YGYNO-975436; No. of pages: 5; 4C: Gynecologic Oncology xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Characteristics of clear cell ovarian cancer arising from endometriosis: A two center cohort study Giovanna Scarfone a, Alice Bergamini b, Stefania Noli a, Antonella Villa a, Sonia Cipriani c, Gianluca Taccagni d, Paola Vigano' e, Massimo Candiani b, Fabio Parazzini c, Giorgia Mangili e,⁎ a
Department of Obstetrics, Gynecology and Neonatology, IRCCS Fondazione Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy Università Vita-Salute, San Raffale Scientific Institute, Milano, Italy Mario Negri Pharmacological Research Institute, Milan, Italy d Department of Surgical Pathology, San Raffaele Scientific Institute, Milano, Italy e Obstetrics and Gynecology Unit, San Raffaele Scientific Institute, Milano, Italy b c
H I G H L I G H T S • Clinical and histological features of the largest series of clear cell carcinomas arising in endometriosis are analyzed. • No difference in stage, grade, survival and endometrial cancer incidence was found between tumors arising or not in endometriosis. • Younger age, unilateral ovarian involvement and absence of ascites were more frequently found in cases arising in endometriosis.
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Article history: Received 19 January 2014 Accepted 10 March 2014 Available online xxxx Keywords: Endometriosis Clear cell ovarian cancer Endometriosis associated ovarian cancer
a b s t r a c t Objective. Endometrioid and clear cell ovarian tumors have been referred to as “endometriosis associated ovarian cancers”. However, very few studies have compared clinical and prognostic features of endometriosisassociated cancers or cancers not associated with endometriosis according to specific histotypes. We have investigated clinical and histological features of the largest published series of clear cell ovarian cancers arising in endometriosis using a retrospective database. Methods. Seventy three patients with a primary diagnosis of either pure clear cell ovarian cancer and mixed endometrioid-clear cell ovarian cancer have been divided into two groups according to the detection of cancer strictly arising from ovarian endometriosis or not (n = 27 and n = 46, respectively). Clinical and pathological data have been compared. Results. Patients with clear cell carcinomas arising from endometriosis tend to be significantly younger (51.4 ± 10.0 and 58.4 ± 11.2 years, p = 0.02). FIGO stage, laterality, prevalence of pure versus mixed histology, and presence of synchronous endometrial carcinoma were not significantly different between the two groups. Unilateral ovarian involvement was more frequent in cases arising in endometriosis (85% vs 63%, p = 0.04). Ascites was not found in any of the endometriosis-associated cancer cases vs 19.5% in patients without endometriosis. The presence of endometriosis did not affect 5-year overall survival rates. Conclusions. Endometriosis per se does not appear to be associated with a lower stage tumor or to predict prognosis in ovarian clear cell cancers. Unilateral involvement and reduced presence of ascites may be linked to the cystic nature of endometriosis which frequently presents as monolateral and in which associated tumors are more likely to be longer confined to the ovary before spreading. © 2014 Elsevier Inc. All rights reserved.
Introduction Endometriosis is a risk factor for epithelial ovarian cancer [1,2]. Based on the results of a large international collaborative study, self-
⁎ Corresponding author at: Obstetrics and Gynecology Unit, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milano, Italy. E-mail address: [email protected] (G. Mangili).
reported endometriosis was associated with an overall risk increase of nearly 50% [Odds Ratio, 1.46; 95% confidence intervals (CIs), 1.31– 1.63] [3]. This issue is of particular clinical relevance given the prevalence of endometriosis, estimated to be around 5%, with a peak between 25 and 35 years of age [4]. It is also well known that tumors associated with endometriosis are confined to specific subcategories of disease, endometrioid and clear cell ovarian cancers, and the risk of detecting these histotypes is estimated to be about 4-fold higher in women with the disease [5].
http://dx.doi.org/10.1016/j.ygyno.2014.03.017 0090-8258/© 2014 Elsevier Inc. All rights reserved.
