Epithelioid trophoblastic tumor (ETT) of the uterus is a rare tumor introduced recently, which is distinct from placental site trophoblastic tumor (PSTT) and choriocarcinoma with the histological appearance of resembling low-grade squamous cell carcinomas.1-5 Definition and treatment of this disease is still not very clear because of its very low incidence and epithelioid trophoblastic lesions. ETT generally behaves in a benign fashion with metastatic and death rates about 25% and 10%, respectively. 5,6 Here we report three cases of ETT, in which one had metastasis and eventually died from the disease.
A 36-year-old multipara was admitted to a local hospital on May 26, 1998 because of irregular vaginal spotting for two months and an enlarged uterine. Ultrasonography showed two subserous and one submucous leiomyomas in the uterus sized 1 cm × 1 cm, 1 cm × 1 cm, and 4 cm × 2 cm, respectively. The patient had no pregnant event in the recent years. The serum level of β-hCG was not determined. After a total hysterectomy, pathological examination showed that the tumor was ETT. During a 27-month follow-up, no recurrence occurred.
A 46-year-old multipara complaining of increased leucorrhoea, vaginal spotting, and pelvic pain for 20 days was admitted to a local hospital on December 11, 2000. She had been menopaused for 1 year and the last pregnancy occurred in 1994. Gynecological examination revealed that the uterus was enlarged to three months gestational size, a 4 cm × 3 cm × 3 cm tumor was found in the cervix. Serum β-hCG level was 31.5 mIU/ml (reference: <3.1 mIU/ml). The cervical biopsy showed that the tumor was ETT. After a total hysterectomy, the patient had no recurrence during a 28-month followed-up.
A 48-year-old multipara was admitted to a local hospital on December 4, 2000 because of vaginal spotting and increased leucorrhoea for two months. Gynecological examination showed a 3.0 cm × 3.0 cm neoplasm in the cervix. Ultrasonography revealed a mass sized 4.3 cm × 4.2 cm in the uterine cavity. The patient had been menopaused for 2 years without hormone replacement therapy, and had no pregnancy in recent years. The level of serum β-hCG was 12.0 mIU/ml (reference range < 3.1 mIU/ml). Biopsy of the cervical neoplasm revealed that it was ETT and then a total hysterectomy was performed. Twenty-four months after operation, a metastatic tumor was detected in the left tonsil with an elevated β-hCG level (144 mIU/ml). She was admitted to our hospital and underwent left tonsillectomy combined with four-course EMA-CO chemotherapy. Then the serum level of β-hCG returned to normal. In July 2004, the patient received chest X-ray because of severe cough, which suggested extensive metastatic lesions of ETT in the lungs. She refused operation but only received EMA-CO chemotherapy, and died of lungs and brain metastasis in December 2004.
Grossly, in all the three cases, the tumors were located at the lower uterine segment or cervix with a size ranged 2－5 cm in diameter. All the tumors were solitary expansive nodules invading into the adjacent tissues. The cut surface was solid or cystic, typically tan or brown displaying various amounts of hemorrhage and necrosis.
Microscopy showed that the ETT samples were well circumscribed with a nodular expansive growth pattern. The tumors were composed of a relatively uniform population of mononucleate trophoblastic cells arranged in nests or cords. Sometimes the cords and nests were intimately associated with an eosinophilic, fibrillar, hyaline-like material and necrotic debris, which created a “geographic” pattern (Fig. 1). Immunoreactivity of hPL (Fig. 2), PLAP, Mel-CAM, and inhibin-α were scattered in a minority of tumor cells. Immunoreactivity of β-hCG were also scattered but only in a few cells. In contrast, diffuse immunoreactivity of CK (pan) (Fig. 3), CK18, EMA, and EGFR were obvious.
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Fig. 1. Islands of viable tumor cells surrounded by extensive necrosis creating a “geographic” pattern (HE, original magnification×200).
Fig. 2. Tumor cells of ETT positive for hPL were scattered (SP staining, original magnification×200).
Fig. 3. Tumor cells of ETT were diffusely positive for CK (pan) (SP staining, original magnification×200).
