European Journal of Obstetrics & Gynecology and Reproductive Biology 181 (2014) 163–170
Contents lists available at ScienceDirect
European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
Review
Clinical characteristics and outcomes of uterine tumors resembling ovarian sex-cord tumors (UTROSCT): a systematic review of literature Erin A. Blake a,b, Todd B. Sheridan c, Karen L. Wang d, Tsuyoshi Takiuchi e, Michiko Kodama e, Kenjiro Sawada e, Koji Matsuo a,f,* a Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Los Angeles County Medical Center, University of Southern California, Los Angeles, CA, USA b Department of Obstetrics and Gynecology, University of Colorado, Denver, CO, USA c Department of Pathology, Mercy Medical Center, Baltimore, MD, USA d Department of Obstetrics and Gynecology, Mountain Area Health Education Center, Asheville, NC, USA e Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan f Norris Comprehensive Cancer Center, Los Angeles, CA, USA
A R T I C L E I N F O
A B S T R A C T
Article history: Received 21 February 2014 Received in revised form 19 July 2014 Accepted 29 July 2014
Uterine tumor resembling ovarian sex-cord tumors (UTROSCT) is an extremely rare type of uterine tumor, and its clinical characteristics are not fully understood. A systematic literature search was conducted in PubMed and MEDLINE using the keywords, ‘‘uterine tumors resembling ovarian sex cord tumors’’, limited to case reports. Clinico-pathological characteristics and survival data were abstracted and evaluated for the analysis. Among 43 cases reporting UTROSCT, Type I (endometrial stromal tumors with sex cord-like elements, ESTSCLE) and Type II (classic UTROSCT) were reported in 5 (11.6%) and 17 (39.5%), respectively, and nearly half of reported UTROSCT did not subcategorize the histology pattern into Type I or II (unspecified, n = 21, 48.8%). Mean age was 52.2. The two most common symptoms were postmenopausal vaginal bleeding (44.2%) and abnormal menstruation (39.5%). The majority underwent total hysterectomy with adnexectomy (65.1%) followed by hysterectomy alone (18.6%) and tumor resection alone (14.0%). Mean tumor size was 6.2 cm, and extra-uterine spread was seen in 7.0%. By immunohistochemistry, calretinin expression was significantly correlated with CAM5.2, inhibin, and progesterone receptor expression (all, p < 0.05). In survival analysis, disease-free survival (DFS) rates for all 43 cases at 1, 2, and 5 years for all cases were 97.0%, 92.7%, and 69.7%, respectively. Among recurrent cases, median time to recur was 24 months (range 9–48). Decreased DFS was significantly associated with pelvic pain (2-year rate, 81.8% versus 94.7%, p = 0.006), histology subcategory (Type I versus II, 23.8% versus 100%, p = 0.006), tumor size 10 cm (75.0% versus 100%, p = 0.046), cervical/extra-uterine metastasis (46.7% versus 100%, p = 0.024), and lymphovascular space involvement (50% versus 100%, p = 0.002). Treatment patterns were not statistically associated with DFS (hysterectomy, p = 0.28; and adnexectomy, p = 0.38). When histology patterns were examined, Type II disease was associated with less aggressive tumor behavior when compared to Type I disease: extrauterine spread (Type I versus II, 40% versus 5.9%, p = 0.007) and lymphovascular space invasion (50% versus 6.7%, p = 0.012). Among 17 cases of Type II disease, disease recurrence was reported in 1 (5.9%) case at 3 years after the initial treatment. In conclusion, our study showed that UTROSCT was often not subcategorized. Because classic UTROSCT has a distinct clinical outcome and characteristic histological patterns when compared to ESTSCLE, distinguishing UTROSCT from ESTSCLE is an integral component of the diagnosis. While classic UTROSCT typically has a favorable prognosis, it has been known to develop a late recurrence. If risk factors for recurrence are absent, both hysterectomy and mass resection alone are possible options for management. ß 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Uterine tumors resembling ovarian sex cord tumors Risk factor Survival Review
* Corresponding author at: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Los Angeles County Medical Center, University of Southern California, 2020 Zonal Avenue, IRD520, Los Angeles, CA 90033, USA. Tel.: +1 323 226 3416; fax: +1 323 226 3427. E-mail address: [email protected] (K. Matsuo). http://dx.doi.org/10.1016/j.ejogrb.2014.07.050 0301-2115/ß 2014 Elsevier Ireland Ltd. All rights reserved.
