We report an epithelioid trophoblastic tumor (ETT), a recently delineated type of gestational trophoblastic tumor (GTT), discovered in the uterus of a 66-year-old woman. She had been treated for a hydatidiform mole 17 years previously without chemotherapy. The resected uterus contained a solid/cystic tumor located entirely within the myometrium. Microscopically, there was an epithelial-like growth pattern. The tumor was circumscribed, with a pushing border, and the tumor cells grew in cords, nests, and sheets within which were aggregates of hyaline material and necrotic debris. Most tumor cells were mononuclear and had an epithelioid appearance with distinct cell borders, eosinophilic cytoplasm, and nuclei with occasional indistinct nucleoli. Scattered multinucleated cells consistent with syncytiotrophoblastic cells were also present. Immunohistochemical staining revealed strong diffuse reactivity for cytokeratins (CK7, AE1/AE3, CAM 5.2, CK18) and epidermal growth factor receptor, and focal reactivity, mainly in syncytiotrophoblastic cells, for beta-human chorionic gonadotropin, human placental lactogen, and inhibin-alpha. The histologic and immunohistochemical features were characteristic of ETT, and helped to distinguish the tumor from other trophoblastic tumors and squamous cell carcinoma. An unusual observation was a high mitotic count, reflected in a Ki-67 proliferative index of 68.6[percnt]. Our findings indicate that ETT, like other types of GTT, can occur in postmenopausal women, even years after a gestational event.
From the Department of Pathology, University of California, San Francisco and San Francisco General Hospital, San Francisco, California, U.S.A.
Address correspondence and reprint requests to Charles Zaloudek, MD, Department of Pathology, Box 0102, University of California, San Francisco, San Francisco, CA 94143, U.S.A.; e-mail[colon] chuckz[commat]itsa.ucsf.edu
Hydatidiform mole, choriocarcinoma, and placental site trophoblastic tumor (PSTT) are well-established forms of gestational trophoblastic disease. Epithelioid trophoblastic tumor (ETT), an unusual type of trophoblastic tumor in which its growth pattern mimics a carcinoma, has only recently been described. 8 Originally termed [ldquo]atypical choriocarcinoma,[rdquo] it was first described in patients with lung metastases that were chemoresistant but amenable to surgical resection. 2,6 Similar tumors found after the evacuation of uterine hydatidiform moles were reported as [ldquo]multiple nodules of intermediate trophoblast.[rdquo]11 Most patients had been treated with chemotherapy, and it was suggested that the chemotherapy prolonged the course of the disease allowing the atypical pattern to emerge, or that it directly influenced the growth of tumor cells by drug-induced alterations. 6 Recently, 14 cases of ETT with no history of chemotherapy were reported, suggesting that ETT is a distinct pathologic entity and not simply a treatment-related finding. 8
Epithelioid trophoblastic tumors are rare. Only 31 cases have been reported, including tumors termed [ldquo]atypical choriocarcinoma[rdquo] and [ldquo]nodules of intermediate trophoblast.[rdquo] All previously reported cases, including those reported under other names but included as epithelioid trophoblastic tumors by Shih and Kurman, occurred in women of reproductive age (range, 15[ndash]48 years old). 1,8 We report an ETT arising in the uterus of a postmenopausal woman 17 years after the evacuation of a hydatidiform mole.
A 66-year-old Filipino woman, gravida 10, para 8, spontaneous abortion 1, was referred to the hospital in August 1998 because of postmenopausal bleeding and a pelvic mass. The patient, who was 17 years postmenopausal, was not taking hormone replacement therapy. Her last pregnancy, in 1981, was a molar pregnancy that was treated by dilatation and curettage in the Philippines; there was no history of chemotherapy. A computed tomographic (CT) scan of the abdomen and pelvis revealed a 9.8-cm cystic midline pelvic mass, which could not be distinguished from the uterus (Fig. 1). A Papanicolaou smear was within normal limits; an endometrial biopsy revealed an atrophic endometrium; a chest x-ray showed no evidence of metastatic disease. The patient underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy with pelvic lymph node dissection and selective para-aortic lymph node sampling. Intraoperative findings included an enlarged uterus with a smooth surface (approximately 18 wks in size), atrophic ovaries, normal fallopian tubes, and absence of ascites and lymphadenopathy. An intraoperative frozen section of the uterine mass was interpreted as carcinoma. The patient's postoperative serum beta-human chorionic gonadotropin ([bgr]-hCG) level was 118 IU/L (normal [lt]2 IU/L). The level decreased to 7 IU/L after 1 month, and further decreased to 4 IU/L where it remained 15 months after surgery. There was no clinical evidence of disease at her last follow-up visit 15 months postsurgery.
