A Case Series of Five Patients With Pure or Mixed Gestational Epithelioid Trophoblastic Tumors and a Literature Review on Mixed Tumors

Ka Yu Tse, MRCOG; Keith Wan Hang Chiu, FRCR; Karen Kar Loen Chan, FRCOG; Mandy Man Yee Chu, MRCOG; Siew Fei Ngu, MRCOG; Annie Nga Yin Cheung, FRCPath; Hextan Yuen Sheung Ngan, FRCOG; Philip Pun Ching Ip, FRCPath

Disclosures

Am J Clin Pathol. 2018;150(4):318-332. 

In This Article

Results

In total, 190 patients diagnosed with GTN, excluding those with partial and complete hydatidiform moles, were identified during the study period, including two pure ETTs (patients A and B) and three mixed ETTs and choriocarcinoma (CC) (patients C, D, and E). All were Chinese, and the median age at diagnosis was 32.5 years (range, 25–50 years).

All tumors were confined in the uterus, and the median interval from the antecedent pregnancy was 31.8 months (range, 21.6–94.3 months). ETT was not suspected before the initiation of treatment in all patients. Those with mixed ETT and CC had a higher hCG level (median, 1,400 IU/mL; range, 192.2–3,139 IU/L) than those with pure ETT (<0.5 IU/L). Their high hCG level led to a clinical suspicion of pregnancy-related disorders before treatment. The details of their clinical presentations are as follows.

Patient A

Patient A, 32 years old, gravida 3 para 2, had amenorrhea for 1 year after stopping oral contraceptive pills in 2008. She had abdominal pain 2 years later (March 2010), and CT showed a complex mass measuring 8 × 7 × 4 cm in the lower part of the uterus Image 1. Laparotomy was performed for suspected malignancy. An 8-cm uterine cystic mass was found intraoperatively, and both ovaries appeared normal. Total abdominal hysterectomy (TAH) was performed. Pathologic examination showed ETT involving the uterine corpus with extensions to the uterine serosa, endocervix, and paracervical adventitia, compatible with FIGO stage I. The mitotic count was two mitotic figures (MFs)/10 high-power fields (hpfs), and the MIB1 proliferative index (Ki-67) was 10%. The time interval between her preceding miscarriage and the diagnosis of ETT was not exactly known but was thought to be within 1 year. The WHO score was estimated to be 3 to 5. She had been followed up, and her hCG level was normal all along. The patient complained of urinary leakage from the vagina in April 2016, about 6 years after the initial diagnosis of GTN, and vesicovaginal fistula was diagnosed by a CT urogram (Image 1). However, positron emission tomography (PET)–CT did not reveal any recurrence. A right ureteric resection and reimplantation were performed in July 2016. Recurrent ETT was found in the ureteric specimen. This tumor was morphologically identical to the primary tumor and expressed AE1/AE3, CD10, E-cadherin, p63, inhibin, and placental alkaline phosphatase. The Ki-67 index was 30% to 40%. The tumor involved surgical margins, and the patient was offered adjuvant chemotherapy but declined. She remained well, and there was no recurrence about 1.5 years after the surgery.

Image 1.

Computerized tomography urogram of patient A at recurrence. (A) A postcontrast sagittal image of the abdomen and pelvis. There was a large cystic lesion (arrowheads) in the lower uterus (arrow) abutting the cervix (black arrow). The lesion was nodular in contour and demonstrates septations. Calcifications were also noted within this lesion. (B) This postcontrast coronal image of the abdomen and pelvis shows a nodular cystic lesion (arrows). (C) The contrast axial image of the pelvis shows a nodular cystic lesion (arrowheads) arising from the uterus (arrow). There was no evidence of pelvic sidewall or adjacent structure invasion. (D) Selected axial image of the abdomen showing foci of calcifications (arrow) within the cystic lesion (bone window). (E) Postcontrast image of the pelvis at the time of recurrence. Previous hysterectomy was noted, and there was no evidence of gross tumor. Fluid was seen within the vaginal vault (arrow). (F) A delayed (10 minutes) postcontrast image of the pelvis. Intravenous contrast material could be seen excreted into the urinary bladder (arrow). There was a contrast-fluid level within a fluid-filled vaginal vault (arrowhead), implying the presence of a vesicovaginal fistula.

Patient B

Patient B, 25 years old, gravida 1 para 0, had acute abdominal pain for 3 days in May 2010. An ultrasound showed a posterior uterine cystic lesion that measured 11.9 × 10.4 × 8.5 cm. There was no solid component. An emergency laparotomy was performed, during which a cystic mass was found over the posterior uterine serosa extending from the uterine fundus to the pouch of Douglas. It contained old blood. The cyst was excised and was histologically confirmed to be ETT. The mitotic count was two MFs/10 hpfs, and the Ki-67 index was 20%. Microsatellite analysis of the cyst and the patient's blood confirmed that the tumor was gestational in origin. In view of the patient's young age and the desire for fertility preservation, a hysterectomy was not performed; adjuvant chemotherapy was also not given due to the likelihood of a potential poor response. Serial hCG blood tests and MRI did not reveal any recurrence. The patient had a full-term delivery by caesarean section in April 2014 and another full-term normal vaginal delivery in October 2017, about 4 and 7.5 years after her initial diagnosis, respectively.

