Gynecologic Oncology 131 (2013) 598–603
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Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Early stage papillary serous or clear cell carcinoma confined to or involving an endometrial polyp: outcomes with and without adjuvant therapy Christine N. Chang-Halpenny a,⁎, Sathima Natarajan b, Julie Hwang-Graziano a a b
Department of Radiation Oncology, Kaiser Permanente Southern California, Los Angeles CA, USA Department of Pathology, Kaiser Permanente Southern California, Los Angeles CA, USA
H I G H L I G H T S • Clinical outcomes of patients with stage IA UPSC/CC involving a polyp were reviewed • 3/32 patients with disease confined to a polyp and 1/19 patients with endometrial surface spread or myometrial invasion progressed • No vaginal recurrences occurred
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Article history: Received 11 September 2013 Accepted 8 October 2013 Available online 14 October 2013 Keywords: Papillary serous Clear cell Polyp Endometrial cancer
a b s t r a c t Objective. To investigate clinical outcomes of stage IA uterine papillary serous (UPSC) and clear cell carcinoma (CC) arising from or associated with a polyp. Methods. From 1995 to 2011, we identified 51 cases of stage IA UPSC (67%), CC (8%) or mixed histology (26%) endometrial cancer. Of these, 32 had disease confined to polyp (seven with no residual disease after hysterectomy), 14 had surface spread, 1 had myometrial invasion (MMI) and 4 had both. The majority of patients did not receive adjuvant therapy (80%). Patients given adjuvant treatment (either platinum-based chemotherapy alone, radiation alone, or a combination of the two) had incomplete staging or abnormal cytology. Results. At mean follow-up of 58.3 months, only 4 patients had progressed, via pelvic adenopathy, carcinomatosis or both. There were no vaginal cuff recurrences. Kaplan–Meier 5 year estimates were pelvic control of 92.1%, disease-free survival 93% and OS 80.6%. Only 9% (3/32) of cases confined to polyp progressed. One responded to salvage chemoradiation, but two died despite salvage. Only 5% (1/19) of cases with surface and MMI progressed. On univariate analysis, only MMI and abnormal/positive cytology were significantly associated with increased pelvic recurrence (MMI p = 0.0059, cytology p = 0.0036) and worse DFS (MMI p = 0.0018, cytology p = 0.0054). Two patients given adjuvant treatment developed new gynecologic malignancies. Conclusion. In our study, patients with limited UPSC/CC disease involving a polyp who have complete workup did well without adjuvant therapy, with recurrence rates similar to UPSC/CC stage IA disease. Late and extensive pelvic relapses may occur in the few who do relapse. © 2013 Elsevier Inc. All rights reserved.
Introduction Endometrial cancer is the fourth most common cancer diagnosis in women with 49,560 new cases expected from 2013 [1]. While the 5 year survival for stage IA endometrioid adenocarcinoma is approximately 99% [2], type II subtypes are known to carry a worse prognosis. Included among type II are uterine papillary serous carcinoma (UPSC) and clear cell (CC) carcinoma, considered more
⁎ Corresponding author at: 4950 Sunset Blvd, Los Angeles, CA 90027, USA. Fax: +1 323 783 5927. E-mail address: [email protected] (C.N. Chang-Halpenny). 0090-8258/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ygyno.2013.10.010
high-risk endometrial carcinoma subtypes compared to endometrial adenocarcinoma. UPSC and CC appear to have higher tendency for lymphovascular invasion, with pattern of failure commonly involving spread via intraperitoneal or extra-abdominal invasion [3,4]. Prognostic factors for UPSC/CC appear to differ from endometrioid adenocarcinoma. Only stage has consistently been shown to correlate with survival, while myometrial invasion (MMI) has prognostic significance in some but not all studies [4–8]. No standard treatment regimen exists for early stage UPSC or CC, and stage I–II disease has variably been treated with observation, radiation, chemotherapy or combination modality treatment [8–11]. In addition, radiation options include therapy given by external beam (EBRT) to the pelvis or by high-dose rate vaginal
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brachytherapy (VB). Recent papers suggest VB alone may be adequate adjuvant treatment for patients with surgical stage I papillary serous or clear cell carcinoma, given subsequent low vaginal recurrence rates after VB from 0% to 3% and pelvic recurrence of 4–9% [12–14]. Overall recurrence rates for FIGO 2002 stage IA UPSC from retrospective studies have been reported from 9% to 11%, and up to 13% for stage IA by currently used FIGO 2009 criteria [7,15]. Observation has been proposed as a reasonable option for stage IA disease, particularly if no myometrial invasion is present [15]. Endometrial cancer confined to a polyp is a clinical scenario that offers particular difficulty given rarity of disease and limited available published data. Given the limited extent of disease but aggressive biologic behavior of UPSC/CC it is unclear whether adjuvant therapy is warranted. While case reports and small series have been published mainly in the pathology literature [16–19], these often include all stages of UPSC, with inconsistent description of the adjuvant treatment given or details of patients' clinical outcomes. We conducted a retrospective review of our institution's incidence and clinical outcomes of patients with surgical stage IA UPSC/CC involving a polyp observed after surgery or given adjuvant therapy (radiation, chemotherapy, or both). Materials and methods Following Institutional Review Board approval, we queried our institution's Cancer Registry for cases of endometrial cancer. Based on stage and histology, we identified 236 cases of stage IA pure UPSC, pure CC or mixed endometrial cancer, diagnosed from 1995 to 2011. The mixed endometrial cancer patients included data of all histologic subtypes, which we then sorted for UPSC/CC. The International Federation of Gynecology and Obstetrics (FIGO) previously defined stage IA disease as endometrial cancer with no myometrial invasion (MMI). Starting in 2009, patients with less than half MMI were also included in our study based on changes in definition of FIGO IA criteria. Pathology reports were reviewed for mention of polyp involvement with carcinoma. Classically, the pathological definition of a polyp is a grossly pedunculated mass composed of cystically dilated glands with fibrous stroma and thick walled blood vessels, associated with a stalk. Endometrial cancer found only in the polyp was considered confined to and arising from polyp. It is