Please cite this article as: Scarfone G, et al, Characteristics of clear cell ovarian cancer arising from endometriosis: A two center cohort study, Gynecol Oncol (2014), http://dx.doi.org/10.1016/j.ygyno.2014.03.017
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G. Scarfone et al. / Gynecologic Oncology xxx (2014) xxx–xxx
Controversy remains regarding the possibility that endometriosisassociated cancers might represent a distinct entity from the correspondent typical histotype. Some studies have indeed suggested that patients with endometriosis tend to be younger, to be diagnosed in earlier stages and with lower grade lesions and to have an overall better survival rate whereas other studies fail to confirm these findings [6–13]. Importantly, very few of these studies have evaluated clinical and prognostic differences between endometriosis-associated cancers or cancers not associated with endometriosis according to the specific histotype [8,9,13,14]. This might have prevented the identification of characteristics potentially linked to a specific subcategory of disease. In this context, in a recent study [8], we have analyzed a cohort of patients diagnosed with endometrioid ovarian cancer and confirmed that women with endometriosis-associated cancer were significantly younger at the diagnosis, had a lower disease stage and a less prevalent high grade tumor. A difference in survival rate could not be confirmed between patients with and without endometriosis. Importantly, a synchronous endometrial precancerous or cancerous condition has been detected at a significantly higher rate in endometriosis-associated endometrioid cancers, possibly leading to various and novel interpretations for the mechanisms of this cancer development. Along this line, in this study, we have evaluated the clinical and prognostic features of endometriosis-associated ovarian cancers of clear cell histotype and compared them with those of clear cell tumors without endometriosis. Results of the present study considering the most numerous series of cancers of clear cell and mixed endometrioid-clear cell histotype arising in endometriosis and of our previous study on ovarian endometrioid tumors [8] tend to support the idea that endometrioid and clear cell cancers associated with endometriosis should be no more considered a single entity with similar risk and prognostic factors and biologic mechanisms of development. Materials and methods This is a retrospective study of 73 cases of clear cell ovarian carcinoma consecutively observed at two centers, the Department of Obstetrics and Gynecology of the Fondazione Ospedale Maggiore Policlinico and the Obstetrics and Gynecology Unit of the Scientific Institute San Raffaele in Milan, Italy between 1990 and 2012. Institutional Review Board approval has been obtained for this retrospective study. All patients with a primary diagnosis of either pure clear cell ovarian cancer or mixed endometrioid-clear cell ovarian cancer have been included in the study. Patients whose diagnosis was made elsewhere were excluded. Patients older than 75 were not included in survival analysis. Some data from 33 patients have been already included in a previous paper [7]. All patients underwent surgery, received chemotherapy and were followed up at our institutions. Surgical staging was performed according to FIGO guidelines for ovarian cancer, including total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy and removal of all macroscopic diseases [15]. Radical upper abdominal techniques were applied in selected cases to achieve optimal cytoreduction. All pathological analyses were performed by the same two gynecologic pathologists, who, in both institutions, are completely dedicated to gynecological cases. Patients were divided into two groups according to the detection of cancer arising from ovarian endometriosis or not, on the basis of pathological reports. The definition of ovarian cancer arising from endometriosis was given according to Sampson's [16] and Scott's criteria [17], that included: 1) the coexistence of carcinoma and endometriosis in the same ovary; 2) presence of tissue similar to endometrial stroma surrounding characteristic epithelial glands; 3) exclusion of a metastatic tumor to the ovary; and 4) presence of benign endometriosis histologically contiguous to the malignant tissue. Patients with clear cell carcinoma associated with but not arising in endometriosis were excluded.
Data including age at diagnosis, clinical presentation, disease status, last follow-up and all pathological information, such as histology, stage, laterality, and presence of concurrent endometrial carcinoma were collected from surgical and pathology reports. Stages higher than IIA were classified as advanced, while lower stages were considered early. All the abovementioned variables were described for each of the two groups and statistically compared. The Pearson Chi-square test or Fisher Exact test, as required, was used to assess the significance of differences in clinical and pathological characteristics between the two groups. Survival comparisons were obtained using the long-rank test in an unadjusted Kaplan Meier model, survival rates being calculated from the date of histological diagnosis. Finally, to account for the effect of potential confounding factors simultaneously, we used the Cox regression model (after checking the proportional hazards assumption) to obtain the hazards ratio (HR) and their corresponding 95% CIs. In all analysis, a p value of b 0.05 was considered statistically significant. Follow-up was updated in May 2013, being median follow-up of 68 months (95% CI, 55–103).
Results Seventy-three patients met the inclusion criteria. Of these, n = 27 (37%) cases have been affected by tumors arising in endometriosis (Fig. 1), while n = 46 patients (67%) had no concomitant endometriosis. Patients and tumor characteristics of the two groups are summarized in Table 1. In both groups, the most common diagnosis was incidental, followed by the detection of an abdominal mass. Symptoms did not differ statistically between the two groups except for presence of ascites that was only detected in patients without endometriosis (19.5% versus none of the patients in the endometriosis group). Patients with endometriosis-associated clear cell carcinomas or of mixed histology tend to be significantly younger than cases without endometriosis with mean age ± SD being 51.4 ± 10.0 and 58.4 ± 11.2 for tumors arising in endometriosis and not, respectively (p = 0.02). Among endometriosis-free patients, n = 23 (50%) were diagnosed in early stages while 50% in advanced stages. In the other group, n = 18 (66.7%) were in early stages, and n = 9 (33.3%) were in advanced. FIGO stages were not significantly different between the two groups (p = 0.16). The prevalence of patients with pure clear cell histology and mixed histology was respectively 76.1% and 23.9% in the endometriosis-free group and 70.4% and 29.6% in the endometriosis group. No statistically significant difference was detected (p = 0.59).
Fig. 1. A typical ovarian clear cell carcinoma of papillary type, grown into the lumen of an endometriotic cyst lined by columnar endometrioid type cells. (Hematoxylin and eosin × 125.)
Please cite this article as: Scarfone G, et al, Characteristics of clear cell ovarian cancer arising from endometriosis: A two center cohort study, Gynecol Oncol (2014), http://dx.doi.org/10.1016/j.ygyno.2014.03.017
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Table 1 Clinical and pathological characteristics of clear cell carcinomas arising or not from endometriosis. Clinical features
Age Mean ± SD (range) Stage I–IIA IIB–IV Histology Clear cell Mixed Ovarian involvement Monolateral Bilateral Laterality Right Left Symptoms Abnormal uterine bleeding Constipation Abdominal/pelvic mass History of adnexal cyst Ascites Incidental diagnosis Paraneoplastic syndrome Abdominal pain Synchronous endometrial cancer Year of diagnosis 1990–2000 2001–2012 a
Endometriosis
p-Value
No (n = 46)
Arising (n = 27)
58.4 ± 11.2 (41–89)
51.4 ± 10.0 (30–71)
23 (50.0%) 23 (50.0%)
18 (66.7%) 9 (33.3%)
35 (76.1%) 11 (23.9%)
19 (70.4%) 8 (29.6%)
29 (63.0%) 17 (37.0%)
23 (85.0%) 4 (15.0%)
15 (52.0%) 14 (48.0%)
10 (43.0%) 13 (57.0%)
4 (4.0%) 3 (6.5%) 5 (10.8%) 2 (4.3%) 9 (19.5%) 19 (41.3%) 4 (4.0%) 15 (32.6%) 2 (4.0%)
5 (2.2%) 0 7 (30.4%) 3 (13.0%) 0 7 (30.4%) 1 (4.3%) 4 (17.3%) 0
16 (34.8%) 30 (65.2%)
5 (18.5%) 22 (81.5%)
0.02
0.17
0.59
0.04
0.55
0.28a 0.29a 0.11a 0.35a 0.02a 0.18 0.64a 0.09 0.53a 0.14
Fisher exact test.