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E.A. Blake et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 181 (2014) 163–170
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . Materials and methods . . . . . . . . . . . . . . . . . Source of the study. . . . . . . . . . . . . . . Study selection . . . . . . . . . . . . . . . . . . Clinical information . . . . . . . . . . . . . . Statistical analysis. . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Characteristics and symptoms . . . . . . Treatment patterns . . . . . . . . . . . . . . . Pathology findings . . . . . . . . . . . . . . . Survival outcomes. . . . . . . . . . . . . . . . Salvage treatment for recurrent case . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . Disclosure. . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding support. . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Introduction Uterine tumor resembling ovarian sex-cord tumor (UTROSCT) is a rare, relatively newly defined clinical entity. The original identification of UTROSCT as a histopathological entity by Clement and Scully in 1976 included two distinct tumors of unclear origin; hypothesized originating cells included endometrial stromal cells, adenomyosis, stromal myosis, endometriosis, or multipotential cells within the myometrium [1]. Since then, the entity has been recently delineated into the two distinct subtypes. Type I tumors, known as endometrial stromal tumors with sex cord-like elements (ESTSCLE), have been recognized to have more malignant potential than Type II, and the outcome of Type I disease is contingent upon type, grade, and stage of the underlying stromal neoplasm [2]. Type II tumors, comprising classic UTROSCTs, are considered to be of low-grade malignant potential secondary to occasional recurrence, although they typically exhibit benign behavior [2]. While both ESTSCLE and UTROSCT most likely arise from pluripotential uterine mesenchymal cells, UTROSCT is predominantly differentiated into sex-cord components, unlike ESTSCLEs, which typically express only one sex-cord marker [2]. This classification of UTROSCT into two histologic subtypes is relatively new, and a large portion of literature refers to UTROSCT generally without subcategorization. Diagnosis of UTROSCT is primarily based upon morphologic features on hematoxylin/eosin staining with confirmation by immunohistochemical staining. Positive staining for at least two sex-cord markers is supportive, including calretinin and at least one other marker [3–5]. Other commonly expressed markers include are inhibin, cluster of differentiation 99 (CD99), and Melan A [5]. Additionally, these tumors are variably immunoreactive for mesenchymal and epithelial elements as well; frequently positive stains include vimentin, desmin, cytokeratin, epithelial membrane antigen (EMA), CD10, and estrogen/progesterone receptors (ER/PR) [3]. A review of immunohistochemical markers associated with UTROSCTs identified inhibin as the most specific marker and calretinin as the most sensitive marker of the tumor [3,6,7]. Given its rarity, the diagnosis of UTROSCT is usually made postoperatively per histopathological analysis. In addition, current available literature mainly focuses on the diagnosis of UTROSCT, and there is scant information available to define the clinical characteristics and outcomes of UTROSCT. The purpose of this study was to elucidate clinical, as opposed to pathological, characteristics of UTROSCT in order to best recognize the condition in clinical practice. Furthermore, optimal treatment for the disease has yet to be defined. As such, by conducting a detailed literature
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review of cases of UTROSCT, optimal treatment methodologies for the disease will be proposed. Materials and methods Source of the study This review was conducted based on MOOSE guidelines for systematic literature searches using PubMed and MEDLINE between January 1955 and December 2013 [8]. Keywords searched included ‘‘UTROSCT’’ or ‘‘uterine tumor resembling ovarian sex cord tumor’’ limited to English literature. Study selection Case reports or case series with a detailed description of both clinical and histopathological findings were included. Exclusion criteria included review papers, cases with no or inadequate clinical information to extrapolate data from, such as cases without details regarding symptoms and/or survival, duplicated reports from different journals, and cases of confirmed stromomyoma. Due to the uncertainty whether tumors were classified correctly into ESTSCLE or UTROSCT, all uterine tumors that had sex-cord elements were included in this study. Clinical information Information abstracted from the articles included demographic