MATERIALS AND METHODS
The hysterectomy/bilateral salpingo-oophorectomy specimen and the dissected pelvic and para-aortic lymph nodes were fixed in 10[percnt] neutral-buffered formalin. Representative sections were embedded in paraffin, cut at 5-[mgr]m, placed on slides, and stained with hematoxylin-eosin. For immunohistochemical staining, additional 5-[mgr]m thick sections of the tumor tissue were deparaffinized, rehydrated, and stained using the labeled streptavidin-biotin complex technique (LSAB[plus] detection kit, Dako, Carpinteria, CA, USA). The reaction product was detected with 3,3[acute]-diaminobenzidine chromogen (DAB[plus], Dako). The primary antibodies, their sources and dilutions were as follows[colon] cytokeratin 7 (Dako; 1[colon]500 dilution), cytokeratin 18 (Dako; 1[colon]25 dilution), cytokeratin 20 (Dako; 1[colon]80 dilution), cytokeratin AE1/AE3 (Chemicon, Temecula, CA, USA; 1[colon]600 dilution), cytokeratin CAM 5.2 (Becton-Dickinson, San Jose, CA, USA; 1[colon]100 dilution), high molecular weight cytokeratin 34[bgr]E12 (Enzo, Farmingdale, NY, USA; 1[colon]2 dilution), beta-human chorionic gonadotropin (Biomeda, Foster City, CA, USA; 1[colon]40 dilution), human placental lactogen (Dako; 1[colon]10,000 dilution), placental alkaline phosphatase (Biogenics, San Ramon, CA) (1[colon]6 dilution), epidermal growth factor receptor (Calbiochem, La Jolla, CA, USA; 1[colon]200 dilution), MIB-1 (Immunotech, Miami, FL; 1[colon]500 dilution), and inhibin-alpha (Sero-Tech, Raleigh, NC, USA; 1[colon]1000 dilution).
The tumor, a grossly circumscribed, partly solid and partly cystic tan to dark-brown mass, was located within the myometrial wall of the left uterine fundus. After the release of dark brown fluid when the tumor was opened intraoperatively, it measured 3.5 [times] 4.0 [times] 3.0 cm (Fig. 2). The tumor was entirely intramural and did not communicate with the uterine cavity. It grew to within 0.6 cm of the serosal surface. The endometrium was 0.1 cm thick and unremarkable. The cervix and fallopian tubes were unremarkable and the ovaries appeared atrophic.
Microscopically, the tumor had an epithelioid appearance, both in terms of its pattern of growth and the morphology of the neoplastic cells. It had an expansile pushing border and was surrounded by a lymphoplasmacytic infiltrate, which extended into the intratumoral stroma (Fig. 3). There was an epithelial-like pattern of anastomosing cords, nests, islands, and sheets of tumor cells. Dense eosinophilic hyaline-like material and necrotic debris, which in some areas vaguely resembled keratin, was present in some tumor cell nests (Fig. 4). Atypical epithelioid cells with moderate amounts of lightly eosinophilic or amphophilic cytoplasm, distinct cell borders, and occasional intracytoplasmic vacuoles predominated. The nuclei were oval to round with slight nuclear membrane irregularities and coarse chromatin. Nucleoli were inconspicuous but were occasionally seen in larger nuclei. Binuclear cells, similar to the mononuclear cells, were also observed, and occasional cells had one or more giant, hyperchromatic nuclei. The neoplastic cells resembled intermediate trophoblastic cells; they were larger than cytotrophoblastic cells but smaller than implantation site intermediate trophoblastic cells. Mitotic figures were abundant in the mononuclear tumor cells with an average of 30 mitotic figures (MF) per 10 high-power fields (HPF). There were scattered multinucleated tumor cells compatible with syncytiotrophoblastic cells, with dark eosinophilic cytoplasm and small or large, darkly stained nuclei, some of which were pyknotic (Fig. 5). Other findings included foci of hemorrhage and the absence of chorionic villi or vascular or lymphatic invasion.