possible that cases with MMI or surface invasion had cancer arising from elsewhere in the endometrium instead of from the polyp itself, but typically there was limited extension outside of polyp since only stage IA disease was included. Statistical analysis included Kaplan–Meier estimates for 5year pelvic recurrence-free survival (RFS), disease-free survival (DFS) and overall survival (OS). Time to event was calculated from date of surgical staging. Log-rank analysis was used for univariate analysis to determine possible prognostic variables. The variables looked at in our study were age (≤60 or N60 years), adjuvant treatment (yes/no), LVI (yes/no), cytology (abnormal or positive versus negative), adenomyosis (yes/ no), endometrial intraepithelial neoplasia (yes/no), MMI (yes/no), and tumor spread on endometrial surface (yes/no). Due to small number of events, multivariate analysis was not conducted. GraphPad Prism (version 6.0) was used for analysis. Results We identified 51 cases of stage IA UPSC, CC or mixed UPSC/CC involving a polyp, from 1997 to 2011. An additional two patients qualified, but lacked sufficient follow-up data. Medical records of the 51 patients were reviewed for work-up, potential prognostic factors, and clinical outcomes. Slides were reviewed with a gynecologicaloncology pathologist specialist if there were incomplete reports, if patients had later progression of disease, or if later development of other gynecologic malignancies occurred. All patients underwent surgical staging with hysterectomy (typically abdominal or laparoscopic, one with radical hysterectomy)
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and bilateral salpingo-oophrectomy. Cytology specimens were collected from peritoneal fluid obtained during hysterectomy. Lymph node dissection of para-aortic (PA) and pelvic lymph nodes (PLND) was done for 32 patients (63%) with average of 20 dissected nodes. One patient had PA dissection only, 9 had PLND only and an additional 9 either refused or did not have any dissection done. Cytology was known for 40 patients (78.4%), of which 2 were positive for malignant cells and 3 had “atypical” cells. Omental biopsy was done for 26 patients (51%), all negative. Mean follow-up from date of surgical staging was 58.3 months (median follow-up 45.2 months, from 1.8 to 188.2 months). Median follow-up for patients treated who are NED and still alive was 33.6 months. The majority of patients had pure UPSC (66.7%), the fewest had pure CC (7.8%) and the remainder had mixed UPSC/CC/ adenocarcinoma (25.5%). Median age was 65 years at time of diagnosis. Six patients were nulliparous (11.7%). Median BMI was 41 and 20% of patients had previous endocrine treatment for breast cancer. See Table 1 for additional characteristics. Five patients had MMI and extent of MMI ranged from 3% to 30%. Polyp size was reported for 36 patients and tumor size reported for 15 patients. Six patients had multiple polyps on gross pathology, of which two had multiple polyps involved with tumor (one superficial and limited to polyps and the other appearing to arise from polyps and limited to endometrium with no MMI). Twenty-five patients had disease confined to polyp, defined as only involving the polyp with no MMI or endometrial surface spread beyond polyp (see Fig. 1). An additional 7 patients had cancer on endometrial biopsy or curettage (arising in a polyp) but no residual disease at time of hysterectomy. Thus, in total, 32 patients had disease confined to polyp, either before or after hysterectomy. Table 1 Clinical and pathologic characteristics. Characteristics
Value (%)
Median age Race
65 (51–85) years 2 (4%) 16 (31%) 9 (18%) 24 (47%) 10 (20%) 35 (68.6%) 6 (11.8%) 6 (11.8%) 4 (7.8%) 3 (5.9%) 21 (41%) 13 (25.5%) 7 (13.7%) 1 (2%) 32 (63%) 20 1 (2%) 2 9 (18%) 11 9 (18%) 2 (4%) 3 (6%) 26 (51%) 34 (66.7%) 4 (7.8%) 13 (25.5%) 32 (63%) 25 (49%) 7 (14%) 14 (27%) 1 (2%) 4 (7.7%) 1.2 (0.5 to 4) cm 3 (0.6 to 8.5) cm 17 (33%) 1 (2%) 2 (4%) 8 (16%)
Asian Black Hispanic White History of endocrine therapy for breast cancer Presenting symptoms Vaginal bleeding Abnormal pap Abnormal imaging Abdominal pain/pressure Unknown Preoperative imaging CT chest, abdomen, pelvis CT abdomen, pelvis MRI pelvis Lymph node dissection Para-aortic and pelvic Mean# dissected Para-aortic only Mean# dissected Pelvic only Mean# dissected Refused/not done Cytology Positive Atypical Omental biopsy performed Yes Histology UPSC CC Mixed UPSC/CC Confined to polyp before or after TAH Polyp only after TAH No residual disease after TAH Endometrial surface spread only Myometrial invasion (MMI) only Both surface spread and MMI Size of tumor (median) Size of polyp (median) Adenomyosis Lymphovascular invasion Outside of polyp Within polyp Endometrial intraepithelial neoplasia
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Fig. 1. H&E stains of endometrial polyp with serous carcinoma (left side low powered field at 4× magnification and right side high powered at 10× magnification).
Adjuvant treatment
Outcomes
Eighty percent of patients were followed with observation alone (41 patients). Of the ten patients who did receive adjuvant treatment, 3 had chemotherapy alone, 1 had radiation alone and 6 had combined modality treatment (see Table 2). Median time from staging surgery to adjuvant treatment was 1.6 months (0.62 to 3.42 months). Patients treated had either evidence of myometrial invasion on pathology, lacked lymph node dissection, cytology or omental biopsy, or had positive or atypical cytology from intraoperative pelvic washings. The usual chemotherapy given was carboplatin and paclitaxel. Usual EBRT dose was 4500 cGy and VB dose 2100 cGy. The single patient treated with radiation alone was given VB to 2100 cGy over three fractions. This patient died 5 months later from disease unrelated to cancer or treatment. Combined modality treatment was given sequentially with chemotherapy followed by radiation, except for one case. For that patient, 2 cycles of carboplatin and paclitaxel were given, followed by pelvic EBRT to 4500 cGy, then VB to 1400 cGy, then an additional cycle of chemotherapy. Brachytherapy was typically given to 5 cm length and 0.5 cm depth. Toxicity was scored per both Radiation Therapy Oncology Group and National Cancer Institute Common Toxicity Criteria. All patients given chemotherapy had some degree of peripheral neuropathy (grade 2 for seven patients, grade 1 for one patient, and grade 3 for one patient). Two patients also experienced grade 1 arthralgia. One patient developed supraventricular tachycardia requiring cardioversion. No grade 3 or 4 GI or GU radiation related toxicities and no grade 4 hematologic toxicities were reported.