Patient C

Patient C had previously been reported by our group but is included in the current analysis due to additional follow-up information.[14] This 50-year-old woman, gravida 7 para 4, had a history of molar pregnancy in October 1997. She had persistent vaginal bleeding in December 1997, and her hCG level was raised to 242 IU/L. She was effectively treated as having postmolar GTN with six courses of methotrexate and actinomycin D in March 1998. Twenty-three months after completion of the primary treatment, in February 2000, the hCG rose again to 192 IU/L. Five courses of CHAMOC (cyclophosphamide, hydroxyurea, actinomycin D, methotrexate with folinic acid, and vincristine) were given in the ensuing 3 months for recurrent GTN (stage I: 5).[15] However, the hCG level rose to 2,600 IU/L 2 months after chemotherapy. An ultrasound showed a 0.9 × 0.7 × 1.1-cm uterine nodule with focal vascular flow. In September 2000, because of the lack of response and possibility of rare GTN, a laparoscopic-assisted vaginal hysterectomy and bilateral salpingo-oophorectomy were performed. The pathology was mixed ETT and CC in which one-third of the tumor was composed of CC. The ETT element had one MF/10 hpfs and a Ki-67 index of less than 1%. No further chemotherapy was given, and she has remained disease free for 17 years.

Patient D

This 34-year-old woman, gravida 4 para 1, had a history of postmolar GTN, which was treated with chemotherapy in mainland China in 1995. She had a full-term delivery by caesarean section in 1998. In January 2006, 11 years after her initial GTN, she complained of vaginal bleeding, and her hCG was elevated to 807 IU/L. A transvaginal scan revealed no gestational sac. A diagnostic laparoscopy was then performed, but no abnormality was found. The suction evacuation yielded endometrium only. Two courses of methotrexate were given for a provisional diagnosis of ectopic pregnancy of unknown location. However, her hCG level was increasing, and PET-CT showed increased uptake inside the uterine cavity. The patient was referred to our unit. The repeated hCG level was 1,400 IU/L. The patient was managed as having recurrent GTN stage I: 7, and seven cycles of EMA-CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine with folinic acid rescue) were given between May and August 2006. Her hCG level normalized until February 2007, when it rose again to 172.6 IU/L in March 2007. The ultrasound and chest X-ray were unremarkable. Nine more cycles of EMA-CO were given in the ensuing 3 months with normalization of the hCG. However, in August 2007, 2 months after treatment was completed, her hCG rose again for the third time. In view of the unsatisfactory response, total laparoscopic hysterectomy was performed in September 2007. The pathology revealed mixed ETT and CC Image 2, where the mitotic count was two MFs/10 hpfs, and the Ki-67 index was less than 1% in the ETT component. Adjuvant chemotherapy was not administered. The patient remained disease free for 10 years.

Image 2.

Representative microphotographs of patient D with mixed epithelioid trophoblastic tumor (ETT) and choriocarcinoma (CC). (A) ETT component. Circumscribed tumor nodules contained nests and cords of uniform tumor cells associated with intercellular eosinophilic hyaline or fibrillar material (H&E, ×10). (B) ETT component. The tumor cells were mononuclear with abundant eosinophilic or occasional clear cytoplasm (H&E, ×20). (C) CC component. Areas of hemorrhage were surrounded by an admixture of mononuclear cytotrophoblasts and syncytiotrophoblastic giant cells creating a bilaminar pattern of growth (H&E, ×10). (D) CC component. The syncytiotrophoblastic giant cells were multinucleated and often showed multiple cytoplasmic vacuoles (H&E, ×20).

Patient E

Patient E, 33 years old, gravida 3 para 0, had a history of postmolar GTN requiring chemotherapy in 2003 and had a termination of pregnancy in 2005. She had vaginal bleeding in December 2008, 5 years after the initial diagnosis of GTN, and her hCG level was 3,139 IU/L. An ultrasound showed a 4.7 × 3.8 × 3.6-cm left uterine cornual mass. She was treated with three cycles of low-dose methotrexate for a provisional diagnosis of cornual pregnancy, and her hCG level dropped slowly but remained elevated at 39 IU/L. A laparoscopy was performed in February 2009, during which a 2-cm mass was found in the uterine fundus. The tumor was resected and conversion to a laparotomy was required because of extensive bleeding. The pathologic diagnosis was mixed ETT and CC, with a mitotic count of 1 MF/10 hpfs, and the Ki-67 index was 20%. In March 2009, TAH was performed and residual CC was found. In view of the CC component, two cycles of CHAMOC were completed as consolidation in April 2009. The hCG remained normal, and there was no evidence of recurrence after a follow-up duration of 8 years.

In our current series, the median follow-up for all five patients was 102 months (range, 88–238 months), and all patients survived. The clinical features and pathologic findings of the above patients are listed in Table 1 and Table 2, respectively.

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