Evaluation of the specimen also revealed chronic cervicitis, an inactive endometrium, and focal adenomyosis in the uninvolved myometrium. The ovaries were atrophic and the fallopian tubes were unremarkable. Seven pelvic lymph nodes and two para-aortic lymph nodes were free of tumor.
Cytokeratins 7 (CK7), 18 (CK18), AE1/AE3, and CAM 5.2 showed diffuse strong reactivity in the tumor cells with a cytoplasmic and membranous pattern of staining (Fig. 6). Epithelial membrane antigen (EMA) highlighted the cytoplasm and apical membranes of the tumor cells toward the center of the nests. There was focal reactivity for [bgr]-hCG, human placental lactogen (hPL), and inhibin-alpha, limited to syncytiotrophoblastic cells and a few of the larger mononuclear and binuclear cells (Fig. 7). Staining with epidermal growth factor receptor (EGF-R) showed moderate membrane reactivity in the mononuclear cells and syncytiotrophoblastic cells. Rare mononuclear cells were positive for high molecular weight cytokeratin 34 [bgr]E12 (HMWK), and cytokeratin 20- (CK20) stained scattered mononuclear trophoblastic cells and syncytiotrophoblastic cells. Using a slide stained with an antibody against MIB-1, we found the Ki-67 proliferation index to be 68.6[percnt]. The tumor cells were negative for placental alkaline phosphatase (PLAP).
We report what is, to our knowledge, the first case of an epithelioid trophoblastic tumor occurring in a postmenopausal woman. All previously reported patients with ETT have been women of reproductive age. The most common presentation, as in our case, is with abnormal vaginal bleeding, although the presentation in some cases is with lung metastases. 1 Most patients have elevated serum [bgr]-hCG levels, although not to the same degree as found in classic choriocarcinoma. As with other gestational trophoblastic tumors, ETT is usually associated with a prior gestational event. There may be a long latency period between the event and the diagnosis of ETT, with the longest reported interval being 18 years. A hydatidiform mole or a choriocarcinoma preceded the ETT in more than half of the published cases. 8 Our patient had a hydatidiform mole evacuated 17 years before the discovery of the ETT.
Epithelioid trophoblastic tumors, as exemplified by our case, have a distinctive growth pattern and immunohistochemical profile. They arise in the uterine corpus, lower uterine segment, or endocervix, and grow in a nodular expansile fashion. The tumor cells are mononuclear intermediate trophoblastic cells that have been termed [ldquo]chorionic-type intermediate trophoblasts[rdquo] because of their resemblance to the intermediate trophoblastic cells of the chorion laeve of the normal placenta. 8,10 There is a varied population of cells, some with pale or clear vacuolated cytoplasm and others with eosinophilic, nonvacuolated cytoplasm. 8,13 Scattered among the mononuclear cells are clusters of syncytiotrophoblastic cells. 2,6 The tumor cells grow in cords, sheets, and nests, some of which contain eosinophilic, hyaline-like material and necrotic debris that can resemble keratin. This material is immunoreactive for type IV collagen and fibronectin of oncofetal and adult types. 8 In half of the cases reported by Shih and Kurman, 8 there was a lymphocytic infiltrate surrounding the tumor, and in approximately 30[percnt], foci of dystrophic calcification were present in necrotic areas.
