A 30-year-old woman gravida 3, para 2 gave birth to a healthy baby at 37 weeks' gestation and delivered the intact placenta spontaneously. The pregnancy was complicated by preeclampsia (which had occurred during her previous pregnancies as well), but fetal monitoring and ultrasound were normal throughout gestation. She was asymptomatic and denied experiencing cough, shortness of breath, nausea, and vomiting. She took no medications during pregnancy, reported no smoking, and drinks only rarely but not when pregnant. Her family history is positive for diabetes mellitus, atherosclerosis, and head and neck cancer in her paternal grandmother. She reported no allergies. All 3 of her children are healthy.
Her physical examination was unremarkable, with normal neurologic function and no evidence of jaundice, anemia, or lymphadenopathy. Results of her chest examination were normal, with no suggestion of pulmonary consolidation, effusion, or cardiac anomaly. A rectovaginal examination revealed a normal-sized uterus for her postpartum status. The sidewalls and cul-de-sac were smooth, and the adnexal areas were clear. A Papanicolaou smear was performed 7 weeks after delivery and was unremarkable. β-Human chorionic gonadotropin (hCG) levels were in the normal postpartum range: 17 mIU/mL 1 month after delivery, 7 mIU/mL 6 weeks after delivery, and less than 5 mIU/mL thereafter. Computed tomographic scans of the mother's chest, brain, abdomen, and pelvis were normal. Her baby had a completely normal examination, appropriate for gestational age.
The placenta weighed 585 g and exhibited an area that suggested hemorrhagic infarction measuring 3 cm in diameter (Figure 1). Microscopically, there was evidence of focal parenchymal villitis, focal chronic ischemic changes, chorionic villous edema, fetal erythropoiesis, and an intervillous thrombus. The grossly infarcted area was composed of a necrotic mass surrounded by sheets of atypical cells showing marked nuclear pleomorphism and hyperchromasia (Figures 2 and 3). The analysis of these atypical cells by immunohistochemistically staining them for β-hCG demonstrated strong positivity (Figure 4).
What is your diagnosis?
Pathologic Diagnosis: Intraplacental Choriocarcinoma
Although most cases of gestational choriocarcinoma arise from other forms of gestational trophoblastic disease, one third of the cases of choriocarcinoma follow normal pregnancy.1 Intraplacental choriocarcinoma is a very rare subset of these cases, but it has been reported in the literature since 1963. In a single case report, Driscoll1 described this phenomenon as “choriocarcinoma in situ” because no metastatic lesions were identified, the mother and child were completely healthy, and the malignancy was found incidentally while examining an “infarcted area” within the placenta. Since then, many cases have been described. Jacques et al2 reported several cases of the in situ lesion in which the smooth transition from benign to malignant was observed and documented near the surface of the villi. The traditional belief about the origin of gestational choriocarcinoma is that it arises from the retained trophoblastic tissue of a gestational event. However, because Driscoll and subsequent authors have identified choriocarcinoma within the placenta of viable pregnancies, the prior assumptions about the origin of gestational choriocarcinoma are challenged, and Fox and Laurini3 have posited that the placenta is the usual site for gestational choriocarcinoma in most cases. It has been proposed by many of the authors who report intraplacental choriocarcinoma that this lesion may be more common than currently recognized but that it goes undetected because of insufficient sampling. The lesion can be so small, however, as to render such meticulous inspection of the placenta difficult and impractical. Lung and brain metastases arising from intraplacental choriocarcinoma have been reported after initial discovery of the primary lesion within the placenta by Lage and Roberts.4 On rare occasions, choriocarcinoma metastatic to distant organs could potentially be derived from an unidentified primary lesion in the placenta. In these cases, it has been suggested that the primary lesion arose within the placenta but has spontaneously regressed or been overlooked. Necrosis and fragmentation of these lesions may be responsible for metastases from intraplacental choriocarcinoma, as proposed by Brewer and Gerbie.5 Term pregnancy complicated by intraplacental choriocarcinoma has occurred, however, without detriment to the infant and despite maternal metastasis that was found within a week of delivery.4 Complications specific to intraplacental choriocarcinoma during pregnancies include severe neonatal anemia with fetal-maternal hemorrhage, fetomaternal transfusion, fetal hydrops, retroplacental hemorrhage, placental abruption, elevated maternal serum α-fetoprotein, and stillbirth.4,6–9
