Transformation of a post-cesarean section placental site nodule into a coexisting epithelioid trophoblastic tumor and placental site trophoblastic tumor: a case report
© Chen et al.; licensee BioMed Central Ltd. 2013
Received: 30 December 2012
Accepted: 9 May 2013
Published: 20 May 2013
Placental site nodules (PSNs) and epithelioid trophoblastic tumors (ETTs) respectively represent non-neoplastic and neoplastic lesions of chorionic-type intermediate trophoblasts (ITs). Many patients with a PSN have a history of a cesarean section (CS) or therapeutic abortion. Recent evidence shows that a PSN may progress to an ETT. Herein, we describe a coexisting ETT and placental site trophoblastic tumor (PSTT) intimately associated with PSNs in the post-cesarean lower uterine segment of a 41-year-old woman. The patient presented with abnormal vaginal bleeding 1 year after a cesarean delivery for her most recent pregnancy. We speculated that the neoplasms had transformed from PSNs, the formation of which was related to faulty expulsion of the placental tissue or abnormal colonization of chorionic-type ITs during the CS. Neoplastic trophoblastic cells derived from PSNs displayed differentiation plasticity toward chorionic-type ITs and implantation site ITs that were respectively constituted of an ETT and PSTT.
The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1597949195882123
KeywordsPlacental site nodule Epithelioid trophoblastic tumor Placental site trophoblastic tumor Intermediate trophoblast Cesarean section
Gestational trophoblastic neoplasms are a group of fetal trophoblastic tumors including choriocarcinomas, epithelioid trophoblastic tumors (ETTs), and placental site trophoblastic tumors (PSTTs) . Recent studies demonstrated distinct trophoblastic differentiation in these tumors [1–4]. A choriocarcinoma consists of an admixture of syncytiotrophoblasts, cytotrophoblasts, and intermediate trophoblasts (ITs), whereas an ETT and PSTT respectively show differentiation of chorionic-type ITs and implantation-site ITs. Mixed gestational trophoblastic neoplasms of combinations of choriocarcinomas, ETTs, and/or PSTTs were also described [3, 5–7]. The most common combination is a choriocarcinoma admixed with an ETT and/or PSTT. To our knowledge, only one case of a mixed ETT and PSTT was reported in the literature . Although cellular differentiation of gestational trophoblastic neoplasms has clearly been elucidated, their pathogenesis remains poorly understood. In contrast to choriocarcinomas that commonly occur subsequent to a molar pregnancy, only a minority of cases with an ETT or PSTT had an antecedent molar pregnancy [1, 4]. Little is known about the morphologic transition from a precursor lesion to a gestational trophoblastic neoplasm. Herein, we report a case of a coexisting ETT and PSTT centered in the post-cesarean lower uterine segment. Placental site nodules (PSNs) were intimately associated with the neoplasm. We speculated that the formation of these PSNs was related to a cesarean section (CS), and the PSNs subsequently progressed to the coexisting ETT and PSTT.
A 41-year-old woman presented with abnormal vaginal bleeding for 2 months. She had a history of two cesarean deliveries and one spontaneous abortion. She had undergone excision of a uterine adenomyosis 3 years previous. Her latest pregnancy resulted in the delivery of a full-term baby 1 year previous. The physical examination was otherwise normal. Pelvic ultrasonography showed focal thickening of the endometrium. She received endometrial curettage with a clinical diagnosis of endometrial hyperplasia. A serum β-human chorionic gonadotropin (β-hCG) measurement was performed 1 week later because an IT tumor was suspected after pathologic examination of the endometrial curettage specimen. The β-hCG level was not elevated (1 mIU/ml; reference range: 0 ~ 5 mIU/ml). The abdominal and pelvic computed tomographic scans exhibited an enlarged uterus with an irregular contour and heterogeneous contrast enhancement without para-aortic or pelvic lymphadenopathy. No metastatic lesion was detected on a chest x-ray. She underwent a total abdominal hysterectomy. Neither postoperative chemotherapy nor radiotherapy was given. She was alive with no evidence of local recurrence or distant metastasis 30 months after the hysterectomy.