Bilateral ovarian involvement was detected in 17 patients (37%) in the endometriosis-free group, compared to 4 (15%) patients with clear cell tumor or of mixed histology arising in endometriosis (p = 0.04). In monolateral ovarian involvement, laterality did not differ between the two groups (p = 0.55). The presence of a synchronous endometrial carcinoma was found only in 2 patients with clear cell ovarian cancer without concomitant endometriosis. The presence of endometriosis did not affect 5-year survival rates even after taking into account potential confounding factors (Fig. 2, Table 2). Mean 5-year overall survival was 60.1 months (95% CI 41–75) in endometriosis-free group versus 73.0 months (95% CI 49–87) in the endometriosis group (log rank = 0.43). Overall survival has been also analyzed stratifying for selected characteristics (Table 2); none of them was significantly associated with an increased overall survival. Discussion The association between ovarian cancer and endometriosis has been largely documented [1,18], even if clinico-pathological mechanisms are still for many aspects unclear. In particular, several studies have focused on the link between endometriosis and clear cell or endometrioid histologies, suggesting that about one third of these cancers arise from endometriosis [5]. The two histologies are often considered as a single entity, as “endometriosis-associated ovarian tumors”. However, there is increasing evidence suggesting that endometrioid and clear cell ovarian carcinomas may behave differently with respect to their association with endometriosis and that might even arise from distinct types of endometriosis with different cells of origin [19]. In a very interesting paper, Kajihara and coworkers hypothesized that clear cell ovarian cancers associated with endometriosis may arise from preexisting endometriosis derived from regurgitated endometrial cells whereas ovarian Mullerian metaplasia may initiate neoplastic modifications
Endometriosis No Yes
2/46 1/27
N. events/N. of patients at risk 3/36 2/30 1/25 5/23 0/22 3/21 1/18 1/16
Fig. 2. Kaplan–Meier survival functions in clear cell carcinoma cases arising or not in endometriosis.
in endometriosis-associated endometriod cancers. Support to this hypothesis derived from the analysis of hepatocyte nuclear factor (HNF)1β, a nuclear factor associated with endometriosis whose expression has been found in epithelial cells of ectopic, eutopic endometrium and clear cell ovarian carcinomas, but not in ovarian cortical inclusion cysts nor in endometrioid ovarian cancer. The potential diverse origins of different histotypes of endometriosisassociated cancers imply that they should be considered different clinical entities. As a matter of fact, very few studies have specifically studied clinical and prognostic factors of tumors associated with endometriosis according to the specific histotype [8,9,13,14]. Two studies, one from our group [8], have focused on the endometrioid histotype, suggesting that endometriosis-associated endometrioid ovarian cancer has a different clinical behavior with respect to the non-endometriosis-associated tumor of similar histology. Both the studies agree that the first tends to arise at younger ages, with lower stages, with a less prevalent high grade and with a significantly higher incidence of synchronous endometrial tumors [8,9]. Along this line, the present study aimed at evaluating the clinical and prognostic features of clear cell histotype arising or not in endometriosis. For this analysis, the larger series of clear cell or of mixed histotype tumors arising in endometriosis ever published for this rare tumor has been enrolled. No difference in tumor stage, grade, survival rate and incidence of synchronous endometrial cancers was found between clear cell cancers arising or not in endometriosis. As a consequence, the results of this study also support the idea that clear cell or endometrioid tumors associated with endometriosis should be considered different entities as clinical features vary greatly between the two. The only characteristic in common is represented by the occurrence at younger ages compared to the correspondent histologic type not associated with endometriosis. However, in this context, a potential role of a diagnostic bias could also explain, at least partially, the increased diagnosis at initial stages for both histotypes of tumors. Indeed, patients with concomitant endometriosis could be diagnosed earlier considering that this disease is frequently associated with specific symptoms and endometriosis women tend to be better followed up whereas ovarian cancers are frequently asymptomatic until advanced stages are reached [5]. The prevalence of ascites and bilateral disease is the only other clinical discrepancies found between clear cell carcinoma arising and not in
Please cite this article as: Scarfone G, et al, Characteristics of clear cell ovarian cancer arising from endometriosis: A two center cohort study, Gynecol Oncol (2014), http://dx.doi.org/10.1016/j.ygyno.2014.03.017
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Table 2 Five-year survival in cases with clear cell carcinoma arising or not from endometriosis. Variable
Cox regressiona
Endometriosis No (13 events) 5-year survival, % (95% CI)
Arising (6 events) 5-year survival, % (95% CI)
HR (95% CI)
p-Value
Age ≤54 N54
84.0 (49–96) 51.2 (28–70)
80.7 (51–93) 57.1 (17–84)
1.07 (0.2–6.5) 0.83 (0.2–3.0)
0.94 0.78
Stage I–IIa IIb–IV
94.7 (68–99) 21.1 (5–44)
92.3 (57–99) 44.4 (14–72)
1.38 (0.1–22.1) 0.68 (0.2–1.9)
0.82 0.46
Histology Clear cells Mixed
55.6 (34–73) 75.8 (30–94)
81.3 (52–94) 52.5 (12–82)
0.39 (0.1–1.4) 2.83 (0.5–17.4)
0.14 0.26
Year of diagnosis 1990–2000 2001–2012 Overall
71.4 (41–88) 53.1 (28–73) 60.1 (41–75)
75.0 (13–96) 72.6 (46–88) 73.0 (49–87)
NE 0.46 (0.2–1.4) 0.68 (0.3–1.8)
0.17 0.43
NE: non estimable due to low number of events. a Adjusted for stage, modeled in each strata of interesting variables, comparing endometriosis arising versus no endometriosis.