Our case exhibited all of the usual gross, light microscopic, and immunohistochemical features of an epithelioid trophoblastic tumor. Unusual findings in the case include the advanced age of the patient and the increased mitotic activity exhibited by the tumor. Previous studies have documented the occurrence of choriocarcinoma and placental site trophoblastic tumors in postmenopausal women but ETT has not been reported in this age group. 4,5,8 Because of the paucity of cases of PSTT and choriocarcinoma reported in postmenopausal women, any effect of age on prognosis remains unclear. The mechanism of latency in postmenopausal gestational tumors is poorly understood. Chorionic villi and placental fragments have been identified in the uterus many years after the last pregnancy or menopause. 3 It has been proposed that these trophoblastic remnants undergo malignant change after a period of latency, the trigger of which is unknown. 3
The behavior of ETT has been likened to that of PSTT. Both tend to behave in a benign fashion but metastasis and death occur in [sim]25[percnt] and 10[percnt] of patients, respectively. 8 In general, malignant examples of PSTT have a high mitotic index, with [gt]5 MF per 10. In our case of ETT, the mitotic index and Ki-67 proliferative index (30 MF/10 HPF and 68[percnt]) were both significantly higher than was observed in the cases of ETT reported by Shih and Kurman. It is unknown whether a high mitotic index is prognostically significant in ETT, as it is in PSTT, but we tentatively view this as an unfavorable prognostic finding. Nevertheless, our patient is well with no clinical evidence of tumor at last follow up 15 months after hysterectomy. It is important to distinguish ETT and PSTT from choriocarcinoma because the recommended treatments differ. While the primary treatment for choriocarcinoma is chemotherapy, PSTT tends to be chemoresistant and the recommended primary treatment is surgical intervention. 7,12 Given the similarities in behavior between PSTT and ETT, it is reasonable to treat ETT like PSTT rather than like choriocarcinoma. PSTT is relatively resistant to chemotherapy, but there are a few reports of complete response to multiagent chemotherapy. 5,7,12 Chemotherapy should be considered in ETT if surgical therapy fails.
The differential diagnosis includes choriocarcinoma and placental site trophoblastic tumor (PSTT), the other gestational trophoblastic tumors without a villous component, and squamous cell carcinoma (SCC) of the uterine cervix. Like ETT, choriocarcinoma invades the myometrium with a pushing border. However, choriocarcinoma consists of a dimorphic population of cytotrophoblastic and syncytiotrophoblastic cells growing in a plexiform-like pattern with marked central hemorrhagic necrosis. 7 Syncytiotrophoblastic cells are present in ETT, but they are scattered and are not a prominent component of the tumor as they are in choriocarcinoma. PSTT, derived from implantation site intermediate trophoblastic cells, consists of intermediate trophoblastic cells that infiltrate the myometrium in a distinctive pattern, weaving between muscle bundles and fibers and often invading blood vessels. 8 Mitotic counts can assist in the differential diagnosis, because choriocarcinoma is mitotically active (typically more than 10 MF/10 HPF) while there is usually a lower mitotic rate in ETT and PSTT. 7 Shih and Kurman reported an average mitotic index in ETT of 2 MF per 10 HPF and a mean Ki-67 proliferative index of 17.7 [plusmn] 4.5[percnt] (range, 10[percnt][ndash]25[percnt]). 8
Immunohistochemical studies can help to differentiate epithelioid trophoblastic tumor from choriocarcinoma and PSTT. In ETT, immunohistochemical stains for [bgr]-hCG, hPL, and PLAP exhibit focal reactivity in scattered small clusters of cells (less than 2[percnt] of the tumor cell population). 8 This is in distinct contrast to the staining patterns seen in choriocarcinoma and PSTT. In choriocarcinoma, [bgr]-hCG is diffusely positive, highlighting numerous syncytiotrophoblastic cells, whereas hPL-positive cells are less conspicuous. The converse is typical of PSTT, in which there is diffuse positive staining for hPL and staining for [bgr]-hCG tends to be focal or absent.