data, such as age, gravity, and parity, past medico-surgical history, and clinical characteristics including chief complaint and physical exam findings. Imaging modality was recorded when available, along with treatment course. Details of treatment modalities were collected. Macroscopic pathology and histopathology results were collected in conjunction with immunohistochemical staining. Immunohistochemistry studies tested in more than 10 cases were considered for statistical evaluation. These included actin, calretinin, CAM5.2, CD10, CD56, CD99, desmin, EMA, ER, keratin, inhibin, PR, and vimentin. Survival outcomes and other relevant survival data, including metastatic site at diagnosis, recurrence site, and subsequent pregnancy were also collected. Statistical analysis For the data evaluation, descriptive analysis of characteristics of UTROSCT was performed expressed with a number (%) for categorical variables. Fisher exact test or chi-square test was used
E.A. Blake et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 181 (2014) 163–170
to examine the statistical significance of categorical variables expressed with odds ratio (OR) and 95% confidence interval (CI). Normality of continuous variables was evaluated with Kolmogorov–Smirnov test and expressed as a mean (SD) or median (range). Disease-free survival (DFS) was defined as the time interval between the date of surgery for treatment and the first recurrence or last follow-up date. Overall survival (OS) was defined as the time interval between the date of surgery and the date of death due to UTROSCT or last follow-up date. Survival curves were constructed by Kaplan–Meier method, and statistical significance was determined by Log-lank test. Two-tailed tests with p < 0.05 were considered significant in our study. The statistical significance of the data was determined using Statistical Package for Social Scientists software (SPSS, Inc., version 12.0, Chicago, IL). Results Characteristics and symptoms There were 35 articles with a total of 43 cases of tumors classified as UTROSCT identified during the study period [2,7,9– 14,3,15–40]. Among 43 cases reporting UTROSCT, Type I and Type II were reported in 5 (11.6%) and 17 (39.5%), respectively, and nearly half of reported UTROSCT did not subcategorize the histology pattern into Type I or II (unspecified, n = 21, 48.8%). Patient demographics are shown in Table 1. The majority of cases were published in 2001 or later (79.1%). The majority of publications were from Europe (72.1%). Mean age at the time of diagnosis of UTROSCT was 52.2 (18.2), and age younger than 40 accounted for less than one third of cases (30.2%). There were 15 cases that described parity, and nearly half were nulliparous (53.3%). There were 4 (9.3%) cases with a personal history of breast cancer taking
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tamoxifen. There was 1 (2.3%) case of synchronous of ovarian sexcord stromal tumor diagnosed at the time of primary surgery [9], and another 1 (2.3%) case of multiple gastrointestinal stromal tumors diagnosed at the time of recurrence of UTROSCT [13]. For presenting symptoms, postmenopausal vaginal bleeding (44.2%) and abnormal menstruation (39.5%) were the two most common symptoms, followed by pelvic pain (18.6%). There were 2 (4.7%) cases that UTROSCT was incidentally diagnosed during the treatment of uterine prolapse [22]. Ultrasonography was commonly used for preoperative imaging (53.5%) while CT and MRI were infrequently used (14.0%). Treatment patterns Characteristics of management for tumors classified as UTROSCT are shown in Table 2. Total hysterectomy with bilateral adnexectomy was the most common treatment pattern (65.1%) followed by total hysterectomy alone (18.6%) and mass resection alone (14.0%). There was 1 (2.3%) case that underwent definitive radiotherapy without hysterectomy due to morbid obesity [22]. Treatment patterns were significantly different when age and parity factors were taken in account. Patients with age younger than 40 were significantly less likely to receive total hysterectomy with adnexectomy (14.3% versus 85.7%) and more likely to undergo mass resection alone (83.3% versus 16.7%) when compared to patients with age of 40 or older (p = 0.004, Table 3). Similarly, nulliparous patients were significantly more likely to proceed with mass resection alone (100% versus 0%) when compared to multiparous patients (p = 0.003, Table 3). There was one case that postoperative radiotherapy was given after hysterectomy [19]. There were three cases with reported pregnancy results [10,18,35]. Of those, two cases were postoperative conceptions during the follow-up (28 and 32-year-old nulligravid) [10,18], and the other
Table 1 Demographics and presenting symptom of UTROSCT.
