Case 3 -

Metastatic Placental Site Trophoblastic Tumor Presenting as Vaginal Polyps Kenneth R. Lee Brigham and Women's Hospital Boston, MA

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Clinical History A 33 year-old woman described a sensation of "falling out." She was found to have 4 or 5 discrete vaginal polyps, each 1 to 2 cm, in the area of the hymenal ring. One of these was biopsied. Case 3 - Figure 1 - Vaginal polyp at low power showing normal surface squamous epithelium and cellular and edematous stroma. Case 3 - Figure 2 - Higher power demonstrating a zone of connective tissue separating the surface from the more cellular deep stroma. Case 3 - Figure 3 - Vaginal polyp with atypical epithelioid cells in a "cuffing" pattern around a blood vessel. Case 3 - Figure 4 - Mononuclear and multinucleated cells in an edematous stroma with rare mitotic figures (shown). Case 3 - Figure 5 - Mononuclear and multinucleated cells with small and large cytoplasmic vacuoles. Diagnosis Metastatic placental site trophoblastic tumor presenting as vaginal polyps Histologic Features The polyp contained a benign squamous surface overlying a proliferation of mostly single epithelioid cells with abundant eosinophilic, foamy or vacuolated cytoplasm and round to oval nuclei with rare mitotic figures in an edematous stroma. Discussion Differential diagnosis of vaginal polyps Benign Fibroepithelial polyps with atypical stromal cells [2, 7] cellular pseudosarcomatous [8] Decidual polyp Post operative spindle cell nodule rhabdomyoma leiomyoma Prolapsed fallopian tube Malignant Primary Carcinoma Sarcoma Melanoma Yolk sac tumor Metastatic Carcinoma (Uterus, Ovaries, Colon) Sarcoma, Melanoma [3] Trophoblastic Based on the microscopic appearance he remaining considerations were: Fibroepithelial polyp with stromal typia Metastatic carcinoma or melanoma Epithelioid smooth muscle tumor (primary or metastatic) Metastatic trophoblastic neoplasm Special stain results were as follows: Positive: AE1/AE3, CK7, CK20, EMA, HCG(few), HPL(rare) Negative: S-100, SMA, Desmin, Inhibin, Calretinin, Mucin These results narrowed the considerations to metastatic carcinoma or a trophoblastic neoplasm, with the fairly convincing HCG staining strongly supporting the latter. Additional history revealed that the patient had delivered a term infant 13 months previously, had no pregnancies prior to this, and was not currently pregnant or experiencing vaginal bleeding. A serum B-hCG was ordered and was "slightly elevated" at 16 mIU/ml. A D&C was recommended and it revealed blood clot containing cells similar to those in the vaginal polyp. A hysterectomy and vaginal polypectomies were performed. The uterus contained a placental site trophoblastic tumor (PSTT) involving the fundus and invading to the serosa. Residual PSTT was present in the vaginal polyps. The patient was subsequently treated with several cycles of a six-drug combination chemotherapy regimen until the B-hCG normalized. She has been without signs of a recurrence six months after presentation. Placental site trophoblastic tumor 1976 – Designated "trophoblastic pseudotumor" [5] based on 12 cases and felt to be an exaggerated form of "syncytial endometritis." Characterized as composed of large aggregates of cells resembling intermediate trophoblasts [6] but with nuclear pleopmorphism and variable mitotic activity. These cells extend between the myometrial fibers without extensive hemorrhage or necrosis. Replacement of vascular endothelium and extensive fibrin around vessels and elsewhere are characteristic [10]. 1981 – Potential for malignant behavior recognized, term "PSTT" coined for this neoplasm derived from implantation site trophoblasts 1999 – Review of reported experience totaling 88 cases [1]: Average age – 29y, most common symptom – vaginal bleeding, mean B-hCG – 800 (1 to 8300), usual antecedent - normal pregnancy, followed by abortion (either spontaneous or induced) and then complete mole. 83 cases with follow-up: Stage I & II - 62 cases, 3 deaths Stage III & IV – 21 cases, 15 deaths Metastases correlate with prior term delivery (82% vs 57%) and longer interval to symptoms (24 mo vs 12 mo) No ability to predict behavior with age, mitotic count (although some small series indicated increased mitoses as a predictor), hCG level, ploidy Immunohistochemistry of PSTT Positive AE1/AE3 CK18 Inhibin HPL Mel-CAM Ki-67 (14% + 7%) Negative (or rare positive cells) B-hCG PlAP Differential diagnosis of PSTT [10] Exaggerated placental site Placental site nodule Choriocarcinoma Epithelioid trophoblastic tumor Carcinoma Smooth muscle tumors Melanoma The exaggerated placental site (EPS) is a variant of a normal implantation wherein the trophoblastic proliferation is exuberant. It differs from a PSTT by the absence of large confluent accumulations of trophoblasts and with