At the time of analysis, 11 patients had died, with 3 deaths from progression of their original endometrial malignancies, 2 from progression of new gynecologic primaries and the remainder from non-malignant disease, including cardiac and renal etiologies. OS was 78.4% and DFS was 92.5%. Disease progression occurred in 4/51 patients (7.8%) in our study, including in one patient given adjuvant treatment. Time to recurrence ranged from little over one year to almost 7 years after initial surgery. All four patients developed pelvic recurrence, with either extensive carcinomatosis (including to the abdomen for one patient) or lymphadenopathy or both. There were no vaginal recurrences. Of those who progressed, one patient had myometrial invasion (3%) and spread outside polyp onto the endometrial surface for which she received 5 cycles of adjuvant carboplatin and paclitaxel followed by VB to 2100 cGy. Despite this, she experienced pelvic recurrence 2.7 years later, was given surgical debulking and chemotherapy but had functional decline and died of disease. The remaining three patients who progressed had not previously received adjuvant treatment, as two patients had disease confined only to polyp and an additional patient had no residual disease seen on hysterectomy after polypectomy. Thus, in total, 3/32 patients (9.4%) who had disease confined to polyp progressed. One patient had isolated pelvic mass, for which she was given salvage chemotherapy and external beam radiation with boost to gross disease. She responded well, with negative PET CT and is currently alive with no evidence of disease. Of the other two patients with recurrence, one progressed despite salvage chemotherapy (with lung nodule, skin nodules and extension to bladder) and the other went on hospice rather than receive salvage treatment. See Table 3 for details regarding patients who progressed. Surprisingly, two patients were later found to have new gynecologic malignancies less than 20 months after initial staging surgery; rhabdosarcoma and carcinosarcoma, respectively. Diagnosis of rhabdosarcoma was made after one patient was noted to have abnormal tissue at vaginal cuff while undergoing adjuvant treatment with EBRT. Pelvic CT showed new right pelvic side wall mass and workup with biopsy of vaginal mass revealed rhabdosarcoma. The second patient was diagnosed 20 months after completion of adjuvant treatment (chemotherapy and VB) with findings of elevated CA125 with ascites and peritoneal implants on imaging. Debulking of tumor revealed carcinosarcoma. Slides for these patients (from biopsy, hysterectomy and at time of recurrence) were reviewed with a gynecological oncology pathologist specialist, who confirmed both the initial diagnosis (of UPSC or CC) and subsequent new gynecologic primary. These patients
Table 2 Observation versus adjuvant treatment and outcomes. Adjuvant treatment Intervention Observation after surgery Adjuvant treatment Adjuvant treatment details: Chemotherapy alone Vaginal brachytherapy (VB) alone Sequential chemoradiation External beam RT Chemotherapy and: External beam, then VB VB
f
Abbreviations: RT = radiation.
Recurrence
Death
41 (80%) 10 (20%)
3 (7.3%) 1 (10%)
2 (4.9%) 1 (10%)
3 (6%) 1 (2%)
0 0
0 0
6 (12%) 2 3 1
0 0 0 1
0 0 0 1
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Table 3 Characteristics of patients with recurrence. ID
Age
Histology
Confined to polyp
Disease beyond polyp
LVI
#Pelvic LN
#PA LN
Omental biopsy
Cytology
Adjuvant therapy
TTR (years)
First recurrence
DFS (years)
Vital status
1 2
56 62
Pure UPSC Mixed UPSC
+ −
− +a
− −
13 16
7 0
Not done Not done
− Atypical
2.87 1.11
Pelvic mass along side-wall Pelvic carcinomatosis, LAD
3.40 1.63
Alive, NED Died of disease
3
70
Mixed UPSC/CC
+b
−
−
14
2
Negative
−
− Chemotherapy then VB −
2.71
4.48
Died of disease
4
68
Mixed UPSC
+
−
−
2
2
Negative
−
−
6.83
Pelvic/abdominal carcinomatosis, ascites Pelvic/retroperitoneal LAD, colon implants
7.92
Died of disease
Abbreviations: UPSC = uterine papillary serous carcinoma, CC = clear cell, LVI = lymphovascular invasion, LN = lymph node, VB = vaginal brachytherapy, TTR = time to recurrence, LAD = lymphadenopathy, RT = radiation, DFS = disease free survival, NED = no evidence of disease. a 3% myometrial invasion, superficial spread at endometrial surface. b Tumor found with polypectomy but none after TAH.
died of disease related to sarcoma but were not considered to have progressed from original UPSC/CC. Estimated 5year Kaplan–Meier rate of pelvic RFS was 92.1%, DFS was 93%, and OS was 80.6% (see Fig. 2). On univariate analysis, only positive/
atypical cytology (HR 12.33, p = 0.0036) and presence of MMI (HR 11.58, p = 0.0059) were significantly associated with pelvic recurrence (see Fig. 3). Cytology was also associated with worse DFS (HR 12.63, p = 0.0054) and OS (HR 9.09, p b 0.0001). Adjuvant treatment was initially associated with shorter interval from diagnosis to death or progression, but was not significant after the two patients who died from new gynecologic primaries were excluded. Disease beyond polyp in the form of MMI had worse DFS (HR 15.63, p = 0.0018) and OS (HR 4.697, p = 0.0253), and superficial spread of tumor on endometrial surface was associated with worse OS (HR3.25, p = 0.0464). Discussion
Fig. 2. Kaplan–Meier survival curves for all 51 patients.