Cases Year of publication 1955–2000 2001–2013 Area of publication Europe North America Asia Africa Age 60 Paritya Nullipara Multipara Past history Breast cancer Tamoxifen use Presenting symptom Postmenopausal bleeding Abnormal menstruation Pelvic pain Mass sensation Incidental Diagnostic modality US CT MRI
All reported
Type I (ESTSCLE)
Type II (UTROSCT)
Unspecified
N = 43 (100%)
n = 5 (11.6%)
n = 17 (39.5%)
n = 21 (48.8%)
3 (17.6%) 14 (82.4%)
4 (19.0%) 17 (81.0%)
13 (76.5%) 1 (5.9%) 3 (17.6%) 0 45.9 (18.1) 7 (41.1%) 6 (35.3%) 4 (23.5%)
16 (76.2%) 3 (14.3%) 2 (9.5%) 0 58.8 (17.2) 4 (19.0%) 3 (14.3%) 14 (66.7%)
p value
0.53 9 (20.9%) 34 (79.1%)
2 (40%) 3 (50%)
0.046 31 (72.1%) 6 (14.0%) 5 (11.6%) 1 (2.3%) 52.2 (18.2) 13 (30.2%) 11 (25.6%) 19 (44.2%)
2 (40%) 2 (40%) 0 1 (20%) 46.2 (15.8) 2 (40%) 2 (40%) 1 (20%)
8 (53.3%) 7 (46.7%)
0 2 (100%)
6 (75%) 2 (25%)
2 (40%) 3 (60%)
4 (9.3%) 4 (9.3%)
1 (20%) 1 (20%)
1 (5.9%) 1 (5.9%)
2 (9.5%) 2 (9.5%)
0.075
0.13
19 17 8 3 2
(44.2%) (39.5%) (18.6%) (7.0%) (4.7%)
2 (40%) 2 (40%) 2 (40%) 0 0
20 (46.5%) 6 (14.0%) 6 (14.0%)
4 (80%) 1 (20%) 0
2 12 3 3 0
(11.7%) (70.6%) (17.6%) (17.6%)
8 (47.1%) 2 (11.7%) 4 (23.5%)
15 3 3 0 2
(71.4%) (14.3%) (14.3%)
0.63 0.63
(9.5%)
0.001 0.002 0.41 0.085 0.33
8 (38.1%) 3 (14.3%) 2 (9.5%)
0.24 0.90 0.29
43 cases reported as UTROSCT in the literature are grouped based on histology types (Type I, Type II, or unclassified). Mean (SD) or number (%) is shown. Chi-square test for p values. a 15 cases reported gravidity. Abbreviations: ESTSCLE, endometrial stromal tumors with sex cord-like elements; UTROSCT, uterine tumors resembling ovarian sex-cord tumors; US, ultrasonography; CT, computed tomography; and MRI, magnetic resonance imaging.
