Gynecologic Oncology 137 (2015) 456–461
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Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Epithelioid trophoblastic tumor: A single institution case series at the New England Trophoblastic Disease Center M.R. Davis a,⁎, B.E. Howitt d, B.J. Quade d, C.P. Crum d, N.S. Horowitz a,b,c, D.P. Goldstein a,b,c, R.S. Berkowitz a,b,c a
Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA Dana Farber Cancer Institute, Boston, MA, USA New England Trophoblastic Disease Center, Donald P. Goldstein MD Trophoblastic Tumor Registry, Boston, MA, USA d Division of Women's and Perinatal Pathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA b c
H I G H L I G H T S • This series describes the first asymptomatic cases with extrauterine disease. • Patients with ETT demonstrated resistance to multiple agent chemotherapy. • Surgical management with hysterectomy improved outcomes in patients with ETT.
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Article history: Received 30 December 2014 Accepted 4 March 2015 Available online 12 March 2015 Keywords: Epithelioid trophoblastic tumor Gestational trophoblastic neoplasia
a b s t r a c t Objective. Epithelioid trophoblastic tumor (ETT) is a rare form of gestational trophoblastic neoplasm which is distinct based on its development from intermediate trophoblast cells and nodular growth pattern. The aim of this study is to describe a case series from a single institution with a review of the literature to better understand the clinical characteristics and outcomes for patients with ETT. Methods. A retrospective review was performed using the IRB approved New England Trophoblastic Disease Center (NETDC) database from 1998 to 2014. Eight patients were identified of which seven had complete records. Follow-up data was obtained from the longitudinal medical records. Results. Four (57.1%) patients presented with vaginal bleeding and two (28.6%) patients were asymptomatic at presentation. Three (42.9%) patients had extrauterine disease. All three patients with extrauterine disease who received chemotherapy had stable or progressive disease at follow-up. Only two (29%) patients who presented with non-metastatic disease and underwent hysterectomy were alive with no evidence of disease. The mean interval following antecedent pregnancy was 104 months. All patients with an interval N4 years demonstrated stable or progressive disease despite intensive chemotherapy. Two patients with non-metastatic disease who declined hysterectomy developed stable or progressive disease despite chemotherapy. Conclusions. This series highlights several features of ETT including the potential for asymptomatic presentation of extrauterine disease. The series also demonstrates chemoresistance, even with multi-agent therapy and a poor prognosis with extrauterine disease and an interval greater than 4 years following the antecedent pregnancy suggesting that surgery remains critical in disease control. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Epithelioid trophoblastic tumor (ETT) is an extremely rare form of gestational trophoblastic neoplasia (GTN) representing less than 2% of all gestational trophoblastic diseases [1]. The first report, a series of 14 cases by Shih and Kurman in 1998, described this unique type of tumor comprised of chorionic type intermediate trophoblastic cells distinct from placental site trophoblastic tumor (PSTT) and choriocarcinoma
⁎ Corresponding author.
http://dx.doi.org/10.1016/j.ygyno.2015.03.006 0090-8258/© 2015 Elsevier Inc. All rights reserved.
with features that more closely resembled carcinoma [2,3]. Clinically, these tumors have been shown to present predominantly in reproductive age women with 67% of antecedent gestations being a full term pregnancy [2,4,5]. This population is also unique in that it has been shown to have a delayed interval to presentation, with reports ranging from 1–18 years following the antecedent pregnancy [2,5,6]. Case reports have demonstrated that patients with ETT typically present with vaginal bleeding and will often have an elevated beta human chorionic gonadotropin (hCG) yet are frequently misdiagnosed pre-operatively, largely because of their rarity and diverse presentation [2,4,7]. Pathologic findings have been described as a nodular growth of nested and corded
M.R. Davis et al. / Gynecologic Oncology 137 (2015) 456–461
monomorphic, epithelioid cells often with areas of necrosis [4]. These tumors may be confused with squamous cell carcinomas because of their common location in the lower uterine segment and cervix and positive staining for cytokeratin and p63 [2,4]. ETT differs from PSTT in its nested, nodular growth unlike the sheet-like and highly infiltrative growth pattern seen in PSTT [4]. ETT shares some clinical and pathologic characteristics with PSTT including slow growth rates, development from intermediate trophoblastic tissue, relatively low hCG levels, and poor response to chemotherapy making the management of this rare tumor even more challenging [2,8]. Similar to other gestational trophoblastic diseases, the mortality associated with ETT remains low, though the rate of metastasis has been reportedly higher ranging from 25–88.9% [2,6,9]. The WHO scoring system has limited utility in PSTT and ETT unlike other forms of GTD [8,23]. Factors associated with poor prognosis in PSTT include metastatic disease and interval greater than 4 years from the antecedent pregnancy [8,10]. There have been limited prognostic indicators identified for ETT, though these may be similar to those described previously for PSTT. There have been several case reports and small case series since the initial publication by Shih and Kurman in 1998 though the data remains limited. Scott et al. published a case report with a review of the literature in 2012 and described a total of 94 published cases [5]. Using a MEDLINE search, since 2012 there have been eleven additional publications for a total of 14 new cases, accounting for 108 reported cases in the literature [4,6,20–22]. ETT is a rare tumor and despite several small series, the clinical course and presentation remain complex and varied, making the diagnosis and management challenging. Furthermore, other tumors of epithelial origin may mimic ETT and without the aid of immunohistochemical or genetic analysis, may be difficult to distinguish [2]. The aim of this study is to review a series of cases treated at a single institution, the New England Trophoblastic Disease Center (NETDC). This study highlights the clinical presentation, treatment, and outcomes of patients diagnosed and treated with ETT at the NETDC to provide further information regarding this rare malignancy while describing a unique case of an asymptomatic presentation of ETT with extrauterine disease. 2. Methods After obtaining institutional review board (IRB) approval for this project, we conducted a retrospective chart review of all patients in the NETDC database who were diagnosed and treated with ETT from 1998 to 2014. We identified eight patients seen in consultation or treated at NETDC. The pathologic diagnosis of ETT was confirmed by three subspecialty gynecologic pathologists with the aid of immunohistochemical and genetic markers when available. One patient had a composite tumor of both ETT and choriocarcinoma. One patient was excluded due to insufficient clinical follow-up data available for analysis. The remainder of the clinical information was extracted from the electronic longitudinal medical record. Patients were followed at the NETDC or with their primary provider following their definitive treatment with weekly hCG values until undetectable for three weeks, then monthly for one year. If the patient lived at a substantial distance from Boston such that the above follow-up could not be achieved, this was performed at their local institution and information on clinical status and follow-up was requested on a monthly basis. The hCG assay utilized at our institution demonstrates an undetectable result with values less than 2 mIU/mL. For patients at a distance, clinicians were encouraged to use the most sensitive assay available. 3. Results Seven patients were included in the series with diagnosis between 2010 and 2014. No patients were identified in the database with
