Discovery of a cell: Reflections on the checkered history of intermediate trophoblast and update on its nature and pathologic manifestations

In 1976, a series of 12 cases describing a lesion that had previously not been well characterized was reported as "trophoblastic pseudotumor of the uterus." Up until that time rare reports of the lesion had classified it most often as an unusual type of sarcoma associated with pregnancy. All patients in that series were alive and well except for one who died from complications of a uterine perforation occurring at the time of a diagnostic curettage. Thus, it appeared to be a benign neoplasm but subsequently it was found that some exhibited malignant behavior and the tumor was renamed "placental site trophoblastic tumor." A variety of observations pointed to an origin in a distinctive cell of the placental site, designated "intermediate trophoblast," which physiologically is seen in the normal implantation site. Subsequently, another subset of intermediate trophoblast cells originating from the chorion laeve have been shown to give rise to the placental site nodule/plaque, a well-circumscribed and usually microscopic incidental finding as well as the epithelioid trophoblastic tumor, its putative malignant counterpart. The initial description of "trophoblastic pseudotumor" opened a new area of research which brought to bear immunohistochemical and molecular genetic analyses that eventually has led to new insights in the diverse morphologic changes occurring in early placentation and also led to the development of a new classification of trophoblastic tumors and tumor-like lesions.