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Table 2 Treatment patterns of UTROSCT. All reported
Type I (ESTSCLE)
Type II (UTROSCT)
Unspecified
Cases
N = 43 (100%)
n = 5 (11.6%)
n = 17 (39.5%)
n = 21 (48.8%)
TAH + BSO TAH alone Mass resection alone Radiotherapy alone*
28 8 6 1
4 (80%) 0 1 (20%) 0
10 (58.8%) 3 (17.6%) 4 (23.5%) 0
14 5 1 1
(65.1%) (18.6%) (14.0%) (2.3%)
(66.7%) (23.8%) (4.8%) (4.8%)
p value
0.53
Number (%) is shown. p value for chi-square test. Abbreviations: ESTSCLE, endometrial stromal tumors with sex cord-like elements; UTROSCT, uterine tumors resembling ovarian sex-cord tumors; TAH, total abdominal hysterectomy; and BSO, bilateral salpingo-oophorectomy. * Definitive radiotherapy. Table 3 Treatment patterns based on age and parity. All cases
Parityb
Age 40
Contents lists available at ScienceDirect
European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
Review
Clinical characteristics and outcomes of uterine tumors resembling ovarian sex-cord tumors (UTROSCT): a systematic review of literature Erin A. Blake a,b, Todd B. Sheridan c, Karen L. Wang d, Tsuyoshi Takiuchi e, Michiko Kodama e, Kenjiro Sawada e, Koji Matsuo a,f,* a Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Los Angeles County Medical Center, University of Southern California, Los Angeles, CA, USA b Department of Obstetrics and Gynecology, University of Colorado, Denver, CO, USA c Department of Pathology, Mercy Medical Center, Baltimore, MD, USA d Department of Obstetrics and Gynecology, Mountain Area Health Education Center, Asheville, NC, USA e Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan f Norris Comprehensive Cancer Center, Los Angeles, CA, USA
A R T I C L E I N F O
A B S T R A C T
Article history: Received 21 February 2014 Received in revised form 19 July 2014 Accepted 29 July 2014
Uterine tumor resembling ovarian sex-cord tumors (UTROSCT) is an extremely rare type of uterine tumor, and its clinical characteristics are not fully understood. A systematic literature search was conducted in PubMed and MEDLINE using the keywords, ‘‘uterine tumors resembling ovarian sex cord tumors’’, limited to case reports. Clinico-pathological characteristics and survival data were abstracted and evaluated for the analysis. Among 43 cases reporting UTROSCT, Type I (endometrial stromal tumors with sex cord-like elements, ESTSCLE) and Type II (classic UTROSCT) were reported in 5 (11.6%) and 17 (39.5%), respectively, and nearly half of reported UTROSCT did not subcategorize the histology pattern into Type I or II (unspecified, n = 21, 48.8%). Mean age was 52.2. The two most common symptoms were postmenopausal vaginal bleeding (44.2%) and abnormal menstruation (39.5%). The majority underwent total hysterectomy with adnexectomy (65.1%) followed by hysterectomy alone (18.6%) and tumor resection alone (14.0%). Mean tumor size was 6.2 cm, and extra-uterine spread was seen in 7.0%. By immunohistochemistry, calretinin expression was significantly correlated with CAM5.2, inhibin, and progesterone receptor expression (all, p < 0.05). In survival analysis, disease-free survival (DFS) rates for all 43 cases at 1, 2, and 5 years for all cases were 97.0%, 92.7%, and 69.7%, respectively. Among recurrent cases, median time to recur was 24 months (range 9–48). Decreased DFS was significantly associated with pelvic pain (2-year rate, 81.8% versus 94.7%, p = 0.006), histology subcategory (Type I versus II, 23.8% versus 100%, p = 0.006), tumor size 10 cm (75.0% versus 100%, p = 0.046), cervical/extra-uterine metastasis (46.7% versus 100%, p = 0.024), and lymphovascular space involvement (50% versus 100%, p = 0.002). Treatment patterns were not statistically associated with DFS (hysterectomy, p = 0.28; and adnexectomy, p = 0.38). When histology patterns were examined, Type II disease was associated with less aggressive tumor behavior when compared to Type I disease: extrauterine spread (Type I versus II, 40% versus 5.9%, p = 0.007) and lymphovascular space invasion (50% versus 6.7%, p = 0.012). Among 17 cases of Type II disease, disease recurrence was reported in 1 (5.9%) case at 3 years after the initial treatment. In conclusion, our study showed that UTROSCT was often not subcategorized. Because classic UTROSCT has a distinct clinical outcome and characteristic histological patterns when compared to ESTSCLE, distinguishing UTROSCT from ESTSCLE is an integral component of the diagnosis. While classic UTROSCT typically has a favorable prognosis, it has been known to develop a late recurrence. If risk factors for recurrence are absent, both hysterectomy and mass resection alone are possible options for management. ß 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Uterine tumors resembling ovarian sex cord tumors Risk factor Survival Review
* Corresponding author at: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Los Angeles County Medical Center, University of Southern California, 2020 Zonal Avenue, IRD520, Los Angeles, CA 90033, USA. Tel.: +1 323 226 3416; fax: +1 323 226 3427. E-mail address: [email protected] (K. Matsuo). http://dx.doi.org/10.1016/j.ejogrb.2014.07.050 0301-2115/ß 2014 Elsevier Ireland Ltd. All rights reserved.