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pathologically confirmed ETT prior to 2010. The mean age at presentation was 39.7 years (range 31 to 51 years) including two postmenopausal patients. The symptoms at presentation varied, with the majority (57.1%) of patients experiencing vaginal bleeding. However, two patients were entirely asymptomatic at the time of diagnosis. In one patient (Case 5), ETT was diagnosed in an umbilical hernia repair specimen and in one patient (Case 1), ETT was diagnosed in a morcellated laparoscopic myomectomy specimen. One patient (Case 7) presented with pain at the site of a prior cesarean section scar and was found to have a 9 cm mass in the left rectus abdominis muscle abutting the deep fascia which was diagnosed as ETT on pathologic examination following wide local excision. The majority of cases (57.1%) were confined to the uterus, presenting in the fundus or lower uterine segment similar to the locations originally described by Shih and Kurman, though no patient presented with an endocervical tumor as has been described in the literature [2,6]. No patient had radiographic disease above the diaphragm at diagnosis. Three patients (42.9%) had extrauterine disease at the time of diagnosis. In regards to obstetric history, six (85.7%) patients had a documented antecedent pregnancy prior to diagnosis; one patient (Case 1) was thought to be nulliparous but was found to have ETT at the time of laparoscopic myomectomy, likely with an undocumented spontaneous abortion. Two patients had an antecedent molar pregnancy (Cases 3 and 4) and in Case 4 the only prior pregnancy being a partial mole. The mean time interval for all cases from antecedent pregnancy to diagnosis of ETT was 104 months (range 12 to 264 months). Four patients (57.1%) presented following a full term delivery, two of which had an antecedent vaginal delivery and two underwent a cesarean section. Two patients had a bilateral tubal ligation prior to their diagnosis of ETT. Four patients (57.1%) had serum human chorionic gonadotropin (hCG) levels less than 10 at the time of diagnosis and two of those patients had undetectable hCG levels. The median hCG value was 9 (range 1 to 538,330 mIU/mL). The two patients who presented with hCG values N 100,000 both had an antecedent molar pregnancy. Patients with an initially elevated hCG had their values followed similar to standard monitoring for gestational trophoblastic neoplasia (GTN) and the hCG levels were a useful marker of clinical response. All patients underwent surgical intervention, four (57.1%) of which were treated with hysterectomy. Two additional patients (Case 1 and Case 4) were recommended hysterectomy but declined given their desire for ongoing fertility. One subsequently developed a cervical recurrence with stable uterine disease on recent biopsy and the other was lost to follow-up but had progressive disease at that time. Patients with extrauterine disease underwent multiple surgical procedures with a mean number of three surgical procedures for all cases. Six patients (85.7%) received chemotherapy, which included chemotherapy initially used to treat presumed GTN prior to the diagnosis of ETT. Four patients (57.1%) underwent a multiple agent regimen consisting of etoposide, methotrexate, actinomycin-D, cisplatinum (EMA-EP) for the treatment of ETT [11]. The number of cycles received varied ranging from two to nine cycles with only one patient stopping chemotherapy for associated toxicity. Two patients (28.6%) had no evidence of disease at the time of follow-up. Both of these patients underwent surgical management with hysterectomy and had disease confined to the uterus. Two patients (28.6%) had stable disease and three patients (42.9%) had progressive disease with metastasis to the lung, vagina, and pubic symphysis at the time of follow-up. While the review by Palmer et al. demonstrated 13% of patients dead of disease with follow-up ranging from 1–39 months; no patient in this series was dead of disease during a similar follow-up period of 3–40 months [6]. The mean follow-up in this series was 24.0 months. Table 1 outlines the individual clinical outcomes for all cases. Supplemental Table 1 addresses the pathologic variables for all cases when available including mitotic count, lymphovascular invasion, and depth of invasion. Case 5 will be highlighted in more detail given the unique presentation and pathology. Furthermore, to our knowledge, a presentation of asymptomatic, extrauterine disease with heavily calcified tumor has never previously been reported in the literature.
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Table 1 Case based clinical outcomes. Case Age Symptoms Antecedent Tumor size pregnancy (cm)
Serum Metastasis hCG (mIU/mL)
Surgical treatment
Chemotherapy Response to Follow-up Outcome for ETT chemotherapy (months)
b2
Peritoneum
RA-myomectomy, morcellation
EMA-EP
Partial response
26
1
31
None
Unknown
b3 cm
2
38
VB
TAH, PLND
None
–
40
51
VB
Multi-focal, b2 b0.5 cm b3 cm 538, 330
No
3
No
TLH, BSO
None
–
23
NED
4
31
VB
D&C
None
–
26
49
None
Intra-abdominal TAH, BSO and tumor debulking
EMA-EP-prior to surgery
No response
18
6
34
VB
FTD, 9 years
150,000 Single focus b1 cm Multi-focal, 6.9 largest 8.5 cm 6.8 cm 1354
No
5
FTD, 2 years Mole, 1 year Partial mole, 2 years FTD, 16 years
Stable disease—uterus and cervix NED
No
RA-TLH
EMA-EP
No response
3
7
44
Pain
FTD, 22 years
Abdominal wall
Diagnostic laparoscopy, resection of abdominal wall mass 4×
EMA-EP
Partial response
Progressive disease — lung metastasis Stable disease — small bowel mesentery Progressive disease—vaginal and lung metastasis Progressive disease — pubic symphysis metastasis
9 cm
9
26
VB — vaginal bleeding; FTD — full term delivery; RA — Robotic-assisted; TAH — total abdominal hysterectomy; PLND — pelvic lymph node dissection; TLH-BSO — total laparoscopic hysterectomy, bilateral salpingo-oopherectomy; EMA-EP — etoposide, methotrexate, actinomycin-D, cisplatinum; MTX — methotrexate; NED — no evidence of disease. Partial response: a greater than 50% reduction in tumor burden or a fall of hCG by N50% sustained for N1 month as evaluated by the primary oncologist [22].
