Atypical Placental Site Nodule and Related Lesions: Interobserver Reproducibility

Placental site nodule (PSN) and atypical placental site nodule (APSN) are chorionic-type intermediate trophoblastic lesions, the latter characterized by worrisome histologic characteristics and risk for subsequent trophoblastic neoplasia, mainly epithelioid trophoblastic tumor (ETT). There is no consensus or evidence-based criteria on which and how many features are needed for APSN diagnosis. We assessed interobserver reproducibility of APSN, PSN, and ETT. Five expert pathologists evaluated representative whole slide images (1 hematoxylin-and-eosin and 1 Ki-67/AE1-AE3 immunohistochemical stain) of 50 cases with APSN, PSN, or ETT index diagnosis and recorded independently diagnostic impressions and worrisome histologic characteristics (extensive lesional tissue, severe nuclear atypia, hypercellularity, mitotic activity, irregular borders, tumor necrosis, and Ki-67 index ≥5%). Diagnostic consensus was reached in 96% (agreement of ≥3 experts), and there was agreement with the index diagnosis in 75%. Overall, Fleiss' kappa score (κ) was 0.46 (highest for PSN [κ=0.58] and lowest for APSN [κ=0.34]). Substantial agreement was reached in evaluating extensive lesional tissue (lesional tissue exceeding normal, κ=0.76) and Ki-67 in the entire lesion (intraclass correlation coefficient=0.62). Most other features showed moderate reproducibility. In cases with a higher degree of agreement, most APSN harbored 3 to 6 worrisome features, while most PSN had <2 and all ETTs had ≥6. In conclusion, APSN diagnosis is challenging, reflected by fair reproducibility among experts. However, agreement was reached in most instances, highlighting the beneficial role of consultation. Criteria refinement may increase reproducibility with the highest agreement of extensive lesional tissue and proliferation in the entire lesion with Ki-67/AE1-AE3. The presence of ≥3 worrisome features might be a reasonable threshold to avoid APSN overdiagnosis.