In the periphery of the nodules, larger pleomorphic cells, which histologically and immunohistochemically differed from tumor cells of the ETT, were seen (Figure 2C, H). They were polygonal with abundant eosinophilic cytoplasm and relatively obvious nuclear atypia. They had invaded the myometrium in cell cords, dissecting and separating the smooth muscle bundles. They were immunoreactive for CD146 and hPL but negative for p63 (Figure 2D-F). Ki-67 labeled about 10% of the tumor cells. These histologic and immunohistochemical findings were consistent with features of a PSTT. At the interface of the ETT and PSTT components, both type of tumor cells merged imperceptibly.
In addition, several microscopic hypocellular nodular lesions, closely associated with the mixed ETT and PSTT, were found in the endometrium of the lower uterine segment, the surface of the endocervix, and the fibrous scar of the CS (Figure 2B). They had circumscribed margins and were round or plaque-like in shape. They were composed of mononucleate ovoid cells arranged in single cells and small sheets in a hyaline background. These cells had uniform nuclei with fine chromatin. The immunohistochemical findings were the same to those of the ETT. Compared to the ETT, the nodular lesions were smaller in size and paucicellular. No necrosis was found. The Ki-67 proliferation index was <5%. Based on the histologic and immunohistochemical features, the smaller nodular lesions represented PSNs. In summary, the tumor represented a rare example of a coexisting ETT and PSTT that had likely transformed from PSNs. Microscopic findings of the endometrial curettage specimen were similar to those of the hysterectomy specimen, except that no PSNs were present in the former.
ETTs and PSTTs are rare gestational trophoblastic neoplasms, with respective differentiation toward chorionic-type ITs and implantation-site ITs . The non-neoplastic counterpart of an ETT is a PSN, whereas that of a PSTT is an exaggerated placental-site reaction (EPSR). The pathogenesis of ETTs and PSTTs remains obscure. A recent study demonstrated a lack of a biologic link between an EPSR and PSTTs . However, atypical PSNs with morphologic features intermediate between typical PSNs and ETTs were described [4, 9]. Transformation of a PSN through an atypical PSN to a malignant ETT was also reported . In a clinicopathologic study of 14 cases of ETTs, two cases were intimately associated with PSNs . Those findings suggest that PSNs have the potential to develop into ETTs. The transition from a PSN to a coexisting ETT and PSTT in the current case further supports the concept. Moreover, a similar distribution of ETTs and PSNs in the uterus also implies a link between them. Approximately half of ETT cases and 40% of PSN cases are located in the lower uterine segment and/or upper endocervix [3, 4, 9, 11, 12]. A recent study showed a lack of a Y-chromosome complement in >80% of cases of ETTs . Analysis of the Y allele in PSNs may be helpful to further clarify the relationship between ETTs and PSNs.
Normal placental-site tissue is expelled from the uterus within several weeks postpartum . Factors contributing to the retention of ITs that lead to PSN formation remain unclear. Much evidence supports surgical interventions, including CSs and therapeutic abortions, being related to PSN formation. Many patients with PSNs have a history of a therapeutic abortion and/or CS [4, 11]. Fistulous tracts of the lower uterine segment, coated by ITs resembling PSNs, were described in patients who had received a CS [14–17]. The endometrium damaged by a CS or therapeutic abortion might not undergo cyclic shedding during subsequent menstrual cycles. Perturbation of endometrial shedding may contribute to PSN formation . The present case showed distribution of PSNs at the CS site, which supports the relationship between PSN formation and surgical interventions.
Interestingly, our case showed mixed features of an ETT and PSTT. The frequency of ETTs combined with other gestational trophoblastic neoplasms is not low. In fact, the histologic, ultrastructural, and immunohistochemical features of ETTs were first described in lungs of patients with a choriocarcinoma following intensive chemotherapy [18, 19]. The largest clinicopathologic study of ETTs, that included 14 patients, showed three cases combined with a choriocarcinoma and/or a PSTT . Only one case of a mixed ETT and PSTT without a choriocarcinoma component was found in the literature . The 15-year-old patient had a history of a preceding complete mole 1 year before the diagnosis of the mixed ETT and PSTT. Abnormal vaginal bleeding was the presenting symptom. The serum β-HCG level was not available. The tumor was limited to the uterus. She underwent a hysterectomy without postoperative chemotherapy and had no evidence of tumor recurrence or metastasis 84 months later. The two cases of a mixed ETT and PSTT, including ours, had clinical presentations similar to those of a pure PSTT or ETT [3, 7, 20, 21]. With a pure PSTT or ETT, abnormal vaginal bleeding is the most common presenting symptom, and serum β-HCG levels are elevated in approximately 80% of patients. Because only two cases of a mixed ETT and PSTT were reported, it is difficult to establish the prognostic factors of the tumor. These two cases, both of which had a tumor limited to the uterus, like most patients with a stage I pure ETT or PSTT, had a favorable prognosis after a hysterectomy. The clinical behavior of a mixed ETT and PSTT seems similar to that of a pure ETT or PSTT, but more cases are required to elucidate its prognosis. Long-term follow-up is essential for patients with a mixed ETT and PSTT, because patients with a stage I pure ETT or PSTT occasionally have local recurrence or distant metastasis during the follow-up period [3, 7, 20, 21]. As the β-HCG level was not elevated in 20% of patients with a PSTT or ETT, glypican 3 was recently suggested to be a potential serum tumor marker of gestational trophoblastic neoplasms . The role of glypican 3 as a tumor marker needs further clinical evaluation.