4. Highlighted case Given the diversity of cases presented, we wanted to highlight a unique case treated at NETDC with an unusual presentation, pathology, and clinical course. The patient is a 49 year old G4P2023 Native American female who was initially evaluated after undergoing an umbilical hernia repair with final pathology demonstrating malignant cells of unknown origin. Her obstetric history was notable for one cesarean delivery for twins followed by one vaginal birth after cesarean section 16 years prior to presentation. She underwent CT imaging of the chest, abdomen, and pelvis which demonstrated minimal apical scarring of the lung parenchyma but otherwise no metastatic nodules or lymphadenopathy. The abdomen and the uterus were unremarkable; however, there was some prominent vascularity of calcifications surrounding the uterus. The remainder of the pelvis was normal and there were no skeletal abnormalities identified. She underwent mammography, thyroid ultrasound, as well as a colonoscopy which all were within normal limits. She had a negative PAP smear evaluation in 2013. She underwent a pelvic ultrasound which demonstrated multiple echogenic foci in the endometrial cavity consistent with calcifications. The endometrium measured 2 mm. There was diffuse heterogeneity of the myometrium consistent with uterine fibroids and the ovaries were unremarkable. Endometrial biopsy demonstrated scant endometrium insufficient for evaluation. Tumor markers included a mildly elevated CA 15-3, at 33 (0–30 U/mL), a normal CA-19.9 at 13 (0–37 U/mL), and CA125 at 7 (0–35 kU/L). The hCG value was 6.9 mIU/mL (undetectable b2 mIU/mL). She underwent a diagnostic laparoscopy which demonstrated multiple calcified nodules varying in size throughout the peritoneal cavity covering the ovaries, uterine serous, pelvic side walls, and pericolic gutters. Biopsies were obtained with the final pathology demonstrating ETT. She received four cycles of multiple agent chemotherapy with EMAEP per protocol used at Brigham and Women's Hospital/Dana Farber Cancer Institute [11,12,25]. Given the minimal decline in her hCG level from 69 to 50 mIU/mL and minimal change on CT imaging following treatment, she underwent a repeat diagnostic laparoscopy to assess the feasibility of surgical resection (Fig. 1). Despite chemotherapy, there was no change in tumor burden compared to pre-treatment
laparoscopy performed four months earlier and the disease was too extensive to complete the surgery laparoscopically. She underwent exploratory laparotomy, total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, right ureterolysis, and extensive resection of the pelvic peritoneum. At the conclusion of surgery, roughly 85 to 90% of her tumor was removed with the only residual tumor being unresectable along the mesentery. Pathologic evaluation revealed ETT with extensive necrosis and calcifications at all sites including bladder nodule, rectosigmoid nodule, posterior cul-de-sac, bilateral ovaries, uterine serosa, and omentum (Fig. 2). The karyotype demonstrated 47,XXX reflecting a constitutional X chromosome aneuploidy. The tumor karyotype was not matched to the genomic DNA from the patient's blood. Post-operatively she recovered well with no clinical evidence of disease despite known small volume mesenteric disease. Her hCG values peaked at 63 mIU/mL prior to starting chemotherapy which normalized post-operatively (b2 mIU/mL). Given her lack of response to chemotherapy, the indolent course of her disease, and her clinical improvement post-operatively, the decision was made to follow her clinically and trend her hCG values with plan for further treatment likely by way of surgical resection if symptomatic. At her last follow-up visit eight months following her laparotomy she was asymptomatic with an undetectable hCG level and no clinical evidence of disease. 5. Conclusions This series highlights seven patients treated at a single institution in the last four years with ETT. Epithelioid trophoblastic tumor remains a rare tumor, predominantly described in the literature via case reports. To our knowledge, this is one of the largest series published with the benefit of all patients receiving treatment at a single institution. It is unclear as to why all the cases reported have been those in the last few years but perhaps it may be related to a referral bias or tumor classification at our institution. Our series emphasizes several known characteristics of ETT. Similar to published reports, the patients in this series predominantly presented at reproductive ages with vaginal bleeding. Our series does document two patients who were postmenopausal at presentation as has been rarely described in the literature previously in only four cases [13,15]. The most common antecedent gestation was a full term
M.R. Davis et al. / Gynecologic Oncology 137 (2015) 456–461
459
Anterior cul de sac tumor
Uterine fundus with tumor inplant Left round ligament
Right Fallopian tube
Fig. 1. Laparoscopic view of the pelvis with multiple calcified tumor deposits of varying dimension implanted along the anterior cul de sac, bladder, uterine fundus, and peritoneum.
pregnancy with three of those patients demonstrating an interval greater than four years from the antecedent pregnancy to diagnosis of ETT (mean 15.6 years). Data on PSTT demonstrates a poor prognosis when the interval from the antecedent pregnancy is greater than 4 years and this is also reflected in our data: 3 out of 3 patients with intervals 4 years or greater since a full term antecedent pregnancy had stable or progressive disease at the time of follow-up [8,10]. We also identified two patients who were asymptomatic at the time of diagnosis. Scott et al. reported an asymptomatic case of ETT in a vaginal hysterectomy specimen, noting only one other documented case of an asymptomatic presentation in the literature [4,6]. Unlike the previous reported asymptomatic cases in which disease was confined to the uterus, the cases in our series demonstrate extrauterine presentation in asymptomatic patients. These patients with extrauterine, asymptomatic disease had a prior cesarean section or morcellation which may represent tumor seeding rather than true metastasis. This is also suggested in the case presenting in a prior cesarean section scar.