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E.A. Blake et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 181 (2014) 163–170
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . Materials and methods . . . . . . . . . . . . . . . . . Source of the study. . . . . . . . . . . . . . . Study selection . . . . . . . . . . . . . . . . . . Clinical information . . . . . . . . . . . . . . Statistical analysis. . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Characteristics and symptoms . . . . . . Treatment patterns . . . . . . . . . . . . . . . Pathology findings . . . . . . . . . . . . . . . Survival outcomes. . . . . . . . . . . . . . . . Salvage treatment for recurrent case . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . Disclosure. . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding support. . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Introduction Uterine tumor resembling ovarian sex-cord tumor (UTROSCT) is a rare, relatively newly defined clinical entity. The original identification of UTROSCT as a histopathological entity by Clement and Scully in 1976 included two distinct tumors of unclear origin; hypothesized originating cells included endometrial stromal cells, adenomyosis, stromal myosis, endometriosis, or multipotential cells within the myometrium [1]. Since then, the entity has been recently delineated into the two distinct subtypes. Type I tumors, known as endometrial stromal tumors with sex cord-like elements (ESTSCLE), have been recognized to have more malignant potential than Type II, and the outcome of Type I disease is contingent upon type, grade, and stage of the underlying stromal neoplasm [2]. Type II tumors, comprising classic UTROSCTs, are considered to be of low-grade malignant potential secondary to occasional recurrence, although they typically exhibit benign behavior [2]. While both ESTSCLE and UTROSCT most likely arise from pluripotential uterine mesenchymal cells, UTROSCT is predominantly differentiated into sex-cord components, unlike ESTSCLEs, which typically express only one sex-cord marker [2]. This classification of UTROSCT into two histologic subtypes is relatively new, and a large portion of literature refers to UTROSCT generally without subcategorization. Diagnosis of UTROSCT is primarily based upon morphologic features on hematoxylin/eosin staining with confirmation by immunohistochemical staining. Positive staining for at least two sex-cord markers is supportive, including calretinin and at least one other marker [3–5]. Other commonly expressed markers include are inhibin, cluster of differentiation 99 (CD99), and Melan A [5]. Additionally, these tumors are variably immunoreactive for mesenchymal and epithelial elements as well; frequently positive stains include vimentin, desmin, cytokeratin, epithelial membrane antigen (EMA), CD10, and estrogen/progesterone receptors (ER/PR) [3]. A review of immunohistochemical markers associated with UTROSCTs identified inhibin as the most specific marker and calretinin as the most sensitive marker of the tumor [3,6,7]. Given its rarity, the diagnosis of UTROSCT is usually made postoperatively per histopathological analysis. In addition, current available literature mainly focuses on the diagnosis of UTROSCT, and there is scant information available to define the clinical characteristics and outcomes of UTROSCT. The purpose of this study was to elucidate clinical, as opposed to pathological, characteristics of UTROSCT in order to best recognize the condition in clinical practice. Furthermore, optimal treatment for the disease has yet to be defined. As such, by conducting a detailed literature
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review of cases of UTROSCT, optimal treatment methodologies for the disease will be proposed. Materials and methods Source of the study This review was conducted based on MOOSE guidelines for systematic literature searches using PubMed and MEDLINE between January 1955 and December 2013 [8]. Keywords searched included ‘‘UTROSCT’’ or ‘‘uterine tumor resembling ovarian sex cord tumor’’ limited to English literature. Study selection Case reports or case series with a detailed description of both clinical and histopathological findings were included. Exclusion criteria included review papers, cases with no or inadequate clinical information to extrapolate data from, such as cases without details regarding symptoms and/or survival, duplicated reports from different journals, and cases of confirmed stromomyoma. Due to the uncertainty whether tumors were classified correctly into ESTSCLE or UTROSCT, all uterine tumors that had sex-cord elements were included in this study. Clinical information Information abstracted from the articles included demographic