somewhat less nuclear atypia. Decidua and villi are often present, and there are more multinucleated cells than in PSTT. Importantly, there are no mitoses in contrast to their presence in PSTT. Mitoses may be difficult to evaluate in curettings, and the use of the Ki-67 index as a surrogate marker has been recommended. It is virtually zero in EST and averages around 14% in PSTT. It may however, be difficult to determine which cells are marking with Ki-67. Thus, some have advocated a double labeling technique using the Mel-CAM antibody to mark the cytoplasm of the trophoblast cells [10]. The placental site nodule [4, 11] may be confused with PSTT in a curetting. The cells, however, surround a central fibrin deposit and are amitotic. It is usually an incidental finding in the lower uterine segment. A choriocarcinoma (CCA) should not be confused with PSTT since it is biphasic with a prominent syncytiotrophoblast component not present in PSTT. There is usually abundant mitotic activity, hemorrhage and necrosis in CCA. Immunostains may help as CCA should be strongly positive for hCG and only minimally positive or negative for HPL, the reverse of that seen in PSTT. The epithelioid trophoblastic tumor (ETT) [9] is a recently described trophoblastic neoplasm felt to be the malignant counterpart of the intermediate trophoblasts of the chorion leave, which have an epitheliod appearance. It is considered by some to be part of the spectrum of PSTT and has a similar behavior. It is distinguished from PSTT by its sharply demarcated, "geographic" pattern of nests and cords of cells and by extensive hyaline material and necrosis. The epithelioid cells are smaller than those of PSTT. It is negative or only focally positive for HPL, HCG, PLAP, and Mel-CAM. The more common mimic of ETT is carcinoma, especially squamous carcinoma since the hyaline material resembles keratin, and unless one is aware of ETT this might be readily diagnosed as such. PSTT may also be diagnosed as carcinoma to those unwary. A non-keratinizing squamous carcinoma might readily be considered in curettings. Melanoma and epithelioid smooth muscle tumors might also appear similar to PSTT. Immunostains are diagnostic, but obviously require an awareness of the various possibilities. The current case is the only one recorded, as far as I can determine, in which the patient presented with a vaginal polyp as the only sign. Although 8 of 88 PSTT cases had vaginal metastases, in all of these the uterine tumor was found simultaneously with or preceded the vaginal tumor. The current case is also unusual in that the morphology and immunohistochemistry are not typical of PSTT. The cells have a sometimes vacuolated or spongy cytoplasm; they do not replace the myometrial vascular endothelium, and are not associated with abundant fibrin; the HPL is positive in only rare cells, whereas HCG is more diffusely positive and the inhibin is negative. Perhaps this variant morphology is related to the unusual presentation without uterine symptoms in this unique case. References Chang YL, Chang TC, Hsueh S, Huang KG, Wnag PN, Liu HP, Soong YK. Prognostic factors and treatment for placental site trophoblastic tumor – report of 3 cases and analysis of 88 cases. Gynecol Oncol 1999;73:216-222. Chirayil SJ, Tobon H. Polyps of the vagina: a clinicopathologic study of 18 cases. Cancer 1981;47:2904-2907. Gupta D, Neto AG, Deavers MT, Silva EG, Malpica A. Metastatic melanoma to the vagina: clinicopathologic and immunohistochemical study of three cases and literature review. Int J Gynecol Pathol 2003;22:136-140. Huettner PC, Gersell DJ. Placental site nodule: a clinicopathologic study of 38 cases. Int J Gynecol Pathol 1994;13:191-198. Kurman RJ, Scully RE, Norris HJ. Trophoblastic pseudotumor of the uterus: an exaggerated form of "syncytial endometritis" stimulating a malignant tumor. Cancer 1976:38:1214-1226. Kurman RJ, Young RH, Norris HJ, Main CS, Lawrence WD, Scully RE. Immunocytochemical localization of placental lactogen and chorionic gonadatropin in the normal placenta and trophoblastic tumors, with emphasis on intermediate trophoblast and the placental site trophoblastic tumor. Int J Gynecol Pathol 1984;3:101-121. Norris HJ, Taylor, HB. Polyps of the vagina. A benign lesion resembling sarcoma botryoides. Cancer 1966;9:227-232. Nucci MR, Young RH, Fletcher CDM. Cellular pseudosarcomatous fibroepithelial stromal polyps of the lower genital tract: an underrecognized lesion often misdiagnosed as sarcoma. Am J Surg Pathol 2000;24:231-240. 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. Shih IM, Kurman RJ. The pathology of intermediate trophoblastic tumors and tumor-like lesions. Int J Gynecol Pathol 2001;20:31-47. Young RH, Kurman RJ, Scully RE. Placental site nodules and plaques: a clinicopathologic analysis of 20 cases. Am J Surg Pathol 1990;14:1001-1009.