endometriosis being lower in the forms associated with the benign disease. An explanation for this may be linked to the different origin of the tumor which may derive from an endometriotic cyst or from an adenofibroma [20]. Endometriosis presents more commonly as a monolateral ovarian cyst. Moreover, a more favorable outcome was observed in cystic clear cell carcinomas. Tumors growing intracystically are more likely to be confined to the ovary for longer periods of time before spreading, thereby allowing them to be diagnosed at lower stage. This might also explain the increased frequency of ascites in tumors not associated with endometriosis. Thus, unilaterality and reduced presence of ascites are most likely a consequence of an endometriotic and, therefore, cystic origin. These features were previously not found to be associated with endometriosis-associated endometrioid ovarian cancer [8]. To the best of our knowledge, there are only two other studies which focused on prognostic implications of endometriosis in the context of clear cell carcinomas and this is not surprising given the rarity of this tumor. In the study by Orezzoli et al. [13], eighty-four patients with clear cell carcinoma were identified with a 49% rate of coexisting endometriosis. However, only 15 of these tumors were found to arise in endometriosis while the others were not in contiguity with the tumor. In line with our results, patients with clear cell cancer arising in endometriosis tended to be younger, to have a pelvic mass at the diagnosis and no ascites. Contrary to our observations, patients with a tumor arising from endometriosis significantly presented at early stage and their median overall survival was remarkably greater than that of patients with clear cell carcinoma without endometriosis although the limited number of patients did not allow for a statistical comparison of this factor. Discrepancies between the two studies may be due to their small sample size and a type II error cannot be excluded. Moreover, the study by Orezzoli et al. encompassed a period of about 30 years during which adjuvant treatments varied greatly among the patients with or without endometriosis. Sixty percent of the patients in whom the tumor arose from endometriosis received platinum-based regimens in combination with taxanes compared to 39% of endometriosis-free patients only. In this latter group, 11% of patients did not receive platinumbased regimens. Conversely, the current study, even though covering a 22 year long period, only consider patients treated after platinum introduction in chemotherapeutic regimens. Thus, all patients have been more homogenously treated with platinum-based regimens. The second study by Cuff et al. is poorly comparable with ours as their definition of endometriosis-associated cancer was not strictly based on Sampson's [16] and Scott's criteria [17]. In any case, endometriosis per se did not appear to predict prognosis in their series of 53 cases of clear cell cancers associated with the disease [14].
In conclusion, based on the results from the present study and from studies focusing on ovarian endometrioid cancers [8,9], it is tempting to speculate that clear cell and endometrioid carcinomas associated with endometriosis should be considered separate diseases with different clinical behavior and prognostic factors. The more recent molecular genetic analyses are not able to clarify whether the two subtypes of tumors derive from distinct types of endometriosis but they certainly support important molecular differences between the two. A high frequency of ARID1A mutations has been detected mostly in endometriosis-associated clear cell carcinomas (46–57%) and less in endometriosis-associated endometrioid tumor (30%). As a matter of fact, loss of protein expression of the ARID1A tumor suppressor gene has been so far demonstrated in endometriosis adjacent to clear cell tumor samples [21]. Conversely, major genetic alterations involved in endometriosis-associated endometrioid ovarian cancer are represented by PTEN, KRAS and β-catenin gene mutations. In our previous paper, we had indeed hypothesized a molecular parallelism between endometriosis-associated ovarian endometrioid cancer and type I endometrial carcinoma that is typically characterized by mutations of the PTEN, K-RAS, PIK3CA and β-catenin genes [8]. Finally, as clear cell carcinomas exhibit very low estrogen receptor expression while endometrioid cancer is predominantly positive for estrogen receptor, the interactions between the iron-mediated oxidative stress due to the repeated hemorrhages in endometriosis [18,22,23] and the down-regulation of estrogen receptor expression have been suggested to be involved in the development of clear cell carcinomas. Future studies, particularly molecular investigations, should be undertaken to definitively clarify this aspect. This is even more important considering that studies on endometriosis-associated ovarian cancer are always faced with a critical issue since the tumor, especially in advanced stages, might have obliterated the tissue of origin hiding any histological evidence of endometriosis. Thus, the better clarification of the genetic background of these two entities, which is a helpful clue to distinguish one from the other, remains a critical matter of investigation. Conflict of interest statement The authors declare no conflict of interest.