The gross pathology of this lesion resembles an area of infarction within the placenta, which has been sampled as a matter of routine in all reported cases, with subsequent detection of the malignancy on microscopic analysis.1–10 Metastases are usually well circumscribed and also hemorrhagic.2 The interface of tumor-to-host tissue is usually well defined. The mass itself often exhibits significant necrosis in the center, and it is possible that viable tumor material will be detected only at the extreme periphery of the lesion, making careful sampling important for an accurate diagnosis.5 The lesion can also present with multifocal nodules instead of a discrete mass.2
The lesion is composed of cytotrophoblastic islands with an intervening syncytial trophoblast. Cytotrophoblastic tissue is more common in the core of the mass. Placental villi are generally not found in gestational choriocarcinomas, but the intraplacental variant involves malignant trophoblastic tissue arising directly from the villi and extending into the intervillous space. There is no invasion of the villous stroma itself.2 Histologic findings that are associated with a better prognosis include a marked lymphoid infiltrate and the presence of thick fibrin deposits at the tumor–host interface.
The differential diagnosis for intraplacental choriocarcinoma includes normal trophoblastic tissue of early gestation, molar pregnancy, placental site trophoblastic tumor, nongestational choriocarcinoma, and metastatic epithelial malignancies. In a placental site trophoblastic tumor, clusters of suspicious trophoblasts may lie near the villi, but they do not arise from them as the intraplacental choriocarcinoma does. Also, immunohistochemical staining of a placental site trophoblastic tumor for β-hCG and human placental lactogen demonstrates diffuse positivity for human placental lactogen with focal areas positive for β-hCG. This pattern is reversed in intraplacental choriocarcinoma, which shows diffuse β-hCG and focal human placental lactogen staining. Metastatic epithelial malignancies such as melanoma and breast carcinoma can be confused with intraplacental choriocarcinoma, but immunohistochemical staining for β-hCG, melanocytic antigen, and milk fat globulin can be very helpful in differentiating epithelial tumors from trophoblastic gestational tumors. A high proliferation index with the marker Ki-67 is seen in intraplacental choriocarcinoma that is greater than levels seen in normal placentas. Chromosomal analysis of the tumor cells can be helpful in ruling out nongestational choriocarcinoma metastatic to the placenta, since these lesions will not exhibit the presence of Y chromosomes, whereas a gestational malignancy will.10
Treatment includes removal of the placenta and subsequent monitoring of the mother for metastases. The newborn child should also be closely monitored. β-hCG levels must be followed to identify metastases but may not always be elevated. Periodic imaging of the mother and child, including chest radiographs and computed tomographic scans, is recommended to rule out metastatic sites that do not produce appreciable amounts of β-hCG. Administration of methotrexate has been extremely successful in eradicating metastases.6
Nongestational choriocarcinomas (those that arise from the ovaries) have a worse prognosis than choriocarcinomas that arise from a gestational event (pregnancy, hydatidiform mole, ectopic pregnancy, etc). However, among cases of gestational choriocarcinoma, intraplacental choriocarcinoma has the worst prognosis (intermediate between other gestational and nongestational choriocarcinomas). Mortality is approximately 10% higher in intraplacental choriocarcinoma than in other forms of gestational choriocarcinoma. Clinical outcomes depend on the stage of metastasis. Before chemotherapy was available, the overall survival at 5 years with hysterectomy alone was 32%, with 41% survival in the absence of metastases and 19% with metastases. Chemotherapy has increased survival to 81% in intraplacental choriocarcinoma without spread and to 70% in cases with metastasis. The prognosis is worse in lesions that develop early in normal gestations. It is not clear how these patients could be treated earlier without compromising the fetus. Increasing the practice of appropriate and careful placental examination could result in the identification of this malignancy more frequently, which would provide the opportunity for earlier intervention and treatment of any potential metastatic disease.