the further management and follow-up of these patients have been presented. Contributors Christos Iavazzo, MD, PhD: study design, data analysis/interpretation, writing of the manuscript. Ioannis D.
Please cite this article in press as: Iavazzo C, et al. Early recurrence of early stage endometrioid endometrial carcinoma: Possible etiologic pathways and management options. Maturitas (2014), http://dx.doi.org/10.1016/j.maturitas.2014.04.009
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Gkegkes, MD: collection of data, data analysis/interpretation, writing of the manuscript. Nikolaos Vrachnis, MD, PhD: data analysis/interpretation, writing of the manuscript. Competing interest The authors declare no conflict of interest. Funding The authors have received no funding for this article. Provenance and peer review Not commissioned, externally peer reviewed. References [1] Tantravahi SK, Werner TL. Locally recurrent endometrial cancer: a case report. J Natl Compr Canc Netw 2012;10(April (4)):442–5. [2] Creasman WT. New gynecology cancer staging. Obstet Gynecol 1990;75(February (2)):287–8. [3] Ayhan A, Tuncer ZS, Tuncer R, Yüce K, Küc¸ükali T. Risk factors for recurrence in clinically early endometrial carcinoma: an analysis of 183 consecutive cases. Eur J Obstet Gynecol Reprod Biol 1994;57(December (3)):167–70. [4] Oaknin A, Barretina MP, Morilla I. Muscle metastasis of low-grade endometrial carcinoma seven years after diagnosis: a case report. Eur J Gynaecol Oncol 2010;31(1):114–6. [5] Salani R, Nagel CI, Drennen E, Bristow RE. Recurrence patterns and surveillance for patients with early stage endometrial cancer. Gynecol Oncol 2011;123(November (2)):205–7. [6] Maxwell GL, Tian C, Risinger JI, Hamilton CA, Barakat RR, Gynecologic Oncology Group Study. Racial disparities in recurrence among patients with early-stage endometrial cancer: is recurrence increased in black patients who receive estrogen replacement therapy? Cancer 2008;113(September (6)):1431–7. [7] Tempfer C, Froese G, Buerkle B, et al. Does duration of hysteroscopy increase the risk of disease recurrence in patients with endometrial cancer? A multi-centre trial. Exp Ther Med 2011;2(September (5)):991–5. [8] Ben-Arie A, Tamir S, Dubnik S, et al. Does hysteroscopy affect prognosis in apparent early-stage endometrial cancer? Int J Gynecol Cancer 2008;18(July–August (4)):813–9. [9] O‘Brien DJ, Flannelly G, Mooney EE, Foley M. Lymphovascular space involvement in early stage well-differentiated endometrial cancer is associated with increased mortality. BJOG 2009;116(June (7)):991–4. [10] Kizer NT, Gao F, Guntupalli S, et al. Lower uterine segment involvement is associated with poor outcomes in early-stage endometrioid endometrial carcinoma. Ann Surg Oncol 2011;18(May (5)):1419–24. [11] McCoy A, Finan MA, Boudreaux FT, et al. The incidence and clinical significance of lymph node micrometastases determined by immunohistochemical staining in stage I – lymph node negative endometrial cancer. Histol Histopathol 2012;27(February (2)):181–5. [12] Song T, Lee JW, Kim HJ, et al. Prognostic significance of DNA ploidy in stage I endometrial cancer. Gynecol Oncol 2011;122(July (1)):79–82. [13] Lim P, Aquino-Parsons CF, Wong F, et al. Low-risk endometrial carcinoma: assessment of a treatment policy based on tumor ploidy and identification of
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Please cite this article in press as: Iavazzo C, et al. Early recurrence of early stage endometrioid endometrial carcinoma: Possible etiologic pathways and management options. Maturitas (2014), http://dx.doi.org/10.1016/j.maturitas.2014.04.009