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Please cite this article as: Scarfone G, et al, Characteristics of clear cell ovarian cancer arising from endometriosis: A two center cohort study, Gynecol Oncol (2014), http://dx.doi.org/10.1016/j.ygyno.2014.03.017
Contents lists available at ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Characteristics of clear cell ovarian cancer arising from endometriosis: A two center cohort study Giovanna Scarfone a, Alice Bergamini b, Stefania Noli a, Antonella Villa a, Sonia Cipriani c, Gianluca Taccagni d, Paola Vigano' e, Massimo Candiani b, Fabio Parazzini c, Giorgia Mangili e,⁎ a
Department of Obstetrics, Gynecology and Neonatology, IRCCS Fondazione Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy Università Vita-Salute, San Raffale Scientific Institute, Milano, Italy Mario Negri Pharmacological Research Institute, Milan, Italy d Department of Surgical Pathology, San Raffaele Scientific Institute, Milano, Italy e Obstetrics and Gynecology Unit, San Raffaele Scientific Institute, Milano, Italy b c
H I G H L I G H T S • Clinical and histological features of the largest series of clear cell carcinomas arising in endometriosis are analyzed. • No difference in stage, grade, survival and endometrial cancer incidence was found between tumors arising or not in endometriosis. • Younger age, unilateral ovarian involvement and absence of ascites were more frequently found in cases arising in endometriosis.
a r t i c l e
i n f o
Article history: Received 19 January 2014 Accepted 10 March 2014 Available online xxxx Keywords: Endometriosis Clear cell ovarian cancer Endometriosis associated ovarian cancer
a b s t r a c t Objective. Endometrioid and clear cell ovarian tumors have been referred to as “endometriosis associated ovarian cancers”. However, very few studies have compared clinical and prognostic features of endometriosisassociated cancers or cancers not associated with endometriosis according to specific histotypes. We have investigated clinical and histological features of the largest published series of clear cell ovarian cancers arising in endometriosis using a retrospective database. Methods. Seventy three patients with a primary diagnosis of either pure clear cell ovarian cancer and mixed endometrioid-clear cell ovarian cancer have been divided into two groups according to the detection of cancer strictly arising from ovarian endometriosis or not (n = 27 and n = 46, respectively). Clinical and pathological data have been compared. Results. Patients with clear cell carcinomas arising from endometriosis tend to be significantly younger (51.4 ± 10.0 and 58.4 ± 11.2 years, p = 0.02). FIGO stage, laterality, prevalence of pure versus mixed histology, and presence of synchronous endometrial carcinoma were not significantly different between the two groups. Unilateral ovarian involvement was more frequent in cases arising in endometriosis (85% vs 63%, p = 0.04). Ascites was not found in any of the endometriosis-associated cancer cases vs 19.5% in patients without endometriosis. The presence of endometriosis did not affect 5-year overall survival rates. Conclusions. Endometriosis per se does not appear to be associated with a lower stage tumor or to predict prognosis in ovarian clear cell cancers. Unilateral involvement and reduced presence of ascites may be linked to the cystic nature of endometriosis which frequently presents as monolateral and in which associated tumors are more likely to be longer confined to the ovary before spreading. © 2014 Elsevier Inc. All rights reserved.
Introduction Endometriosis is a risk factor for epithelial ovarian cancer [1,2]. Based on the results of a large international collaborative study, self-
⁎ Corresponding author at: Obstetrics and Gynecology Unit, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milano, Italy. E-mail address: [email protected] (G. Mangili).
reported endometriosis was associated with an overall risk increase of nearly 50% [Odds Ratio, 1.46; 95% confidence intervals (CIs), 1.31– 1.63] [3]. This issue is of particular clinical relevance given the prevalence of endometriosis, estimated to be around 5%, with a peak between 25 and 35 years of age [4]. It is also well known that tumors associated with endometriosis are confined to specific subcategories of disease, endometrioid and clear cell ovarian cancers, and the risk of detecting these histotypes is estimated to be about 4-fold higher in women with the disease [5].
http://dx.doi.org/10.1016/j.ygyno.2014.03.017 0090-8258/© 2014 Elsevier Inc. All rights reserved.