To our knowledge, this is the largest series reported of stage IA UPSC/CC involving a polyp, with 51 patients in total, 32 of which had disease limited to polyp either at time of hysterectomy or at time of biopsy. Our investigation is limited in retrospective nature (heterogeneity in work-up and staging, variable follow-up time) and by the rarity of this disease, but contributes to the limited body of knowledge on this topic. Previous series have been small with conflicting data, citing recurrence rates from 0% to 33% [17,18,20]. Trahan et al. looked at UPSC “arising” from a polyp and found 3/9 (33%) cases of stage IA disease progressed, two of whom had received adjuvant radiation [17]. Wheeler et al. looked at 21 cases of UPSC in polyps, of which 0/6 stage IA patients progressed (with no adjuvant treatment) after median follow-up of 50 months [20]. Fader et al. found that in their series, 19 patients had disease confined to polyp, with a recurrence rate of 1/19 with noncurable extrapelvic relapse but no recurrences in patients with no residual uterine disease [21]. In contrast, one of the four patients found to progress in our study had no residual disease after hysterectomy but relapsed despite this. For “minimal serous carcinoma”, including intraepithelial serous carcinoma and superficial serous carcinoma, Hui et al. found 14 patients with stage IA UPSC confined to polyp, 0/12 of whom progressed (2 lost to followup), albeit with short follow-up [18]. We found 3/32 (9.4%) with disease confined to polyp progressed and only 5% (1/19) of cases with surface and MMI progressed. Thus, limited UPSC/CC involving a polyp appears to have similar progression rates with minimal spread beyond polyp (in form of endometrial surface spread) versus disease confined only to polyp (unless MMI is present). In our study, 4/51 (7.8%) of all stage IA polyp patients progressed. Estimated 5 year Kaplan–Meier pelvic recurrence rate was 7.9%. Our numbers are similar to the rates of recurrence cited for larger studies of stage I UPSC not necessarily involving a polyp, around 9–13% [7,15]. Specifically, Fader et al. found 16/124 (13%) recurrences for cases that would currently be FIGO IA, 39% of whom did not receive adjuvant treatment after surgery [7]. Of note, recurrence rates in patients with surgical stage IA by FIGO 2002 criteria (i.e. limited to endometrium) has been from 0% to 33% in older series with less than 10 patients [9,11,22–25]. While Havrilesky et al. demonstrated lower risk of
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Fig. 3. Kaplan–Meier survival curves of significant variables for pelvic recurrence free survival, a) cytology status (known for 40 patients) and b) presence of MMI (known for all patients).
recurrence with disease limited to the endometrium (9% vs 29%) compared to having MMI, MMI has not been borne out as a significant prognostic factor in other studies for UPSC [4,6]. Carcangiu et al. found that survival (for 19 patients) with UPSC confined to polyp, mucosa or with no residual cancer was not significantly different from those with stage I with MMI or LVI. In our study, only five patients had MMI, all received adjuvant treatment and one progressed despite this. On univariate analysis, MMI was found to be significant for pelvic recurrence, DFS, and OS and could be a prognostic factor to consider when discussing adjuvant treatment. Our predominant pattern of failure was via peritoneal/abdominal carcinomatosis and pelvic lymphadenopathy. No patients relapsed at the vaginal cuff, even in observed patients. Other studies have cited extrapelvic recurrences from 50% to 80% for early stage UPSC, while recent studies looking at patients treated with vaginal brachytherapy (with or without chemotherapy) had a lower rates from 10% to 11% [7,12,13,15]. Notably, there were patients in our study who were missing components of staging, including omental biopsy (not done for 25 patients) or lymph node dissection (not done for 9 patients). It is possible that some patients may have been upstaged with more complete surgical staging and we do recommend complete surgical staging, including lymph node staging. Given predilection for intraperitoneal or extrapelvic spread, cytology results should be taken into consideration for adjuvant treatment. In our study, atypical or positive cytology was prognostic for pelvic recurrence, DFS and OS. Case series have also shown that serous carcinoma limited to the endometrium, or even limited to polyp can present with simultaneous extrauterine tumors [18,26], and recurrence rates are higher for patients with incomplete workup [3,17]. We also reported that 20% of our patient had history of endocrine therapy for breast cancer. Endometrial polyps are a common pathology found after postmenopausal tamoxifen exposure and one study found 3% rate of malignant features in this cohort of patients compared to 0.48% of control population [27]. The relationship between tamoxifen exposure and development UPSC/CC in a polyp is unclear at present, given rarity of the histology, but may be a relevant area to explore regarding pathogenesis of disease. Interestingly, in our study, 2/51 (4%) patients developed new gynecologic primaries, one with rhabdosarcoma during EBRT and another with carcinosarcoma over a year after adjuvant chemoradiation. Pathology review confirmed distinct primaries rather than misdiagnoses. It is unclear whether these patients were more prone to these malignancies, if the two malignancies were related, or somehow related to the treatment given (although unlikely, given the timing). Further studies or better understanding of the tumor biology may shed light on this phenomenon.
Given the low recurrence rate, observation could be considered for patients with stage IA UPSC or CC confined to a polyp, if appropriate surgical staging with TAH, BSO, PA/PLND, omental biopsy and washings have been done. This is tempered with our lack of adequate prognostic factors for UPSC/CC. Options of adjuvant therapy could include chemotherapy with or without external beam radiation or vaginal brachytherapy. Townamchai et al. have shown lower-dose VB regimen to be a reasonable treatment option for early stage UPSC/CC [14]. Chemotherapy as primary adjuvant therapy has been supported by other studies [7,11,21]. The timing of recurrence occurred at varied intervals in our study, at 1, 2.7, 2.9 and even 6.8 years following diagnosis. Patients are typically followed closely for up to 5 years, but may benefit from longer follow-up and serial CA-125 levels (two of the patients who progressed in our study had rapid elevation of CA125 at the time of recurrence). If followed closely, patients who recur might be salvaged with chemoradiation if disease is localized, as was the case for one of our patients. Even for patients with UPSC/CC confined to a polyp, close follow-up is certainly warranted.