data, such as age, gravity, and parity, past medico-surgical history, and clinical characteristics including chief complaint and physical exam findings. Imaging modality was recorded when available, along with treatment course. Details of treatment modalities were collected. Macroscopic pathology and histopathology results were collected in conjunction with immunohistochemical staining. Immunohistochemistry studies tested in more than 10 cases were considered for statistical evaluation. These included actin, calretinin, CAM5.2, CD10, CD56, CD99, desmin, EMA, ER, keratin, inhibin, PR, and vimentin. Survival outcomes and other relevant survival data, including metastatic site at diagnosis, recurrence site, and subsequent pregnancy were also collected. Statistical analysis For the data evaluation, descriptive analysis of characteristics of UTROSCT was performed expressed with a number (%) for categorical variables. Fisher exact test or chi-square test was used
E.A. Blake et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 181 (2014) 163–170
to examine the statistical significance of categorical variables expressed with odds ratio (OR) and 95% confidence interval (CI). Normality of continuous variables was evaluated with Kolmogorov–Smirnov test and expressed as a mean (SD) or median (range). Disease-free survival (DFS) was defined as the time interval between the date of surgery for treatment and the first recurrence or last follow-up date. Overall survival (OS) was defined as the time interval between the date of surgery and the date of death due to UTROSCT or last follow-up date. Survival curves were constructed by Kaplan–Meier method, and statistical significance was determined by Log-lank test. Two-tailed tests with p < 0.05 were considered significant in our study. The statistical significance of the data was determined using Statistical Package for Social Scientists software (SPSS, Inc., version 12.0, Chicago, IL). Results Characteristics and symptoms There were 35 articles with a total of 43 cases of tumors classified as UTROSCT identified during the study period [2,7,9– 14,3,15–40]. Among 43 cases reporting UTROSCT, Type I and Type II were reported in 5 (11.6%) and 17 (39.5%), respectively, and nearly half of reported UTROSCT did not subcategorize the histology pattern into Type I or II (unspecified, n = 21, 48.8%). Patient demographics are shown in Table 1. The majority of cases were published in 2001 or later (79.1%). The majority of publications were from Europe (72.1%). Mean age at the time of diagnosis of UTROSCT was 52.2 (18.2), and age younger than 40 accounted for less than one third of cases (30.2%). There were 15 cases that described parity, and nearly half were nulliparous (53.3%). There were 4 (9.3%) cases with a personal history of breast cancer taking
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tamoxifen. There was 1 (2.3%) case of synchronous of ovarian sexcord stromal tumor diagnosed at the time of primary surgery [9], and another 1 (2.3%) case of multiple gastrointestinal stromal tumors diagnosed at the time of recurrence of UTROSCT [13]. For presenting symptoms, postmenopausal vaginal bleeding (44.2%) and abnormal menstruation (39.5%) were the two most common symptoms, followed by pelvic pain (18.6%). There were 2 (4.7%) cases that UTROSCT was incidentally diagnosed during the treatment of uterine prolapse [22]. Ultrasonography was commonly used for preoperative imaging (53.5%) while CT and MRI were infrequently used (14.0%). Treatment patterns Characteristics of management for tumors classified as UTROSCT are shown in Table 2. Total hysterectomy with bilateral adnexectomy was the most common treatment pattern (65.1%) followed by total hysterectomy alone (18.6%) and mass resection alone (14.0%). There was 1 (2.3%) case that underwent definitive radiotherapy without hysterectomy due to morbid obesity [22]. Treatment patterns were significantly different when age and parity factors were taken in account. Patients with age younger than 40 were significantly less likely to receive total hysterectomy with adnexectomy (14.3% versus 85.7%) and more likely to undergo mass resection alone (83.3% versus 16.7%) when compared to patients with age of 40 or older (p = 0.004, Table 3). Similarly, nulliparous patients were significantly more likely to proceed with mass resection alone (100% versus 0%) when compared to multiparous patients (p = 0.003, Table 3). There was one case that postoperative radiotherapy was given after hysterectomy [19]. There were three cases with reported pregnancy results [10,18,35]. Of those, two cases were postoperative conceptions during the follow-up (28 and 32-year-old nulligravid) [10,18], and the other
Table 1 Demographics and presenting symptom of UTROSCT.