A
The best clinical outcome was in patients who had disease confined to the uterus and underwent hysterectomy. Lung is the most commonly described extrauterine site of ETT, accounting for 19% of cases; however, our series demonstrates two patients with intra-abdominal extrauterine disease involving the peritoneum and one patient with primary disease found in abdominal wall of a cesarean section scar [14,18–20]. While it is difficult to comment on prognosis in a small case series, extrauterine disease appears to be the most important prognostic factor. Our highlighted case, with diffuse peritoneal nodules; however, appeared to have a more indolent course suggesting a difference in prognosis between true metastasis (ie. lung) vs. presumed tumor seeding in the abdomen. Patients in our series demonstrated a poor response to chemotherapy as highlighted in Case 5 with no decrease in tumor burden on diagnostic laparoscopy following four cycles of EMA-EP. In considering chemotherapy regimens, the benefit of a single institution series is that the majority of patients were treated with a similar regimen of
B
Fig. 2. Microscopic features of epithelioid trophoblastic tumor (ETT). A, Examination at low power magnification reveals extensive necrosis (thick arrow), and nodules of tumor cells (lower right corner). B, At higher magnification, the nested tumor cells are epithelioid with palely eosinophilic cytoplasm and demonstrate mild to moderate nuclear atypia and prominent nucleoli.
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multiple agent chemotherapy with EMA-EP. However, conclusions regarding clinical response to chemotherapy remain limited as patients received varying number of cycles though only one patient had documented significant toxicity leading to discontinuation of treatment. Despite the limitations in this small series, the data does suggest a resistance to chemotherapy, including multiple agent chemotherapy. All patients who did not undergo hysterectomy, treated primarily with chemotherapy, had stable or progressive disease at the time of followup. Similar to published reports of high rates of metastasis associated with ETT, 42.9% of patients in this series had metastatic disease at the time of presentation and five of seven patients (71.4%) had evidence of metastasis following initial therapy. This highlights a treatment challenge when caring for patients with this rare tumor. Additionally, the majority of patients in this series presented with normal or only slightly elevated hCG values making clinical follow-up challenging. Palmer et al. described a modest hCG elevation in patients with ETT, often b2500 mIU/mL [6]. Rarely in the literature have these tumors been associated with negative hCG values at presentation, which was the case in two of our patients [4]. Two patients presented with highly elevated hCG levels N 100,000 which also is inconsistent with prior reported cases [4,6]. These patients in our series were both being treated for post molar GTN with single agent chemotherapy until values plateaued, subsequently undergoing surgical management with final pathology demonstrating ETT. This phenomenon may be a result of mixed pathology in the initial post-molar GTN with the molar or choriocarcinoma (CCA) component being treated effectively with chemotherapy demonstrating only the persistence of ETT on the final pathology. Similarly, one case in this series had ETT admixed with CCA on the final pathology which has also been previously reported in the literature [4]. In the highlighted case there was a minimal decline in hCG prior to surgical resection with extensive necrosis on final pathology. This necrosis may reflect a response to chemotherapy. The results in our series regarding hCG are mixed, though when elevated, hCG has proven to be a useful tool in monitoring clinical response in patients with ETT. Surgical resection remains the cornerstone of treatment as described in prior reviews [4,6]. Similarly, in this series, all patients underwent surgical treatment with 57.1% undergoing definitive management with hysterectomy. Two patients were recommended to undergo hysterectomy but declined because of their age and interest in future fertility. One had a subsequent spontaneous abortion followed by cervical recurrence of ETT with evidence of persistent disease on recent endometrial biopsy, though no evidence of extrauterine disease. The other patient had disease progression with metastasis to the lung. Both were alive with disease at the time of follow-up. In contrast, the cases with disease confined to the uterus that underwent surgical management with hysterectomy, one of whom received no chemotherapy, had no evidence of disease at the time of follow-up. The dichotomy of these cases emphasizes the critical role of complete surgical resection in treatment and cure of these tumors. Unique to this series, our data reveals that patients with ETT often undergo multiple surgical procedures, particularly patients presenting with extrauterine disease. In the context of chemotherapy resistance, repeat surgical management may be necessary to allow for clinical control. There are several limitations to this series by nature of design. Given the rare nature of this tumor the numbers in this series remain small and while it provides useful information in understanding the clinical presentation and treatment of ETT, it is challenging to draw conclusions based on this data alone. Furthermore, not every case had tumor genetics performed raising the question of alternate tumors masking as ETT, in particular Case 1 with no documented antecedent pregnancy. However, all pathology specimens were reviewed by dedicated gynecologic pathologists making this less likely. Genetic analysis, however, remains an important tool in diagnosing these rare tumors and should be implemented further in the future. The information regarding long term follow-up care was also limited to information obtained from the
electronic medical records and while short term follow-up provides valuable understanding of recurrence patterns, it does not provide long term disease outcomes, in particular, since many patients had evidence of disease at the time of follow-up. In conclusion, with only 108 reported cases in the literature, ETT remains a rare and poorly understood tumor distinct from other gestational trophoblastic diseases. This series highlights the importance of surgical management and underscores the previously described impact that extrauterine disease may have on prognosis. It also suggests that like PSTT, an interval greater than 4 years from antecedent pregnancy may also be a marker for poor prognosis. Hysterectomy should be advised in patients with non-metastatic disease to maximize the opportunity for cure. ETT remains a diagnostic challenge due to its diversity in presentation which may lead to delay in treatment and potential mismanagement. As previously proposed by Palmer et al., for rare tumors a centralized database serves to better understand the clinicopathologic features and prognosis, thus future cases should be reported to the International Society for the Study of Trophoblastic Diseases PSTT and ETT database to help guide diagnosis and management (https://pstt. shef.ac.uk/). In realizing the wide spectrum of presentation, it is important to consider epithelioid trophoblastic tumor in the differential diagnosis to optimize management and treatment outcomes for these patients. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ygyno.2015.03.006. Conflict of interest No conflict of interest.