The histology of ETT was firstly described by Mazur in 1989 using the name of “atypical chorilcarcinoma”,1 and then the term “ETT” was introduced by Shih and Kurman in 1998.3 Now it has been accepted widely and used in the latest 2003 WHO classification of uterine corpus tumors.4
Clinically, the patients with ETT are usually in their reproductive years,3,5,6 with antecedent gestational events including full-term deliveries (68%), spontaneous abortions (16%), and hydatidiform moles (16%).5 The interval between the preceding gestation and the diagnosis of an ETT range from 1 to 18 years (average 6.2).5 Abnormal vaginal bleeding is the most common symptom. Extrauterine ETT without an identifiable trophoblastic lesion in the uterus has also been described in the lungs or small bowel.3,7 which probably represent metastatic lesions from a preexisted uterine ETT that was misdiagnosed as a choriocarcinoma and then disappeared after chemotherapy. In patients with ETT, serum levels of β-hCG are usually slightly elevated (<2500 mIU/ml) comparing with those in patients with choriocarcinoma.6
Pathologically, 30% of ETT are located at the uterus corpus, 50% in the lower uterine segment or cervix, and 20% in the extrauterine sites including the lungs and small bowel; metastatic lesion located at the tonsil (case 3) is absolutely rare. Microscopically, the tumors are composed of a relatively uniform population of mononucleate trophoblastic cells, which are different from two populations of trophoblastic cells in choriocarcinoma. These mononucleate trophoblastic cells are typically arranged in nests or cords, which are intimately association with an eosinophilic, fibrillar, hyaline-like material and necrotic debris. The islands of viable tumor cells surrounded by extensive necrosis create a “geographic” looking. Immunohistochemically, consisting with an epithelial origin, all the tumors are positive for CK (pan), CK18, EMA, E-cadherin, and EGFR. The “classic” markers for intermediate trophoblastic cells including hPL, hCG are only focally expressed in the tumors.3,5
Serum level of β-hCG, which was slightly elevated in our patients, can be used as a monitor marker of the disease, especially in case 3. Her β-hCG level was quite low at the onset, but significantly elevated when the metastatic lesion appeared. Whether or not the level of serum β-hCG predicts the outcome of the patients with ETT is still unclear.
Local excision combined with chemotherapy is the main choice for the treatment of ETT, especially in recurrent patients because of the coexistence of the choriocarcinoma in a focal area and metastatic lesions even though ETT is not responsive to the chemotherapeutic agents used in the treatment of other types of gestational trophoblastic diseases. Thus, we used EMA-CO, the most effective therapeutic regimen against malignant gestational trophoblastic diseases, for case 3 after the operations. However, the chemotherapy did not take effect, suggesting that ETT is definitely not responsive to the chemotherapeutic agents. Based on the tumor's immunohistochemical features, we supposed that platinum-based chemotherapeutic agents may be helpful.
1. Mazur MT. Metastatic gestational choriocarcinoma. Unusual pathologic variant following therapy. Cancer 1989; 63: 1370-1377.
2. Silva EG, Tornos C, Lage J, Ordonez NG, Morris M, Kavanagh J. Multiple nodules of intermediate trophoblast following hydatidiform moles. Int J Gynecol Pathol 1993; 12: 324-332.
3. Shih IM, Kurman RJ. Epithelioid trophoblastic tumor. A neoplasm distinct from choriocarcinoma and placental site trophoblastic tumor simulating carcinoma. Am J Surg Pathol 1998; 22: 1393-1403.
4. Tavassoli FA, Devilee P. WHO: Pathology and genetics of tumours of the breast and female genital organs. Lyon: IARC Press 2003; 252.
5. Shih IM, Kurman RJ. The pathology of intermediate trophoblastic tumors and tumor-like lesions. Int J Gynecol Pathol 2001; 20: 31-47.
6. Shih IM, Mazur MT, Kurman RJ. Gestational trophoblastic disease and related lesions. In: Kurman RJ, ed. Blaustein's pathology of the Female Genital Tract, 5th ed. New York: Springer-Verlag; 2002: 1193-1247.
7. Hamazaki S, Nakamoto S, Okino T, Tsukayama C, Mori M, Taguchi K, et al. Epithelioid trophoblastic tumor: morphological and immunohistochemical study of three lung lesions. Hum Pathol 1999; 30: 1321-1327.