Please cite this article as: Scarfone G, et al, Characteristics of clear cell ovarian cancer arising from endometriosis: A two center cohort study, Gynecol Oncol (2014), http://dx.doi.org/10.1016/j.ygyno.2014.03.017
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Controversy remains regarding the possibility that endometriosisassociated cancers might represent a distinct entity from the correspondent typical histotype. Some studies have indeed suggested that patients with endometriosis tend to be younger, to be diagnosed in earlier stages and with lower grade lesions and to have an overall better survival rate whereas other studies fail to confirm these findings [6–13]. Importantly, very few of these studies have evaluated clinical and prognostic differences between endometriosis-associated cancers or cancers not associated with endometriosis according to the specific histotype [8,9,13,14]. This might have prevented the identification of characteristics potentially linked to a specific subcategory of disease. In this context, in a recent study [8], we have analyzed a cohort of patients diagnosed with endometrioid ovarian cancer and confirmed that women with endometriosis-associated cancer were significantly younger at the diagnosis, had a lower disease stage and a less prevalent high grade tumor. A difference in survival rate could not be confirmed between patients with and without endometriosis. Importantly, a synchronous endometrial precancerous or cancerous condition has been detected at a significantly higher rate in endometriosis-associated endometrioid cancers, possibly leading to various and novel interpretations for the mechanisms of this cancer development. Along this line, in this study, we have evaluated the clinical and prognostic features of endometriosis-associated ovarian cancers of clear cell histotype and compared them with those of clear cell tumors without endometriosis. Results of the present study considering the most numerous series of cancers of clear cell and mixed endometrioid-clear cell histotype arising in endometriosis and of our previous study on ovarian endometrioid tumors [8] tend to support the idea that endometrioid and clear cell cancers associated with endometriosis should be no more considered a single entity with similar risk and prognostic factors and biologic mechanisms of development. Materials and methods This is a retrospective study of 73 cases of clear cell ovarian carcinoma consecutively observed at two centers, the Department of Obstetrics and Gynecology of the Fondazione Ospedale Maggiore Policlinico and the Obstetrics and Gynecology Unit of the Scientific Institute San Raffaele in Milan, Italy between 1990 and 2012. Institutional Review Board approval has been obtained for this retrospective study. All patients with a primary diagnosis of either pure clear cell ovarian cancer or mixed endometrioid-clear cell ovarian cancer have been included in the study. Patients whose diagnosis was made elsewhere were excluded. Patients older than 75 were not included in survival analysis. Some data from 33 patients have been already included in a previous paper [7]. All patients underwent surgery, received chemotherapy and were followed up at our institutions. Surgical staging was performed according to FIGO guidelines for ovarian cancer, including total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy and removal of all macroscopic diseases [15]. Radical upper abdominal techniques were applied in selected cases to achieve optimal cytoreduction. All pathological analyses were performed by the same two gynecologic pathologists, who, in both institutions, are completely dedicated to gynecological cases. Patients were divided into two groups according to the detection of cancer arising from ovarian endometriosis or not, on the basis of pathological reports. The definition of ovarian cancer arising from endometriosis was given according to Sampson's [16] and Scott's criteria [17], that included: 1) the coexistence of carcinoma and endometriosis in the same ovary; 2) presence of tissue similar to endometrial stroma surrounding characteristic epithelial glands; 3) exclusion of a metastatic tumor to the ovary; and 4) presence of benign endometriosis histologically contiguous to the malignant tissue. Patients with clear cell carcinoma associated with but not arising in endometriosis were excluded.
Data including age at diagnosis, clinical presentation, disease status, last follow-up and all pathological information, such as histology, stage, laterality, and presence of concurrent endometrial carcinoma were collected from surgical and pathology reports. Stages higher than IIA were classified as advanced, while lower stages were considered early. All the abovementioned variables were described for each of the two groups and statistically compared. The Pearson Chi-square test or Fisher Exact test, as required, was used to assess the significance of differences in clinical and pathological characteristics between the two groups. Survival comparisons were obtained using the long-rank test in an unadjusted Kaplan Meier model, survival rates being calculated from the date of histological diagnosis. Finally, to account for the effect of potential confounding factors simultaneously, we used the Cox regression model (after checking the proportional hazards assumption) to obtain the hazards ratio (HR) and their corresponding 95% CIs. In all analysis, a p value of b 0.05 was considered statistically significant. Follow-up was updated in May 2013, being median follow-up of 68 months (95% CI, 55–103).
Results Seventy-three patients met the inclusion criteria. Of these, n = 27 (37%) cases have been affected by tumors arising in endometriosis (Fig. 1), while n = 46 patients (67%) had no concomitant endometriosis. Patients and tumor characteristics of the two groups are summarized in Table 1. In both groups, the most common diagnosis was incidental, followed by the detection of an abdominal mass. Symptoms did not differ statistically between the two groups except for presence of ascites that was only detected in patients without endometriosis (19.5% versus none of the patients in the endometriosis group). Patients with endometriosis-associated clear cell carcinomas or of mixed histology tend to be significantly younger than cases without endometriosis with mean age ± SD being 51.4 ± 10.0 and 58.4 ± 11.2 for tumors arising in endometriosis and not, respectively (p = 0.02). Among endometriosis-free patients, n = 23 (50%) were diagnosed in early stages while 50% in advanced stages. In the other group, n = 18 (66.7%) were in early stages, and n = 9 (33.3%) were in advanced. FIGO stages were not significantly different between the two groups (p = 0.16). The prevalence of patients with pure clear cell histology and mixed histology was respectively 76.1% and 23.9% in the endometriosis-free group and 70.4% and 29.6% in the endometriosis group. No statistically significant difference was detected (p = 0.59).
Fig. 1. A typical ovarian clear cell carcinoma of papillary type, grown into the lumen of an endometriotic cyst lined by columnar endometrioid type cells. (Hematoxylin and eosin × 125.)
Please cite this article as: Scarfone G, et al, Characteristics of clear cell ovarian cancer arising from endometriosis: A two center cohort study, Gynecol Oncol (2014), http://dx.doi.org/10.1016/j.ygyno.2014.03.017
G. Scarfone et al. / Gynecologic Oncology xxx (2014) xxx–xxx
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Table 1 Clinical and pathological characteristics of clear cell carcinomas arising or not from endometriosis. Clinical features
Age Mean ± SD (range) Stage I–IIA IIB–IV Histology Clear cell Mixed Ovarian involvement Monolateral Bilateral Laterality Right Left Symptoms Abnormal uterine bleeding Constipation Abdominal/pelvic mass History of adnexal cyst Ascites Incidental diagnosis Paraneoplastic syndrome Abdominal pain Synchronous endometrial cancer Year of diagnosis 1990–2000 2001–2012 a
Endometriosis
p-Value
No (n = 46)
Arising (n = 27)
58.4 ± 11.2 (41–89)
51.4 ± 10.0 (30–71)
23 (50.0%) 23 (50.0%)
18 (66.7%) 9 (33.3%)
35 (76.1%) 11 (23.9%)
19 (70.4%) 8 (29.6%)
29 (63.0%) 17 (37.0%)
23 (85.0%) 4 (15.0%)
15 (52.0%) 14 (48.0%)
10 (43.0%) 13 (57.0%)
4 (4.0%) 3 (6.5%) 5 (10.8%) 2 (4.3%) 9 (19.5%) 19 (41.3%) 4 (4.0%) 15 (32.6%) 2 (4.0%)
5 (2.2%) 0 7 (30.4%) 3 (13.0%) 0 7 (30.4%) 1 (4.3%) 4 (17.3%) 0
16 (34.8%) 30 (65.2%)
5 (18.5%) 22 (81.5%)
0.02
0.17
0.59
0.04
0.55
0.28a 0.29a 0.11a 0.35a 0.02a 0.18 0.64a 0.09 0.53a 0.14
Fisher exact test.