Conclusions In our study, stage IA UPSC or CC involving a polyp (with limited spread outside of polyp) appeared to have a low recurrence rate similar to that of other stage IA UPSC/CC patients, although late relapses did occur with relapse pattern of failure consisting of extensive pelvic recurrence. Presence of MMI or abnormal cytology may warrant consideration of adjuvant treatment. If recurrence occurs, confirmatory tissue sample may be useful if feasible as it is not impossible for appearance of a new gynecologic primary. Conflict of interest statement None
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Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Early stage papillary serous or clear cell carcinoma confined to or involving an endometrial polyp: outcomes with and without adjuvant therapy Christine N. Chang-Halpenny a,⁎, Sathima Natarajan b, Julie Hwang-Graziano a a b
Department of Radiation Oncology, Kaiser Permanente Southern California, Los Angeles CA, USA Department of Pathology, Kaiser Permanente Southern California, Los Angeles CA, USA
H I G H L I G H T S • Clinical outcomes of patients with stage IA UPSC/CC involving a polyp were reviewed • 3/32 patients with disease confined to a polyp and 1/19 patients with endometrial surface spread or myometrial invasion progressed • No vaginal recurrences occurred
a r t i c l e
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Article history: Received 11 September 2013 Accepted 8 October 2013 Available online 14 October 2013 Keywords: Papillary serous Clear cell Polyp Endometrial cancer
a b s t r a c t Objective. To investigate clinical outcomes of stage IA uterine papillary serous (UPSC) and clear cell carcinoma (CC) arising from or associated with a polyp. Methods. From 1995 to 2011, we identified 51 cases of stage IA UPSC (67%), CC (8%) or mixed histology (26%) endometrial cancer. Of these, 32 had disease confined to polyp (seven with no residual disease after hysterectomy), 14 had surface spread, 1 had myometrial invasion (MMI) and 4 had both. The majority of patients did not receive adjuvant therapy (80%). Patients given adjuvant treatment (either platinum-based chemotherapy alone, radiation alone, or a combination of the two) had incomplete staging or abnormal cytology. Results. At mean follow-up of 58.3 months, only 4 patients had progressed, via pelvic adenopathy, carcinomatosis or both. There were no vaginal cuff recurrences. Kaplan–Meier 5 year estimates were pelvic control of 92.1%, disease-free survival 93% and OS 80.6%. Only 9% (3/32) of cases confined to polyp progressed. One responded to salvage chemoradiation, but two died despite salvage. Only 5% (1/19) of cases with surface and MMI progressed. On univariate analysis, only MMI and abnormal/positive cytology were significantly associated with increased pelvic recurrence (MMI p = 0.0059, cytology p = 0.0036) and worse DFS (MMI p = 0.0018, cytology p = 0.0054). Two patients given adjuvant treatment developed new gynecologic malignancies. Conclusion. In our study, patients with limited UPSC/CC disease involving a polyp who have complete workup did well without adjuvant therapy, with recurrence rates similar to UPSC/CC stage IA disease. Late and extensive pelvic relapses may occur in the few who do relapse. © 2013 Elsevier Inc. All rights reserved.
Introduction Endometrial cancer is the fourth most common cancer diagnosis in women with 49,560 new cases expected from 2013 [1]. While the 5 year survival for stage IA endometrioid adenocarcinoma is approximately 99% [2], type II subtypes are known to carry a worse prognosis. Included among type II are uterine papillary serous carcinoma (UPSC) and clear cell (CC) carcinoma, considered more
⁎ Corresponding author at: 4950 Sunset Blvd, Los Angeles, CA 90027, USA. Fax: +1 323 783 5927. E-mail address: [email protected] (C.N. Chang-Halpenny). 0090-8258/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ygyno.2013.10.010
high-risk endometrial carcinoma subtypes compared to endometrial adenocarcinoma. UPSC and CC appear to have higher tendency for lymphovascular invasion, with pattern of failure commonly involving spread via intraperitoneal or extra-abdominal invasion [3,4]. Prognostic factors for UPSC/CC appear to differ from endometrioid adenocarcinoma. Only stage has consistently been shown to correlate with survival, while myometrial invasion (MMI) has prognostic significance in some but not all studies [4–8]. No standard treatment regimen exists for early stage UPSC or CC, and stage I–II disease has variably been treated with observation, radiation, chemotherapy or combination modality treatment [8–11]. In addition, radiation options include therapy given by external beam (EBRT) to the pelvis or by high-dose rate vaginal
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brachytherapy (VB). Recent papers suggest VB alone may be adequate adjuvant treatment for patients with surgical stage I papillary serous or clear cell carcinoma, given subsequent low vaginal recurrence rates after VB from 0% to 3% and pelvic recurrence of 4–9% [12–14]. Overall recurrence rates for FIGO 2002 stage IA UPSC from retrospective studies have been reported from 9% to 11%, and up to 13% for stage IA by currently used FIGO 2009 criteria [7,15]. Observation has been proposed as a reasonable option for stage IA disease, particularly if no myometrial invasion is present [15]. Endometrial cancer confined to a polyp is a clinical scenario that offers particular difficulty given rarity of disease and limited available published data. Given the limited extent of disease but aggressive biologic behavior of UPSC/CC it is unclear whether adjuvant therapy is warranted. While case reports and small series have been published mainly in the pathology literature [16–19], these often include all stages of UPSC, with inconsistent description of the adjuvant treatment given or details of patients' clinical outcomes. We conducted a retrospective review of our institution's incidence and clinical outcomes of patients with surgical stage IA UPSC/CC involving a polyp observed after surgery or given adjuvant therapy (radiation, chemotherapy, or both). Materials and methods Following Institutional Review Board approval, we queried our institution's Cancer Registry for cases of endometrial cancer. Based on stage and histology, we identified 236 cases of stage IA pure UPSC, pure CC or mixed endometrial cancer, diagnosed from 1995 to 2011. The mixed endometrial cancer patients included data of all histologic subtypes, which we then sorted for UPSC/CC. The International Federation of Gynecology and Obstetrics (FIGO) previously defined stage IA disease as endometrial cancer with no myometrial invasion (MMI). Starting in 2009, patients with less than half MMI were also included in our study based on changes in definition of FIGO IA criteria. Pathology reports were reviewed for mention of polyp involvement with carcinoma. Classically, the pathological