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Contents lists available at ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Epithelioid trophoblastic tumor: A single institution case series at the New England Trophoblastic Disease Center M.R. Davis a,⁎, B.E. Howitt d, B.J. Quade d, C.P. Crum d, N.S. Horowitz a,b,c, D.P. Goldstein a,b,c, R.S. Berkowitz a,b,c a
Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA Dana Farber Cancer Institute, Boston, MA, USA New England Trophoblastic Disease Center, Donald P. Goldstein MD Trophoblastic Tumor Registry, Boston, MA, USA d Division of Women's and Perinatal Pathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA b c
H I G H L I G H T S • This series describes the first asymptomatic cases with extrauterine disease. • Patients with ETT demonstrated resistance to multiple agent chemotherapy. • Surgical management with hysterectomy improved outcomes in patients with ETT.
a r t i c l e
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Article history: Received 30 December 2014 Accepted 4 March 2015 Available online 12 March 2015 Keywords: Epithelioid trophoblastic tumor Gestational trophoblastic neoplasia
a b s t r a c t Objective. Epithelioid trophoblastic tumor (ETT) is a rare form of gestational trophoblastic neoplasm which is distinct based on its development from intermediate trophoblast cells and nodular growth pattern. The aim of this study is to describe a case series from a single institution with a review of the literature to better understand the clinical characteristics and outcomes for patients with ETT. Methods. A retrospective review was performed using the IRB approved New England Trophoblastic Disease Center (NETDC) database from 1998 to 2014. Eight patients were identified of which seven had complete records. Follow-up data was obtained from the longitudinal medical records. Results. Four (57.1%) patients presented with vaginal bleeding and two (28.6%) patients were asymptomatic at presentation. Three (42.9%) patients had extrauterine disease. All three patients with extrauterine disease who received chemotherapy had stable or progressive disease at follow-up. Only two (29%) patients who presented with non-metastatic disease and underwent hysterectomy were alive with no evidence of disease. The mean interval following antecedent pregnancy was 104 months. All patients with an interval N4 years demonstrated stable or progressive disease despite intensive chemotherapy. Two patients with non-metastatic disease who declined hysterectomy developed stable or progressive disease despite chemotherapy. Conclusions. This series highlights several features of ETT including the potential for asymptomatic presentation of extrauterine disease. The series also demonstrates chemoresistance, even with multi-agent therapy and a poor prognosis with extrauterine disease and an interval greater than 4 years following the antecedent pregnancy suggesting that surgery remains critical in disease control. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Epithelioid trophoblastic tumor (ETT) is an extremely rare form of gestational trophoblastic neoplasia (GTN) representing less than 2% of all gestational trophoblastic diseases [1]. The first report, a series of 14 cases by Shih and Kurman in 1998, described this unique type of tumor comprised of chorionic type intermediate trophoblastic cells distinct from placental site trophoblastic tumor (PSTT) and choriocarcinoma
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http://dx.doi.org/10.1016/j.ygyno.2015.03.006 0090-8258/© 2015 Elsevier Inc. All rights reserved.
with features that more closely resembled carcinoma [2,3]. Clinically, these tumors have been shown to present predominantly in reproductive age women with 67% of antecedent gestations being a full term pregnancy [2,4,5]. This population is also unique in that it has been shown to have a delayed interval to presentation, with reports ranging from 1–18 years following the antecedent pregnancy [2,5,6]. Case reports have demonstrated that patients with ETT typically present with vaginal bleeding and will often have an elevated beta human chorionic gonadotropin (hCG) yet are frequently misdiagnosed pre-operatively, largely because of their rarity and diverse presentation [2,4,7]. Pathologic findings have been described as a nodular growth of nested and corded
M.R. Davis et al. / Gynecologic Oncology 137 (2015) 456–461
monomorphic, epithelioid cells often with areas of necrosis [4]. These tumors may be confused with squamous cell carcinomas because of their common location in the lower uterine segment and cervix and positive staining for cytokeratin and p63 [2,4]. ETT differs from PSTT in its nested, nodular growth unlike the sheet-like and highly infiltrative growth pattern seen in PSTT [4]. ETT shares some clinical and pathologic characteristics with PSTT including slow growth rates, development from intermediate trophoblastic tissue, relatively low hCG levels, and poor response to chemotherapy making the management of this rare tumor even more challenging [2,8]. Similar to other gestational trophoblastic diseases, the mortality associated with ETT remains low, though the rate of metastasis has been reportedly higher ranging from 25–88.9% [2,6,9]. The WHO scoring system has limited utility in PSTT and ETT unlike other forms of GTD [8,23]. Factors associated with poor prognosis in PSTT include metastatic disease and interval greater than 4 years from the antecedent pregnancy [8,10]. There have been limited prognostic indicators identified for ETT, though these may be similar to those described previously for PSTT. There have been several case reports and small case series since the initial publication by Shih and Kurman in 1998 though the data remains limited. Scott et al. published a case report with a review of the literature in 2012 and described a total of 94 published cases [5]. Using a MEDLINE search, since 2012 there have been eleven additional publications for a total of 14 new cases, accounting for 108 reported cases in the literature [4,6,20–22]. ETT is a rare tumor and despite several small series, the clinical course and presentation remain complex and varied, making the diagnosis and management challenging. Furthermore, other tumors of epithelial origin may mimic ETT and without the aid of immunohistochemical or genetic analysis, may be difficult to distinguish [2]. The aim of this study is to review a series of cases treated at a single institution, the New England Trophoblastic Disease Center (NETDC). This study highlights the clinical presentation, treatment, and outcomes of patients diagnosed and treated with ETT at the NETDC to provide further information regarding this rare malignancy while describing a unique case of an asymptomatic presentation of ETT with extrauterine disease. 2. Methods After obtaining institutional review board (IRB) approval for this project, we conducted a retrospective chart review of all patients in the NETDC database who were diagnosed and treated with ETT from 1998 to 2014. We identified eight patients seen in consultation or treated at NETDC. The pathologic diagnosis of ETT was confirmed by three subspecialty gynecologic pathologists with the aid of immunohistochemical and genetic markers when available. One patient had a composite tumor of both ETT and choriocarcinoma. One patient was excluded due to insufficient clinical follow-up data available for analysis. The remainder of the clinical information was extracted from the electronic longitudinal medical record. Patients were followed at the NETDC or with their primary provider following their definitive treatment with weekly hCG values until undetectable for three weeks, then monthly for one year. If the patient lived at a substantial distance from Boston such that the above follow-up could not be achieved, this was performed at their local institution and information on clinical status and follow-up was requested on a monthly basis. The hCG assay utilized at our institution demonstrates an undetectable result with values less than 2 mIU/mL. For patients at a distance, clinicians were encouraged to use the most sensitive assay available. 3. Results Seven patients were included in the series with diagnosis between 2010 and 2014. No patients were identified in the database with
