Endometrial cancer is often discussed as a single disease, but researchers now know that it is made up of several different molecular subtypes. These subtypes can behave very differently, affecting how quickly a cancer grows, how likely it is to return, and which treatments may work best.
A new systematic review and meta-analysis is helping shine a spotlight on one of the least understood groups: high-grade endometrioid endometrial cancers with no specific molecular profile (NSMP). The findings suggest that this subtype represents nearly one-third of high-grade endometrial cancers and may play an important role in the future of personalized cancer care.
What Is NSMP Endometrial Cancer?
Modern molecular testing divides endometrial cancer into four major groups:
- POLE-ultramutated tumors
- Mismatch repair-deficient (MMRd) tumors
- p53-abnormal tumors
- No specific molecular profile (NSMP) tumors
NSMP is diagnosed when a tumor does not fit into any of the other three categories. While it may sound like a catch-all group, researchers now believe NSMP cancers have their own unique biology and may require more personalized treatment approaches.
What the Research Found
Researchers reviewed 31 studies involving more than 2,600 patients with Grade 3 endometrioid endometrial cancer.
The analysis found that approximately 29% of high-grade endometrioid endometrial cancers were classified as NSMP. In other words, nearly one in three patients with this aggressive form of cancer falls into a molecular category that is still being defined.
The review also found regional differences, with NSMP tumors appearing more common in North America than in Europe, although the reasons for these differences remain unclear.
Why This Discovery Matters
Grade 3 endometrial cancers are considered high-risk because they are more likely to grow and spread than lower-grade tumors. However, doctors have long recognized that not all Grade 3 cancers behave the same way.
The study found that NSMP tumors generally have an intermediate prognosis.
They tend to perform:
- Better than p53-abnormal tumors, which are often linked to poorer outcomes
- Worse than POLE-ultramutated tumors, which typically have excellent outcomes
- Similar to some mismatch repair-deficient cancers
This helps explain why some patients with high-grade disease do much better than expected while others face a more aggressive course.
Why NSMP May Not Be Just One Disease
One of the most important conclusions from recent research is that NSMP tumors are highly diverse.
Some are linked to estrogen exposure and obesity and may have relatively favorable outcomes. Others appear more aggressive and may carry additional genetic changes associated with poorer survival.
Researchers are now investigating whether factors such as estrogen receptor status, KRAS mutations, PIK3CA mutations, and L1CAM expression can help further divide NSMP cancers into smaller groups with different risks and treatment needs.
This could allow doctors to better identify which patients need more intensive treatment and which may be able to avoid unnecessary therapies.
The Future of Personalized Endometrial Cancer Care
The growing use of molecular profiling is transforming how endometrial cancer is diagnosed and managed.
This review highlights that NSMP is not a rare subtype but a major part of the high-grade endometrial cancer landscape. As researchers learn more about the biology of these tumors, molecular testing may help guide treatment decisions more accurately than traditional grading systems alone.
For patients, that could mean more personalized care, better treatment selection, and improved outcomes. What was once considered a poorly defined category is quickly becoming one of the most important areas of research in endometrial cancer.
Source:
Casanova J, Ramos AS, Babiciu A, Moutinho F, Tripepi M, da Costa AG, et al. Prevalence of high-grade endometrioid endometrial cancer of no specific molecular profile (NSMP): A systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2026;316:114794. Accessed by: https://www.sciencedirect.com/science/article/pii/S030121152501070X