definition of a polyp is a grossly pedunculated mass composed of cystically dilated glands with fibrous stroma and thick walled blood vessels, associated with a stalk. Endometrial cancer found only in the polyp was considered confined to and arising from polyp. It is possible that cases with MMI or surface invasion had cancer arising from elsewhere in the endometrium instead of from the polyp itself, but typically there was limited extension outside of polyp since only stage IA disease was included. Statistical analysis included Kaplan–Meier estimates for 5year pelvic recurrence-free survival (RFS), disease-free survival (DFS) and overall survival (OS). Time to event was calculated from date of surgical staging. Log-rank analysis was used for univariate analysis to determine possible prognostic variables. The variables looked at in our study were age (≤60 or N60 years), adjuvant treatment (yes/no), LVI (yes/no), cytology (abnormal or positive versus negative), adenomyosis (yes/ no), endometrial intraepithelial neoplasia (yes/no), MMI (yes/no), and tumor spread on endometrial surface (yes/no). Due to small number of events, multivariate analysis was not conducted. GraphPad Prism (version 6.0) was used for analysis. Results We identified 51 cases of stage IA UPSC, CC or mixed UPSC/CC involving a polyp, from 1997 to 2011. An additional two patients qualified, but lacked sufficient follow-up data. Medical records of the 51 patients were reviewed for work-up, potential prognostic factors, and clinical outcomes. Slides were reviewed with a gynecologicaloncology pathologist specialist if there were incomplete reports, if patients had later progression of disease, or if later development of other gynecologic malignancies occurred. All patients underwent surgical staging with hysterectomy (typically abdominal or laparoscopic, one with radical hysterectomy)
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and bilateral salpingo-oophrectomy. Cytology specimens were collected from peritoneal fluid obtained during hysterectomy. Lymph node dissection of para-aortic (PA) and pelvic lymph nodes (PLND) was done for 32 patients (63%) with average of 20 dissected nodes. One patient had PA dissection only, 9 had PLND only and an additional 9 either refused or did not have any dissection done. Cytology was known for 40 patients (78.4%), of which 2 were positive for malignant cells and 3 had “atypical” cells. Omental biopsy was done for 26 patients (51%), all negative. Mean follow-up from date of surgical staging was 58.3 months (median follow-up 45.2 months, from 1.8 to 188.2 months). Median follow-up for patients treated who are NED and still alive was 33.6 months. The majority of patients had pure UPSC (66.7%), the fewest had pure CC (7.8%) and the remainder had mixed UPSC/CC/ adenocarcinoma (25.5%). Median age was 65 years at time of diagnosis. Six patients were nulliparous (11.7%). Median BMI was 41 and 20% of patients had previous endocrine treatment for breast cancer. See Table 1 for additional characteristics. Five patients had MMI and extent of MMI ranged from 3% to 30%. Polyp size was reported for 36 patients and tumor size reported for 15 patients. Six patients had multiple polyps on gross pathology, of which two had multiple polyps involved with tumor (one superficial and limited to polyps and the other appearing to arise from polyps and limited to endometrium with no MMI). Twenty-five patients had disease confined to polyp, defined as only involving the polyp with no MMI or endometrial surface spread beyond polyp (see Fig. 1). An additional 7 patients had cancer on endometrial biopsy or curettage (arising in a polyp) but no residual disease at time of hysterectomy. Thus, in total, 32 patients had disease confined to polyp, either before or after hysterectomy. Table 1 Clinical and pathologic characteristics. Characteristics
Value (%)
Median age Race
65 (51–85) years 2 (4%) 16 (31%) 9 (18%) 24 (47%) 10 (20%) 35 (68.6%) 6 (11.8%) 6 (11.8%) 4 (7.8%) 3 (5.9%) 21 (41%) 13 (25.5%) 7 (13.7%) 1 (2%) 32 (63%) 20 1 (2%) 2 9 (18%) 11 9 (18%) 2 (4%) 3 (6%) 26 (51%) 34 (66.7%) 4 (7.8%) 13 (25.5%) 32 (63%) 25 (49%) 7 (14%) 14 (27%) 1 (2%) 4 (7.7%) 1.2 (0.5 to 4) cm 3 (0.6 to 8.5) cm 17 (33%) 1 (2%) 2 (4%) 8 (16%)
Asian Black Hispanic White History of endocrine therapy for breast cancer Presenting symptoms Vaginal bleeding Abnormal pap Abnormal imaging Abdominal pain/pressure Unknown Preoperative imaging CT chest, abdomen, pelvis CT abdomen, pelvis MRI pelvis Lymph node dissection Para-aortic and pelvic Mean# dissected Para-aortic only Mean# dissected Pelvic only Mean# dissected Refused/not done Cytology Positive Atypical Omental biopsy performed Yes Histology UPSC CC Mixed UPSC/CC Confined to polyp before or after TAH Polyp only after TAH No residual disease after TAH Endometrial surface spread only Myometrial invasion (MMI) only Both surface spread and MMI Size of tumor (median) Size of polyp (median) Adenomyosis Lymphovascular invasion Outside of polyp Within polyp Endometrial intraepithelial neoplasia
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Fig. 1. H&E stains of endometrial polyp with serous carcinoma (left side low powered field at 4× magnification and right side high powered at 10× magnification).
Adjuvant treatment
Outcomes
Eighty percent of patients were followed with observation alone (41 patients). Of the ten patients who did receive adjuvant treatment, 3 had chemotherapy alone, 1 had radiation alone and 6 had combined modality treatment (see Table 2). Median time from staging surgery to adjuvant treatment was 1.6 months (0.62 to 3.42 months). Patients treated had either evidence of myometrial invasion on pathology, lacked lymph node dissection, cytology or omental biopsy, or had positive or atypical cytology from intraoperative pelvic washings. The usual chemotherapy given was carboplatin and paclitaxel. Usual EBRT dose was 4500 cGy and VB dose 2100 cGy. The single patient treated with radiation alone was given VB to 2100 cGy over three fractions. This patient died 5 months later from disease unrelated to cancer or treatment. Combined modality treatment was given sequentially with chemotherapy followed by radiation, except for one case. For that patient, 2 cycles of carboplatin and paclitaxel were given, followed by pelvic EBRT to 4500 cGy, then VB to 1400 cGy, then an additional cycle of chemotherapy. Brachytherapy was typically given to 5 cm length and 0.5 cm depth. Toxicity was scored per both Radiation Therapy Oncology Group and National Cancer Institute Common Toxicity Criteria. All patients given chemotherapy had some degree of peripheral neuropathy (grade 2 for seven patients, grade 1 for one patient, and grade 3 for one patient). Two patients also experienced grade 1 arthralgia. One patient developed supraventricular tachycardia requiring cardioversion. No grade 3 or 4 GI or GU radiation related toxicities and no grade 4 hematologic toxicities were reported.