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pathologically confirmed ETT prior to 2010. The mean age at presentation was 39.7 years (range 31 to 51 years) including two postmenopausal patients. The symptoms at presentation varied, with the majority (57.1%) of patients experiencing vaginal bleeding. However, two patients were entirely asymptomatic at the time of diagnosis. In one patient (Case 5), ETT was diagnosed in an umbilical hernia repair specimen and in one patient (Case 1), ETT was diagnosed in a morcellated laparoscopic myomectomy specimen. One patient (Case 7) presented with pain at the site of a prior cesarean section scar and was found to have a 9 cm mass in the left rectus abdominis muscle abutting the deep fascia which was diagnosed as ETT on pathologic examination following wide local excision. The majority of cases (57.1%) were confined to the uterus, presenting in the fundus or lower uterine segment similar to the locations originally described by Shih and Kurman, though no patient presented with an endocervical tumor as has been described in the literature [2,6]. No patient had radiographic disease above the diaphragm at diagnosis. Three patients (42.9%) had extrauterine disease at the time of diagnosis. In regards to obstetric history, six (85.7%) patients had a documented antecedent pregnancy prior to diagnosis; one patient (Case 1) was thought to be nulliparous but was found to have ETT at the time of laparoscopic myomectomy, likely with an undocumented spontaneous abortion. Two patients had an antecedent molar pregnancy (Cases 3 and 4) and in Case 4 the only prior pregnancy being a partial mole. The mean time interval for all cases from antecedent pregnancy to diagnosis of ETT was 104 months (range 12 to 264 months). Four patients (57.1%) presented following a full term delivery, two of which had an antecedent vaginal delivery and two underwent a cesarean section. Two patients had a bilateral tubal ligation prior to their diagnosis of ETT. Four patients (57.1%) had serum human chorionic gonadotropin (hCG) levels less than 10 at the time of diagnosis and two of those patients had undetectable hCG levels. The median hCG value was 9 (range 1 to 538,330 mIU/mL). The two patients who presented with hCG values N 100,000 both had an antecedent molar pregnancy. Patients with an initially elevated hCG had their values followed similar to standard monitoring for gestational trophoblastic neoplasia (GTN) and the hCG levels were a useful marker of clinical response. All patients underwent surgical intervention, four (57.1%) of which were treated with hysterectomy. Two additional patients (Case 1 and Case 4) were recommended hysterectomy but declined given their desire for ongoing fertility. One subsequently developed a cervical recurrence with stable uterine disease on recent biopsy and the other was lost to follow-up but had progressive disease at that time. Patients with extrauterine disease underwent multiple surgical procedures with a mean number of three surgical procedures for all cases. Six patients (85.7%) received chemotherapy, which included chemotherapy initially used to treat presumed GTN prior to the diagnosis of ETT. Four patients (57.1%) underwent a multiple agent regimen consisting of etoposide, methotrexate, actinomycin-D, cisplatinum (EMA-EP) for the treatment of ETT [11]. The number of cycles received varied ranging from two to nine cycles with only one patient stopping chemotherapy for associated toxicity. Two patients (28.6%) had no evidence of disease at the time of follow-up. Both of these patients underwent surgical management with hysterectomy and had disease confined to the uterus. Two patients (28.6%) had stable disease and three patients (42.9%) had progressive disease with metastasis to the lung, vagina, and pubic symphysis at the time of follow-up. While the review by Palmer et al. demonstrated 13% of patients dead of disease with follow-up ranging from 1–39 months; no patient in this series was dead of disease during a similar follow-up period of 3–40 months [6]. The mean follow-up in this series was 24.0 months. Table 1 outlines the individual clinical outcomes for all cases. Supplemental Table 1 addresses the pathologic variables for all cases when available including mitotic count, lymphovascular invasion, and depth of invasion. Case 5 will be highlighted in more detail given the unique presentation and pathology. Furthermore, to our knowledge, a presentation of asymptomatic, extrauterine disease with heavily calcified tumor has never previously been reported in the literature.
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Table 1 Case based clinical outcomes. Case Age Symptoms Antecedent Tumor size pregnancy (cm)
Serum Metastasis hCG (mIU/mL)
Surgical treatment
Chemotherapy Response to Follow-up Outcome for ETT chemotherapy (months)
b2
Peritoneum
RA-myomectomy, morcellation
EMA-EP
Partial response
26
1
31
None
Unknown
b3 cm
2
38
VB
TAH, PLND
None
–
40
51
VB
Multi-focal, b2 b0.5 cm b3 cm 538, 330
No
3
No
TLH, BSO
None
–
23
NED
4
31
VB
D&C
None
–
26
49
None
Intra-abdominal TAH, BSO and tumor debulking
EMA-EP-prior to surgery
No response
18
6
34
VB
FTD, 9 years
150,000 Single focus b1 cm Multi-focal, 6.9 largest 8.5 cm 6.8 cm 1354
No
5
FTD, 2 years Mole, 1 year Partial mole, 2 years FTD, 16 years
Stable disease—uterus and cervix NED
No
RA-TLH
EMA-EP
No response
3
7
44
Pain
FTD, 22 years
Abdominal wall
Diagnostic laparoscopy, resection of abdominal wall mass 4×
EMA-EP
Partial response
Progressive disease — lung metastasis Stable disease — small bowel mesentery Progressive disease—vaginal and lung metastasis Progressive disease — pubic symphysis metastasis
9 cm
9
26
VB — vaginal bleeding; FTD — full term delivery; RA — Robotic-assisted; TAH — total abdominal hysterectomy; PLND — pelvic lymph node dissection; TLH-BSO — total laparoscopic hysterectomy, bilateral salpingo-oopherectomy; EMA-EP — etoposide, methotrexate, actinomycin-D, cisplatinum; MTX — methotrexate; NED — no evidence of disease. Partial response: a greater than 50% reduction in tumor burden or a fall of hCG by N50% sustained for N1 month as evaluated by the primary oncologist [22].