Cases Year of publication 1955–2000 2001–2013 Area of publication Europe North America Asia Africa Age 60 Paritya Nullipara Multipara Past history Breast cancer Tamoxifen use Presenting symptom Postmenopausal bleeding Abnormal menstruation Pelvic pain Mass sensation Incidental Diagnostic modality US CT MRI
All reported
Type I (ESTSCLE)
Type II (UTROSCT)
Unspecified
N = 43 (100%)
n = 5 (11.6%)
n = 17 (39.5%)
n = 21 (48.8%)
3 (17.6%) 14 (82.4%)
4 (19.0%) 17 (81.0%)
13 (76.5%) 1 (5.9%) 3 (17.6%) 0 45.9 (18.1) 7 (41.1%) 6 (35.3%) 4 (23.5%)
16 (76.2%) 3 (14.3%) 2 (9.5%) 0 58.8 (17.2) 4 (19.0%) 3 (14.3%) 14 (66.7%)
p value
0.53 9 (20.9%) 34 (79.1%)
2 (40%) 3 (50%)
0.046 31 (72.1%) 6 (14.0%) 5 (11.6%) 1 (2.3%) 52.2 (18.2) 13 (30.2%) 11 (25.6%) 19 (44.2%)
2 (40%) 2 (40%) 0 1 (20%) 46.2 (15.8) 2 (40%) 2 (40%) 1 (20%)
8 (53.3%) 7 (46.7%)
0 2 (100%)
6 (75%) 2 (25%)
2 (40%) 3 (60%)
4 (9.3%) 4 (9.3%)
1 (20%) 1 (20%)
1 (5.9%) 1 (5.9%)
2 (9.5%) 2 (9.5%)
0.075
0.13
19 17 8 3 2
(44.2%) (39.5%) (18.6%) (7.0%) (4.7%)
2 (40%) 2 (40%) 2 (40%) 0 0
20 (46.5%) 6 (14.0%) 6 (14.0%)
4 (80%) 1 (20%) 0
2 12 3 3 0
(11.7%) (70.6%) (17.6%) (17.6%)
8 (47.1%) 2 (11.7%) 4 (23.5%)
15 3 3 0 2
(71.4%) (14.3%) (14.3%)
0.63 0.63
(9.5%)
0.001 0.002 0.41 0.085 0.33
8 (38.1%) 3 (14.3%) 2 (9.5%)
0.24 0.90 0.29
43 cases reported as UTROSCT in the literature are grouped based on histology types (Type I, Type II, or unclassified). Mean (SD) or number (%) is shown. Chi-square test for p values. a 15 cases reported gravidity. Abbreviations: ESTSCLE, endometrial stromal tumors with sex cord-like elements; UTROSCT, uterine tumors resembling ovarian sex-cord tumors; US, ultrasonography; CT, computed tomography; and MRI, magnetic resonance imaging.
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Table 2 Treatment patterns of UTROSCT. All reported
Type I (ESTSCLE)
Type II (UTROSCT)
Unspecified
Cases
N = 43 (100%)
n = 5 (11.6%)
n = 17 (39.5%)
n = 21 (48.8%)
TAH + BSO TAH alone Mass resection alone Radiotherapy alone*
28 8 6 1
4 (80%) 0 1 (20%) 0
10 (58.8%) 3 (17.6%) 4 (23.5%) 0
14 5 1 1
(65.1%) (18.6%) (14.0%) (2.3%)
(66.7%) (23.8%) (4.8%) (4.8%)
p value
0.53
Number (%) is shown. p value for chi-square test. Abbreviations: ESTSCLE, endometrial stromal tumors with sex cord-like elements; UTROSCT, uterine tumors resembling ovarian sex-cord tumors; TAH, total abdominal hysterectomy; and BSO, bilateral salpingo-oophorectomy. * Definitive radiotherapy. Table 3 Treatment patterns based on age and parity. All cases
Parityb
Age 40