The hybrid features of the present tumor were consistent with the proposed model of pathogenesis of gestational trophoblastic neoplasms [2, 4]. In this model, transformed trophoblastic stem cells retain differentiation plasticity. Stem cells are able to differentiate toward cytotrophoblast, syncytiotrophoblast, chorionic-type ITs and implantation-site ITs. This model also explains the sensitivity of trophoblastic neoplasms to chemotherapy. Choriocarcinomas, the most primitive trophoblastic tumors, are sensitive to chemotherapy. Conversely, ETTs and PSTTs are not responsive to chemotherapy due to their more-differentiated natures. Because of the differentiation plasticity of neoplastic trophoblasts, it is clinically critical for pathologists to thoroughly examine pathologic specimens, particularly small curettage samples, to identify components of trophoblastic neoplasms: ETTs, PSTTs, choriocarcinomas, or their combinations. Therapeutic approaches to gestational trophoblastic tumors rather depend on the differentiation of neoplastic trophoblasts. An immunohistochemical panel including cytokeratin 18, HLA-G, HSD3B1, β-HCG, β-catenin, hPL, CD146, p63, and Ki-67 can be of great help in establishing a correct diagnosis .
This report supports PSNs possibly being precursor lesions of trophoblastic neoplasms. The present case showed that PSNs had transformed into rare gestational trophoblastic neoplasms which were composed of ETTs and PSTTs. Although PSNs are non-neoplastic lesions of chorionic-type ITs, some trophoblasts of PSNs still retain differentiation plasticity and can differentiate into other trophoblasts such as implantation-site ITs in the present tumor. The intimate association between PSNs and the CS scar indicates that surgical interventions may lead to retention of ITs in the uterus. The present case represents an extremely rare complication of a CS.
Written informed consent was obtained from the patient for publication of this Case Report and all accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
β-Human chorionic gonadotropin
Exaggerated placental site reaction
Epithelioid trophoblastic tumor
Placental-site trophoblastic tumor.
The authors thank Dr. Ie-Ming Shih for his helpful comments on interpreting the curettage specimen.
- Shih IeM: Gestational trophoblastic neoplasia-pathogenesis and potential therapeutic targets. Lancet Oncol. 2007, 8: 642-650. 10.1016/S1470-2045(07)70204-8.View ArticlePubMed
- Mao TL, Kurman RJ, Huang CC, Lin MC, Shih IeM: Immunohistochemistry of choriocarcinoma: an aid in differential diagnosis and in elucidating pathogenesis. Am J Surg Pathol. 2007, 3: 1726-1732.View Article
- 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. 10.1097/00000478-199811000-00010.View ArticlePubMed
- Shih IM, Kurman RJ: The pathology of intermediate trophoblastic tumors and tumor-like lesions. Int J Gynecol Pathol. 2001, 20: 31-47. 10.1097/00004347-200101000-00004.View ArticlePubMed
- Ramondetta LM, Silva EG, Levenback CF, Burke TW: Mixed choriocarcinoma in a postmenopausal patient. Int J Gynecol Cancer. 2002, 12: 312-316. 10.1046/j.1525-1438.2002.01110.x.View ArticlePubMed
- Shen DH, Khoo US, Ngan HY, Ng TY, Chau MT, Xue WC, Cheung AN: Coexisting epithelioid trophoblastic tumor and choriocarcinoma of the uterus following a chemoresistant hydatidiform mole. Arch Pathol Lab Med. 2003, 127: e291-e293.PubMed