4. Highlighted case Given the diversity of cases presented, we wanted to highlight a unique case treated at NETDC with an unusual presentation, pathology, and clinical course. The patient is a 49 year old G4P2023 Native American female who was initially evaluated after undergoing an umbilical hernia repair with final pathology demonstrating malignant cells of unknown origin. Her obstetric history was notable for one cesarean delivery for twins followed by one vaginal birth after cesarean section 16 years prior to presentation. She underwent CT imaging of the chest, abdomen, and pelvis which demonstrated minimal apical scarring of the lung parenchyma but otherwise no metastatic nodules or lymphadenopathy. The abdomen and the uterus were unremarkable; however, there was some prominent vascularity of calcifications surrounding the uterus. The remainder of the pelvis was normal and there were no skeletal abnormalities identified. She underwent mammography, thyroid ultrasound, as well as a colonoscopy which all were within normal limits. She had a negative PAP smear evaluation in 2013. She underwent a pelvic ultrasound which demonstrated multiple echogenic foci in the endometrial cavity consistent with calcifications. The endometrium measured 2 mm. There was diffuse heterogeneity of the myometrium consistent with uterine fibroids and the ovaries were unremarkable. Endometrial biopsy demonstrated scant endometrium insufficient for evaluation. Tumor markers included a mildly elevated CA 15-3, at 33 (0–30 U/mL), a normal CA-19.9 at 13 (0–37 U/mL), and CA125 at 7 (0–35 kU/L). The hCG value was 6.9 mIU/mL (undetectable b2 mIU/mL). She underwent a diagnostic laparoscopy which demonstrated multiple calcified nodules varying in size throughout the peritoneal cavity covering the ovaries, uterine serous, pelvic side walls, and pericolic gutters. Biopsies were obtained with the final pathology demonstrating ETT. She received four cycles of multiple agent chemotherapy with EMAEP per protocol used at Brigham and Women's Hospital/Dana Farber Cancer Institute [11,12,25]. Given the minimal decline in her hCG level from 69 to 50 mIU/mL and minimal change on CT imaging following treatment, she underwent a repeat diagnostic laparoscopy to assess the feasibility of surgical resection (Fig. 1). Despite chemotherapy, there was no change in tumor burden compared to pre-treatment
laparoscopy performed four months earlier and the disease was too extensive to complete the surgery laparoscopically. She underwent exploratory laparotomy, total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, right ureterolysis, and extensive resection of the pelvic peritoneum. At the conclusion of surgery, roughly 85 to 90% of her tumor was removed with the only residual tumor being unresectable along the mesentery. Pathologic evaluation revealed ETT with extensive necrosis and calcifications at all sites including bladder nodule, rectosigmoid nodule, posterior cul-de-sac, bilateral ovaries, uterine serosa, and omentum (Fig. 2). The karyotype demonstrated 47,XXX reflecting a constitutional X chromosome aneuploidy. The tumor karyotype was not matched to the genomic DNA from the patient's blood. Post-operatively she recovered well with no clinical evidence of disease despite known small volume mesenteric disease. Her hCG values peaked at 63 mIU/mL prior to starting chemotherapy which normalized post-operatively (b2 mIU/mL). Given her lack of response to chemotherapy, the indolent course of her disease, and her clinical improvement post-operatively, the decision was made to follow her clinically and trend her hCG values with plan for further treatment likely by way of surgical resection if symptomatic. At her last follow-up visit eight months following her laparotomy she was asymptomatic with an undetectable hCG level and no clinical evidence of disease. 5. Conclusions This series highlights seven patients treated at a single institution in the last four years with ETT. Epithelioid trophoblastic tumor remains a rare tumor, predominantly described in the literature via case reports. To our knowledge, this is one of the largest series published with the benefit of all patients receiving treatment at a single institution. It is unclear as to why all the cases reported have been those in the last few years but perhaps it may be related to a referral bias or tumor classification at our institution. Our series emphasizes several known characteristics of ETT. Similar to published reports, the patients in this series predominantly presented at reproductive ages with vaginal bleeding. Our series does document two patients who were postmenopausal at presentation as has been rarely described in the literature previously in only four cases [13,15]. The most common antecedent gestation was a full term
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Anterior cul de sac tumor
Uterine fundus with tumor inplant Left round ligament
Right Fallopian tube
Fig. 1. Laparoscopic view of the pelvis with multiple calcified tumor deposits of varying dimension implanted along the anterior cul de sac, bladder, uterine fundus, and peritoneum.
pregnancy with three of those patients demonstrating an interval greater than four years from the antecedent pregnancy to diagnosis of ETT (mean 15.6 years). Data on PSTT demonstrates a poor prognosis when the interval from the antecedent pregnancy is greater than 4 years and this is also reflected in our data: 3 out of 3 patients with intervals 4 years or greater since a full term antecedent pregnancy had stable or progressive disease at the time of follow-up [8,10]. We also identified two patients who were asymptomatic at the time of diagnosis. Scott et al. reported an asymptomatic case of ETT in a vaginal hysterectomy specimen, noting only one other documented case of an asymptomatic presentation in the literature [4,6]. Unlike the previous reported asymptomatic cases in which disease was confined to the uterus, the cases in our series demonstrate extrauterine presentation in asymptomatic patients. These patients with extrauterine, asymptomatic disease had a prior cesarean section or morcellation which may represent tumor seeding rather than true metastasis. This is also suggested in the case presenting in a prior cesarean section scar.