At the time of analysis, 11 patients had died, with 3 deaths from progression of their original endometrial malignancies, 2 from progression of new gynecologic primaries and the remainder from non-malignant disease, including cardiac and renal etiologies. OS was 78.4% and DFS was 92.5%. Disease progression occurred in 4/51 patients (7.8%) in our study, including in one patient given adjuvant treatment. Time to recurrence ranged from little over one year to almost 7 years after initial surgery. All four patients developed pelvic recurrence, with either extensive carcinomatosis (including to the abdomen for one patient) or lymphadenopathy or both. There were no vaginal recurrences. Of those who progressed, one patient had myometrial invasion (3%) and spread outside polyp onto the endometrial surface for which she received 5 cycles of adjuvant carboplatin and paclitaxel followed by VB to 2100 cGy. Despite this, she experienced pelvic recurrence 2.7 years later, was given surgical debulking and chemotherapy but had functional decline and died of disease. The remaining three patients who progressed had not previously received adjuvant treatment, as two patients had disease confined only to polyp and an additional patient had no residual disease seen on hysterectomy after polypectomy. Thus, in total, 3/32 patients (9.4%) who had disease confined to polyp progressed. One patient had isolated pelvic mass, for which she was given salvage chemotherapy and external beam radiation with boost to gross disease. She responded well, with negative PET CT and is currently alive with no evidence of disease. Of the other two patients with recurrence, one progressed despite salvage chemotherapy (with lung nodule, skin nodules and extension to bladder) and the other went on hospice rather than receive salvage treatment. See Table 3 for details regarding patients who progressed. Surprisingly, two patients were later found to have new gynecologic malignancies less than 20 months after initial staging surgery; rhabdosarcoma and carcinosarcoma, respectively. Diagnosis of rhabdosarcoma was made after one patient was noted to have abnormal tissue at vaginal cuff while undergoing adjuvant treatment with EBRT. Pelvic CT showed new right pelvic side wall mass and workup with biopsy of vaginal mass revealed rhabdosarcoma. The second patient was diagnosed 20 months after completion of adjuvant treatment (chemotherapy and VB) with findings of elevated CA125 with ascites and peritoneal implants on imaging. Debulking of tumor revealed carcinosarcoma. Slides for these patients (from biopsy, hysterectomy and at time of recurrence) were reviewed with a gynecological oncology pathologist specialist, who confirmed both the initial diagnosis (of UPSC or CC) and subsequent new gynecologic primary. These patients
Table 2 Observation versus adjuvant treatment and outcomes. Adjuvant treatment Intervention Observation after surgery Adjuvant treatment Adjuvant treatment details: Chemotherapy alone Vaginal brachytherapy (VB) alone Sequential chemoradiation External beam RT Chemotherapy and: External beam, then VB VB
f
Abbreviations: RT = radiation.
Recurrence
Death
41 (80%) 10 (20%)
3 (7.3%) 1 (10%)
2 (4.9%) 1 (10%)
3 (6%) 1 (2%)
0 0
0 0
6 (12%) 2 3 1
0 0 0 1
0 0 0 1
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Table 3 Characteristics of patients with recurrence. ID
Age
Histology
Confined to polyp
Disease beyond polyp
LVI
#Pelvic LN
#PA LN
Omental biopsy
Cytology
Adjuvant therapy
TTR (years)
First recurrence
DFS (years)
Vital status
1 2
56 62
Pure UPSC Mixed UPSC
+ −
− +a
− −
13 16
7 0
Not done Not done
− Atypical
2.87 1.11
Pelvic mass along side-wall Pelvic carcinomatosis, LAD
3.40 1.63
Alive, NED Died of disease
3
70
Mixed UPSC/CC
+b
−
−
14
2
Negative
−
− Chemotherapy then VB −
2.71
4.48
Died of disease
4
68
Mixed UPSC
+
−
−
2
2
Negative
−
−
6.83
Pelvic/abdominal carcinomatosis, ascites Pelvic/retroperitoneal LAD, colon implants
7.92
Died of disease
Abbreviations: UPSC = uterine papillary serous carcinoma, CC = clear cell, LVI = lymphovascular invasion, LN = lymph node, VB = vaginal brachytherapy, TTR = time to recurrence, LAD = lymphadenopathy, RT = radiation, DFS = disease free survival, NED = no evidence of disease. a 3% myometrial invasion, superficial spread at endometrial surface. b Tumor found with polypectomy but none after TAH.
died of disease related to sarcoma but were not considered to have progressed from original UPSC/CC. Estimated 5year Kaplan–Meier rate of pelvic RFS was 92.1%, DFS was 93%, and OS was 80.6% (see Fig. 2). On univariate analysis, only positive/
atypical cytology (HR 12.33, p = 0.0036) and presence of MMI (HR 11.58, p = 0.0059) were significantly associated with pelvic recurrence (see Fig. 3). Cytology was also associated with worse DFS (HR 12.63, p = 0.0054) and OS (HR 9.09, p b 0.0001). Adjuvant treatment was initially associated with shorter interval from diagnosis to death or progression, but was not significant after the two patients who died from new gynecologic primaries were excluded. Disease beyond polyp in the form of MMI had worse DFS (HR 15.63, p = 0.0018) and OS (HR 4.697, p = 0.0253), and superficial spread of tumor on endometrial surface was associated with worse OS (HR3.25, p = 0.0464). Discussion
Fig. 2. Kaplan–Meier survival curves for all 51 patients.
