Uncommon Morphologic Types of Endometrial Cancer and Their Mimickers: How Much Does Molecular Classification Improve the Practice for Challenging Cases?

The previous endometrial cancer (EC) FIGO staging primarily relied on the extent of the disease spread into the anatomical sites at diagnosis. The most recent one (2023) incorporates clinicopathological features such as histological subtype, tumor grade, the extent of lymphovascular space invasion (LVI), and, when available, molecular subtypes of EC. The emphasis on accurate histological typing, tumor grading, and the molecular features of the cancer is stronger than ever. This review addresses challenging diagnostic patterns in the histologic subtyping and grading EC under five categories: 1. EC with spindle cells, 2. EC with clear cells, 3. EC with a papillary architecture, 4. EC with a biphasic morphology, and 5. EC with a microglandular architecture. The morphological features differentiating low- and high-grade cancers are discussed, along with relevant clinical work-ups. Recent molecular genetic findings regarding the diagnosis and prognosis of the disease and the results of related clinical trials are summarized. The potential challenges in the evaluation of LVI follow these sections. The final section of the review includes an overview of the literature on incorporating molecular subtypes of EC into clinical practice.