A
The best clinical outcome was in patients who had disease confined to the uterus and underwent hysterectomy. Lung is the most commonly described extrauterine site of ETT, accounting for 19% of cases; however, our series demonstrates two patients with intra-abdominal extrauterine disease involving the peritoneum and one patient with primary disease found in abdominal wall of a cesarean section scar [14,18–20]. While it is difficult to comment on prognosis in a small case series, extrauterine disease appears to be the most important prognostic factor. Our highlighted case, with diffuse peritoneal nodules; however, appeared to have a more indolent course suggesting a difference in prognosis between true metastasis (ie. lung) vs. presumed tumor seeding in the abdomen. Patients in our series demonstrated a poor response to chemotherapy as highlighted in Case 5 with no decrease in tumor burden on diagnostic laparoscopy following four cycles of EMA-EP. In considering chemotherapy regimens, the benefit of a single institution series is that the majority of patients were treated with a similar regimen of
B
Fig. 2. Microscopic features of epithelioid trophoblastic tumor (ETT). A, Examination at low power magnification reveals extensive necrosis (thick arrow), and nodules of tumor cells (lower right corner). B, At higher magnification, the nested tumor cells are epithelioid with palely eosinophilic cytoplasm and demonstrate mild to moderate nuclear atypia and prominent nucleoli.
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multiple agent chemotherapy with EMA-EP. However, conclusions regarding clinical response to chemotherapy remain limited as patients received varying number of cycles though only one patient had documented significant toxicity leading to discontinuation of treatment. Despite the limitations in this small series, the data does suggest a resistance to chemotherapy, including multiple agent chemotherapy. All patients who did not undergo hysterectomy, treated primarily with chemotherapy, had stable or progressive disease at the time of followup. Similar to published reports of high rates of metastasis associated with ETT, 42.9% of patients in this series had metastatic disease at the time of presentation and five of seven patients (71.4%) had evidence of metastasis following initial therapy. This highlights a treatment challenge when caring for patients with this rare tumor. Additionally, the majority of patients in this series presented with normal or only slightly elevated hCG values making clinical follow-up challenging. Palmer et al. described a modest hCG elevation in patients with ETT, often b2500 mIU/mL [6]. Rarely in the literature have these tumors been associated with negative hCG values at presentation, which was the case in two of our patients [4]. Two patients presented with highly elevated hCG levels N 100,000 which also is inconsistent with prior reported cases [4,6]. These patients in our series were both being treated for post molar GTN with single agent chemotherapy until values plateaued, subsequently undergoing surgical management with final pathology demonstrating ETT. This phenomenon may be a result of mixed pathology in the initial post-molar GTN with the molar or choriocarcinoma (CCA) component being treated effectively with chemotherapy demonstrating only the persistence of ETT on the final pathology. Similarly, one case in this series had ETT admixed with CCA on the final pathology which has also been previously reported in the literature [4]. In the highlighted case there was a minimal decline in hCG prior to surgical resection with extensive necrosis on final pathology. This necrosis may reflect a response to chemotherapy. The results in our series regarding hCG are mixed, though when elevated, hCG has proven to be a useful tool in monitoring clinical response in patients with ETT. Surgical resection remains the cornerstone of treatment as described in prior reviews [4,6]. Similarly, in this series, all patients underwent surgical treatment with 57.1% undergoing definitive management with hysterectomy. Two patients were recommended to undergo hysterectomy but declined because of their age and interest in future fertility. One had a subsequent spontaneous abortion followed by cervical recurrence of ETT with evidence of persistent disease on recent endometrial biopsy, though no evidence of extrauterine disease. The other patient had disease progression with metastasis to the lung. Both were alive with disease at the time of follow-up. In contrast, the cases with disease confined to the uterus that underwent surgical management with hysterectomy, one of whom received no chemotherapy, had no evidence of disease at the time of follow-up. The dichotomy of these cases emphasizes the critical role of complete surgical resection in treatment and cure of these tumors. Unique to this series, our data reveals that patients with ETT often undergo multiple surgical procedures, particularly patients presenting with extrauterine disease. In the context of chemotherapy resistance, repeat surgical management may be necessary to allow for clinical control. There are several limitations to this series by nature of design. Given the rare nature of this tumor the numbers in this series remain small and while it provides useful information in understanding the clinical presentation and treatment of ETT, it is challenging to draw conclusions based on this data alone. Furthermore, not every case had tumor genetics performed raising the question of alternate tumors masking as ETT, in particular Case 1 with no documented antecedent pregnancy. However, all pathology specimens were reviewed by dedicated gynecologic pathologists making this less likely. Genetic analysis, however, remains an important tool in diagnosing these rare tumors and should be implemented further in the future. The information regarding long term follow-up care was also limited to information obtained from the
electronic medical records and while short term follow-up provides valuable understanding of recurrence patterns, it does not provide long term disease outcomes, in particular, since many patients had evidence of disease at the time of follow-up. In conclusion, with only 108 reported cases in the literature, ETT remains a rare and poorly understood tumor distinct from other gestational trophoblastic diseases. This series highlights the importance of surgical management and underscores the previously described impact that extrauterine disease may have on prognosis. It also suggests that like PSTT, an interval greater than 4 years from antecedent pregnancy may also be a marker for poor prognosis. Hysterectomy should be advised in patients with non-metastatic disease to maximize the opportunity for cure. ETT remains a diagnostic challenge due to its diversity in presentation which may lead to delay in treatment and potential mismanagement. As previously proposed by Palmer et al., for rare tumors a centralized database serves to better understand the clinicopathologic features and prognosis, thus future cases should be reported to the International Society for the Study of Trophoblastic Diseases PSTT and ETT database to help guide diagnosis and management (https://pstt. shef.ac.uk/). In realizing the wide spectrum of presentation, it is important to consider epithelioid trophoblastic tumor in the differential diagnosis to optimize management and treatment outcomes for these patients. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ygyno.2015.03.006. Conflict of interest No conflict of interest.
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