To our knowledge, this is the largest series reported of stage IA UPSC/CC involving a polyp, with 51 patients in total, 32 of which had disease limited to polyp either at time of hysterectomy or at time of biopsy. Our investigation is limited in retrospective nature (heterogeneity in work-up and staging, variable follow-up time) and by the rarity of this disease, but contributes to the limited body of knowledge on this topic. Previous series have been small with conflicting data, citing recurrence rates from 0% to 33% [17,18,20]. Trahan et al. looked at UPSC “arising” from a polyp and found 3/9 (33%) cases of stage IA disease progressed, two of whom had received adjuvant radiation [17]. Wheeler et al. looked at 21 cases of UPSC in polyps, of which 0/6 stage IA patients progressed (with no adjuvant treatment) after median follow-up of 50 months [20]. Fader et al. found that in their series, 19 patients had disease confined to polyp, with a recurrence rate of 1/19 with noncurable extrapelvic relapse but no recurrences in patients with no residual uterine disease [21]. In contrast, one of the four patients found to progress in our study had no residual disease after hysterectomy but relapsed despite this. For “minimal serous carcinoma”, including intraepithelial serous carcinoma and superficial serous carcinoma, Hui et al. found 14 patients with stage IA UPSC confined to polyp, 0/12 of whom progressed (2 lost to followup), albeit with short follow-up [18]. We found 3/32 (9.4%) with disease confined to polyp progressed and only 5% (1/19) of cases with surface and MMI progressed. Thus, limited UPSC/CC involving a polyp appears to have similar progression rates with minimal spread beyond polyp (in form of endometrial surface spread) versus disease confined only to polyp (unless MMI is present). In our study, 4/51 (7.8%) of all stage IA polyp patients progressed. Estimated 5 year Kaplan–Meier pelvic recurrence rate was 7.9%. Our numbers are similar to the rates of recurrence cited for larger studies of stage I UPSC not necessarily involving a polyp, around 9–13% [7,15]. Specifically, Fader et al. found 16/124 (13%) recurrences for cases that would currently be FIGO IA, 39% of whom did not receive adjuvant treatment after surgery [7]. Of note, recurrence rates in patients with surgical stage IA by FIGO 2002 criteria (i.e. limited to endometrium) has been from 0% to 33% in older series with less than 10 patients [9,11,22–25]. While Havrilesky et al. demonstrated lower risk of
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Fig. 3. Kaplan–Meier survival curves of significant variables for pelvic recurrence free survival, a) cytology status (known for 40 patients) and b) presence of MMI (known for all patients).
recurrence with disease limited to the endometrium (9% vs 29%) compared to having MMI, MMI has not been borne out as a significant prognostic factor in other studies for UPSC [4,6]. Carcangiu et al. found that survival (for 19 patients) with UPSC confined to polyp, mucosa or with no residual cancer was not significantly different from those with stage I with MMI or LVI. In our study, only five patients had MMI, all received adjuvant treatment and one progressed despite this. On univariate analysis, MMI was found to be significant for pelvic recurrence, DFS, and OS and could be a prognostic factor to consider when discussing adjuvant treatment. Our predominant pattern of failure was via peritoneal/abdominal carcinomatosis and pelvic lymphadenopathy. No patients relapsed at the vaginal cuff, even in observed patients. Other studies have cited extrapelvic recurrences from 50% to 80% for early stage UPSC, while recent studies looking at patients treated with vaginal brachytherapy (with or without chemotherapy) had a lower rates from 10% to 11% [7,12,13,15]. Notably, there were patients in our study who were missing components of staging, including omental biopsy (not done for 25 patients) or lymph node dissection (not done for 9 patients). It is possible that some patients may have been upstaged with more complete surgical staging and we do recommend complete surgical staging, including lymph node staging. Given predilection for intraperitoneal or extrapelvic spread, cytology results should be taken into consideration for adjuvant treatment. In our study, atypical or positive cytology was prognostic for pelvic recurrence, DFS and OS. Case series have also shown that serous carcinoma limited to the endometrium, or even limited to polyp can present with simultaneous extrauterine tumors [18,26], and recurrence rates are higher for patients with incomplete workup [3,17]. We also reported that 20% of our patient had history of endocrine therapy for breast cancer. Endometrial polyps are a common pathology found after postmenopausal tamoxifen exposure and one study found 3% rate of malignant features in this cohort of patients compared to 0.48% of control population [27]. The relationship between tamoxifen exposure and development UPSC/CC in a polyp is unclear at present, given rarity of the histology, but may be a relevant area to explore regarding pathogenesis of disease. Interestingly, in our study, 2/51 (4%) patients developed new gynecologic primaries, one with rhabdosarcoma during EBRT and another with carcinosarcoma over a year after adjuvant chemoradiation. Pathology review confirmed distinct primaries rather than misdiagnoses. It is unclear whether these patients were more prone to these malignancies, if the two malignancies were related, or somehow related to the treatment given (although unlikely, given the timing). Further studies or better understanding of the tumor biology may shed light on this phenomenon.
Given the low recurrence rate, observation could be considered for patients with stage IA UPSC or CC confined to a polyp, if appropriate surgical staging with TAH, BSO, PA/PLND, omental biopsy and washings have been done. This is tempered with our lack of adequate prognostic factors for UPSC/CC. Options of adjuvant therapy could include chemotherapy with or without external beam radiation or vaginal brachytherapy. Townamchai et al. have shown lower-dose VB regimen to be a reasonable treatment option for early stage UPSC/CC [14]. Chemotherapy as primary adjuvant therapy has been supported by other studies [7,11,21]. The timing of recurrence occurred at varied intervals in our study, at 1, 2.7, 2.9 and even 6.8 years following diagnosis. Patients are typically followed closely for up to 5 years, but may benefit from longer follow-up and serial CA-125 levels (two of the patients who progressed in our study had rapid elevation of CA125 at the time of recurrence). If followed closely, patients who recur might be salvaged with chemoradiation if disease is localized, as was the case for one of our patients. Even for patients with UPSC/CC confined to a polyp, close follow-up is certainly warranted.
Conclusions In our study, stage IA UPSC or CC involving a polyp (with limited spread outside of polyp) appeared to have a low recurrence rate similar to that of other stage IA UPSC/CC patients, although late relapses did occur with relapse pattern of failure consisting of extensive pelvic recurrence. Presence of MMI or abnormal cytology may warrant consideration of adjuvant treatment. If recurrence occurs, confirmatory tissue sample may be useful if feasible as it is not impossible for appearance of a new gynecologic primary. Conflict of interest statement None
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