- Baergen RN, Rutgers JL, Young RH, Osann K, Scully RE: Placental site trophoblastic tumor: a study of 55 cases and review of the literature emphasizing factors of prognostic significance. Gynecol Oncol. 2006, 100: 511-520. 10.1016/j.ygyno.2005.08.058.View ArticlePubMed
- Dotto J, Hui P: Lack of genetic association between exaggerated placental site reaction and placental site trophoblastic tumor. Int J Gynecol Pathol. 2008, 27: 562-567. 10.1097/PGP.0b013e31816d1d00.View ArticlePubMed
- Mao TL, Seidman JD, Kurman RJ, Shih IeM: Cyclin E and p16 immunoreactivity in epithelioid trophoblastic tumor-an aid in differential diagnosis. Am J Surg Pathol. 2006, 30: 1105-1110.View ArticlePubMed
- Tsai HW, Lin CP, Chou CY, Li CF, Chow NH, Shih IM, Ho CL: Placental site nodule transformed into a malignant epithelioid trophoblastic tumour with pelvic lymph node and lung metastasis. Histopathology. 2008, 53: 601-604.PubMed
- 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. 10.1097/00000478-199011000-00002.View ArticlePubMed
- Huettner PC, Gersell DJ: Placental site nodules: a clinicopathologic study of 38 cases. Int J Gynecol Pathol. 1994, 13: 191-198. 10.1097/00004347-199407000-00001.View ArticlePubMed
- Yap KL, Hafez MJ, Mao TL, Kurman RJ, Murphy KM, Shih IeM: Lack of a y-chromosomal complement in the majority of gestational trophoblastic neoplasms. J Oncol. 2010, 2010: 364508-PubMed CentralView ArticlePubMed
- Ismail SM, Lewis CG, Shaw RW: Postcaesarean section uterovesicle fistula lined by persistent intermediate trophoblast. Am J Surg Pathol. 1995, 19: 1440-1443. 10.1097/00000478-199512000-00011.View ArticlePubMed
- Fischer RJ: Symptomatic cesarean scar diverticulum: a case report. J Reprod Med. 2006, 51: 742-744.PubMed
- O’Neill CJ, Cook I, McCluggage WG: Postcesarean delivery uterine diffuse intermediate trophoblastic lesion resembling placental site plaque. Hum Pathol. 2009, 40: 1358-1360. 10.1016/j.humpath.2009.01.023.View ArticlePubMed
- Liang Y, Zhou F, Chen X, Zhang X, Lü B: Atypical epithelioid trophoblastic lesion with cyst and fistula formation after a cesarean section: a rare form of gestational trophoblastic disease. Int J Gynecol Pathol. 2012, 31: 458-462. 10.1097/PGP.0b013e31824a1dc9.View ArticlePubMed
- Mazur MT: Metastatic gestational choriocarcinoma. Unusual pathologic variant following therapy. Cancer. 1989, 63: 1370-1377. 10.1002/1097-0142(19890401)63:7<1370::AID-CNCR2820630723>3.0.CO;2-G.View ArticlePubMed
- Jones WB, Romain K, Erlandson RA, Burt ME, Lewis JL: Thoracotomy in the management of gestational choriocarcinoma A clinicopathologic study. Cancer. 1993, 72: 2175-2181. 10.1002/1097-0142(19931001)72:7<2175::AID-CNCR2820720718>3.0.CO;2-K.View ArticlePubMed
- Hassadia A, Gillespie A, Tidy J, Everard RGNJ, Wells M, Coleman R, Hancock B: Placental site trophoblastic tumour: clinical features and management. Gynecol Oncol. 2005, 99: 603-607. 10.1016/j.ygyno.2005.06.054.View ArticlePubMed
- Hyman DM, Bakios L, Gualtiere G, Carr C, Grisham RN, Makker V, Sonoda Y, Aghajanian C, Jewell EL: Placental site trophoblastic tumor: analysis of presentation, treatment, and outcome. Gynecol Oncol. 2013, 129: 58-62. 10.1016/j.ygyno.2012.12.029.View ArticlePubMed
- Ou-Yang RJ, Hui P, Yang XJ, Zynger DL: Expression of glypican 3 in placental site trophoblastic tumor. Diagn Pathol. 2010, 5: 64-10.1186/1746-1596-5-64.PubMed CentralView ArticlePubMed
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.