Bilateral ovarian involvement was detected in 17 patients (37%) in the endometriosis-free group, compared to 4 (15%) patients with clear cell tumor or of mixed histology arising in endometriosis (p = 0.04). In monolateral ovarian involvement, laterality did not differ between the two groups (p = 0.55). The presence of a synchronous endometrial carcinoma was found only in 2 patients with clear cell ovarian cancer without concomitant endometriosis. The presence of endometriosis did not affect 5-year survival rates even after taking into account potential confounding factors (Fig. 2, Table 2). Mean 5-year overall survival was 60.1 months (95% CI 41–75) in endometriosis-free group versus 73.0 months (95% CI 49–87) in the endometriosis group (log rank = 0.43). Overall survival has been also analyzed stratifying for selected characteristics (Table 2); none of them was significantly associated with an increased overall survival. Discussion The association between ovarian cancer and endometriosis has been largely documented [1,18], even if clinico-pathological mechanisms are still for many aspects unclear. In particular, several studies have focused on the link between endometriosis and clear cell or endometrioid histologies, suggesting that about one third of these cancers arise from endometriosis [5]. The two histologies are often considered as a single entity, as “endometriosis-associated ovarian tumors”. However, there is increasing evidence suggesting that endometrioid and clear cell ovarian carcinomas may behave differently with respect to their association with endometriosis and that might even arise from distinct types of endometriosis with different cells of origin [19]. In a very interesting paper, Kajihara and coworkers hypothesized that clear cell ovarian cancers associated with endometriosis may arise from preexisting endometriosis derived from regurgitated endometrial cells whereas ovarian Mullerian metaplasia may initiate neoplastic modifications
Endometriosis No Yes
2/46 1/27
N. events/N. of patients at risk 3/36 2/30 1/25 5/23 0/22 3/21 1/18 1/16
Fig. 2. Kaplan–Meier survival functions in clear cell carcinoma cases arising or not in endometriosis.
in endometriosis-associated endometriod cancers. Support to this hypothesis derived from the analysis of hepatocyte nuclear factor (HNF)1β, a nuclear factor associated with endometriosis whose expression has been found in epithelial cells of ectopic, eutopic endometrium and clear cell ovarian carcinomas, but not in ovarian cortical inclusion cysts nor in endometrioid ovarian cancer. The potential diverse origins of different histotypes of endometriosisassociated cancers imply that they should be considered different clinical entities. As a matter of fact, very few studies have specifically studied clinical and prognostic factors of tumors associated with endometriosis according to the specific histotype [8,9,13,14]. Two studies, one from our group [8], have focused on the endometrioid histotype, suggesting that endometriosis-associated endometrioid ovarian cancer has a different clinical behavior with respect to the non-endometriosis-associated tumor of similar histology. Both the studies agree that the first tends to arise at younger ages, with lower stages, with a less prevalent high grade and with a significantly higher incidence of synchronous endometrial tumors [8,9]. Along this line, the present study aimed at evaluating the clinical and prognostic features of clear cell histotype arising or not in endometriosis. For this analysis, the larger series of clear cell or of mixed histotype tumors arising in endometriosis ever published for this rare tumor has been enrolled. No difference in tumor stage, grade, survival rate and incidence of synchronous endometrial cancers was found between clear cell cancers arising or not in endometriosis. As a consequence, the results of this study also support the idea that clear cell or endometrioid tumors associated with endometriosis should be considered different entities as clinical features vary greatly between the two. The only characteristic in common is represented by the occurrence at younger ages compared to the correspondent histologic type not associated with endometriosis. However, in this context, a potential role of a diagnostic bias could also explain, at least partially, the increased diagnosis at initial stages for both histotypes of tumors. Indeed, patients with concomitant endometriosis could be diagnosed earlier considering that this disease is frequently associated with specific symptoms and endometriosis women tend to be better followed up whereas ovarian cancers are frequently asymptomatic until advanced stages are reached [5]. The prevalence of ascites and bilateral disease is the only other clinical discrepancies found between clear cell carcinoma arising and not in
Please cite this article as: Scarfone G, et al, Characteristics of clear cell ovarian cancer arising from endometriosis: A two center cohort study, Gynecol Oncol (2014), http://dx.doi.org/10.1016/j.ygyno.2014.03.017
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Table 2 Five-year survival in cases with clear cell carcinoma arising or not from endometriosis. Variable
Cox regressiona
Endometriosis No (13 events) 5-year survival, % (95% CI)
Arising (6 events) 5-year survival, % (95% CI)
HR (95% CI)
p-Value
Age ≤54 N54
84.0 (49–96) 51.2 (28–70)
80.7 (51–93) 57.1 (17–84)
1.07 (0.2–6.5) 0.83 (0.2–3.0)
0.94 0.78
Stage I–IIa IIb–IV
94.7 (68–99) 21.1 (5–44)
92.3 (57–99) 44.4 (14–72)
1.38 (0.1–22.1) 0.68 (0.2–1.9)
0.82 0.46
Histology Clear cells Mixed
55.6 (34–73) 75.8 (30–94)
81.3 (52–94) 52.5 (12–82)
0.39 (0.1–1.4) 2.83 (0.5–17.4)
0.14 0.26
Year of diagnosis 1990–2000 2001–2012 Overall
71.4 (41–88) 53.1 (28–73) 60.1 (41–75)
75.0 (13–96) 72.6 (46–88) 73.0 (49–87)
NE 0.46 (0.2–1.4) 0.68 (0.3–1.8)
0.17 0.43
NE: non estimable due to low number of events. a Adjusted for stage, modeled in each strata of interesting variables, comparing endometriosis arising versus no endometriosis.