The most important nontrophoblastic tumor in the differential diagnosis is squamous cell carcinoma of the cervix. The epithelioid tumor cells of ETT can easily be mistaken for malignant squamous cells and tumor cells can even replace the surface epithelium and mimic dysplastic squamous epithelium. 8 Differentiation of ETT from squamous cell carcinoma requires recognition of the dual cell population (intermediate and syncytiotrophoblastic cells) in the former. Keratin pearls and intercellular bridges, which can be seen in squamous cell carcinoma, are not present in ETT. Immunohistochemistry is particularly helpful in the differential diagnosis. [bgr]-hCG and hPL-positive cells are generally not present in squamous cell carcinoma. Inhibin-alpha is a highly sensitive and relatively specific marker for gestational trophoblastic lesions. It marks a population of cells in ETT, but staining for inhibin is absent in squamous cell carcinoma. 9 Finally, immunostains for low molecular weight cytokeratins such as cytokeratin 18 are strongly and diffusely positive in ETT but are negative or only focally and weakly positive in squamous cell carcinoma. 8
In summary, we report an epithelioid trophoblastic tumor arising in the uterine corpus of a postmenopausal woman. The diagnosis was confirmed by immunohistochemical stains. Our findings indicate that epithelioid trophoblastic tumor, like choriocarcinoma and PSTT, can occur in postmenopausal women many years after a gestational event. Additional cases need to be studied to determine if the mitotic index is linked to release from a long latency period or if it correlates with the clinical behavior of the tumor.
The authors thank Dr. Robert J. Kurman (Department of Pathology and Gynecology-Obstetrics, School of Medicine, Johns Hopkins University) for reviewing the case and confirming the diagnosis.
1. Hamazaki S, Nakamoto S, Okino T, et al. Epithelioid trophoblastic tumor[colon] morphological and immunohistochemical study of three lung lesions. Hum Pathol 1999; 30[colon]1321[ndash]7.
2. Jones WB, Romain K, Erlandson RA, et al. Thoracotomy in the management of gestational choriocarcinoma[colon] a clinicopathologic study. Cancer 1993; 72[colon]2175[ndash]81.
3. Lathrop JC, Wachtel TJ, Meissner GF. Uterine choriocarcinoma fourteen years following bilateral tubal ligation. Obstet Gynecol 1978; 51[colon]477[ndash]82.
4. Massenkeil G, Crombach S, Dominik F, et al. Metastatic choriocarcinoma in a postmenopausal woman. Gynecol Oncol 1996; 61[colon]432[ndash]7.
5. McLellan R, Buscema J, Currie JL, et al. Placental site trophoblastic tumor in a postmenopausal woman. Am J Clin Pathol 1991; 95[colon]670[ndash]5.
6. Mazur MT. Metastatic gestational choriocarcinoma. Unusual pathologic variant following therapy. Cancer 1989; 63[colon]1370[ndash]7.
7. Redline RW, Abdul-Karim FW. Pathology of gestational trophoblastic disease. Semin Oncol 1995; 22[colon]96[ndash]109.
8. Shih I-M, Kurman RJ. Epithelioid trophoblastic tumor. A neoplasm distinct from choriocarcinoma and placental site trophoblastic tumor simulating carcinoma. Am J Surg Pathol 1998; 22[colon]1393[ndash]403.
9. Shih I-M, Kurman RJ. Immunohistochemical localization of inhibin-alpha in the placenta and gestational trophoblastic lesions. Int J Gynecol Pathol 1999; 18[colon]144[ndash]50.
10. Shih I-M, Seidman JD, Kurman RJ. Placental site nodule and characterization of distinctive types of intermediate trophoblast. Hum Pathol 1999; 30[colon]687[ndash]94.
11. Silva EG, Tornos C, Lage J, et al. Multiple nodules of intermediate trophoblast following hydatidiform moles. Int J Gynecol Pathol 1993; 12[colon]324[ndash]32.
12. Twiggs LB, Hartenbach E, Saltzman AK, et al. Metastatic placental site trophoblastic tumor. Int J Gynaecol Obstet 1998; 60[colon]S51[ndash]5.
13. Yeh I-T, O'Connor DM, Kurman RJ. Vacuolated cytotrophoblast[colon] a subpopulation of trophoblast in the chorion laeve. Placenta 1989; 10[colon]429[ndash]38.
Keywords:[copy] 2000 Lippincott Williams [amp] Wilkins, Inc.
Gestational trophoblastic disease; Epithelioid trophoblastic tumor; Postmenopausal; Long latent period; Chorionic-type intermediate trophoblast