Cyclin E and p16 immunoreactivity in epithelioid trophoblastic tumor--an aid in differential diagnosis

Epithelioid trophoblastic tumor (ETT) is a relatively uncommon trophoblastic tumor that can be confused with several trophoblastic and nontrophoblastic lesions, notably the placental site nodule and invasive squamous carcinoma of the cervix. In this report, we analyzed the immunoreactivity of two cell cycle-regulated proteins, cyclin E and p16, in ETTs, placental site nodules and cervical squamous carcinomas to determine whether they are useful in their differential diagnosis. Other trophoblastic lesions were also evaluated. Using an H-score based on both percentage of positively stained cells and immunointensity, we found that ETTs demonstrated a much higher cyclin E staining score than placental site nodules (P<0.0001) permitting distinction of ETTs and placental site nodules with a sensitivity of 94.7% at a specificity of 91.7% using a cutoff H-score value of >40. Only two placental site nodules had scores above the cutoff and both showed morphologic features that placed them in an intermediate position between a typical placental site nodule and an ETT, so-called "atypical PSN." p16 immunoreactivity, was not detected in any of the ETTs and placental site nodules, whereas it was strongly and diffusely positive in the vast majority of cervical squamous carcinomas examined (83/87 cases) (P<0.001). Therefore, cyclin E expression is useful in distinguishing an ETT from a placental site nodule and p16 expression is useful in distinguishing an ETT from a cervical squamous carcinoma. The majority of other types of trophoblastic lesions showed diffuse and intense nuclear immunoreactivity for cyclin E whereas none were positive for p16.