endometriosis being lower in the forms associated with the benign disease. An explanation for this may be linked to the different origin of the tumor which may derive from an endometriotic cyst or from an adenofibroma [20]. Endometriosis presents more commonly as a monolateral ovarian cyst. Moreover, a more favorable outcome was observed in cystic clear cell carcinomas. Tumors growing intracystically are more likely to be confined to the ovary for longer periods of time before spreading, thereby allowing them to be diagnosed at lower stage. This might also explain the increased frequency of ascites in tumors not associated with endometriosis. Thus, unilaterality and reduced presence of ascites are most likely a consequence of an endometriotic and, therefore, cystic origin. These features were previously not found to be associated with endometriosis-associated endometrioid ovarian cancer [8]. To the best of our knowledge, there are only two other studies which focused on prognostic implications of endometriosis in the context of clear cell carcinomas and this is not surprising given the rarity of this tumor. In the study by Orezzoli et al. [13], eighty-four patients with clear cell carcinoma were identified with a 49% rate of coexisting endometriosis. However, only 15 of these tumors were found to arise in endometriosis while the others were not in contiguity with the tumor. In line with our results, patients with clear cell cancer arising in endometriosis tended to be younger, to have a pelvic mass at the diagnosis and no ascites. Contrary to our observations, patients with a tumor arising from endometriosis significantly presented at early stage and their median overall survival was remarkably greater than that of patients with clear cell carcinoma without endometriosis although the limited number of patients did not allow for a statistical comparison of this factor. Discrepancies between the two studies may be due to their small sample size and a type II error cannot be excluded. Moreover, the study by Orezzoli et al. encompassed a period of about 30 years during which adjuvant treatments varied greatly among the patients with or without endometriosis. Sixty percent of the patients in whom the tumor arose from endometriosis received platinum-based regimens in combination with taxanes compared to 39% of endometriosis-free patients only. In this latter group, 11% of patients did not receive platinumbased regimens. Conversely, the current study, even though covering a 22 year long period, only consider patients treated after platinum introduction in chemotherapeutic regimens. Thus, all patients have been more homogenously treated with platinum-based regimens. The second study by Cuff et al. is poorly comparable with ours as their definition of endometriosis-associated cancer was not strictly based on Sampson's [16] and Scott's criteria [17]. In any case, endometriosis per se did not appear to predict prognosis in their series of 53 cases of clear cell cancers associated with the disease [14].
In conclusion, based on the results from the present study and from studies focusing on ovarian endometrioid cancers [8,9], it is tempting to speculate that clear cell and endometrioid carcinomas associated with endometriosis should be considered separate diseases with different clinical behavior and prognostic factors. The more recent molecular genetic analyses are not able to clarify whether the two subtypes of tumors derive from distinct types of endometriosis but they certainly support important molecular differences between the two. A high frequency of ARID1A mutations has been detected mostly in endometriosis-associated clear cell carcinomas (46–57%) and less in endometriosis-associated endometrioid tumor (30%). As a matter of fact, loss of protein expression of the ARID1A tumor suppressor gene has been so far demonstrated in endometriosis adjacent to clear cell tumor samples [21]. Conversely, major genetic alterations involved in endometriosis-associated endometrioid ovarian cancer are represented by PTEN, KRAS and β-catenin gene mutations. In our previous paper, we had indeed hypothesized a molecular parallelism between endometriosis-associated ovarian endometrioid cancer and type I endometrial carcinoma that is typically characterized by mutations of the PTEN, K-RAS, PIK3CA and β-catenin genes [8]. Finally, as clear cell carcinomas exhibit very low estrogen receptor expression while endometrioid cancer is predominantly positive for estrogen receptor, the interactions between the iron-mediated oxidative stress due to the repeated hemorrhages in endometriosis [18,22,23] and the down-regulation of estrogen receptor expression have been suggested to be involved in the development of clear cell carcinomas. Future studies, particularly molecular investigations, should be undertaken to definitively clarify this aspect. This is even more important considering that studies on endometriosis-associated ovarian cancer are always faced with a critical issue since the tumor, especially in advanced stages, might have obliterated the tissue of origin hiding any histological evidence of endometriosis. Thus, the better clarification of the genetic background of these two entities, which is a helpful clue to distinguish one from the other, remains a critical matter of investigation. Conflict of interest statement The authors declare no conflict of interest.
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Please cite this article as: Scarfone G, et al, Characteristics of clear cell ovarian cancer arising from endometriosis: A two center cohort study, Gynecol Oncol (2014), http://dx.doi.org/10.1016/j.ygyno.2014.03.017
