In a recent study, Mayo Clinic researchers, in collaboration with other institutions, have shown that “high” tumor budding in patients with colorectal carcinoma (CRC) is independently associated with a significantly worse prognosis. CRC ranks second in cancer deaths among malignancies that affect both men and women in the United States. And tumor budding indicates an aggressive form of CRC and has been associated with poor outcomes in multiple studies. However, the methods of evaluation and the composition of study groups have been highly variable to date and, as such, are difficult to reproduce in clinical practice.
In contrast, the new study’s reproducibility data provides support for the routine widespread implementation of tumor budding in clinical reports.
“For many years, an issue with tumor budding has been that a lot of CRC studies focus only on one particular site, such as cancers of the rectum, or they only look at a particular stage, such as early-stage cancer,” says Thomas Smyrk, M.D., Consultant with Mayo’s Department of Laboratory Medicine and Pathology. “We think our study is an improvement in that regard, in that it takes on all stages, a wide age group, and all parts of the colon and rectum.”
The study, published in The American Journal of Surgical Pathology, represents the largest population base of CRC patients evaluated to date. Archived, paraffin-embedded tissue specimens were requested for 553 CRC cases—diagnosed in women who entered the Iowa Women’s Health Study between January 1, 1986, through December 31, 2002, and subsequently developed CRC.
Roughly one-third of cohort patients showed high tumor budding (≥ 10 tumor buds in a ×20 objective field); those patients had a 2.5 times greater likelihood of dying from CRC than those with no or low budding.
A “tumor bud” is strictly defined as separate from the main tumor and constitutes a small group of cells, five or less, which “typically happens at the advancing edge of a tumor, and it looks like these groups of cells are breaking off the edge of the tumor,” says Dr. Smyrk, who is senior author of the study paper. “There are cases where you might only see one or two collections of buds in an entire slide, but if you have more than ten buds in any particular field, that’s a sign of bad prognosis.”
Researchers used a commonly accepted definition of a tumor bud along with a simple bud evaluation method. Although the patient cohort was exclusively Caucasian and did not include men, the study method determined a histologic cutoff for high tumor budding and confirmed its robust prognostic significance.
“We have to acknowledge the study’s not perfect, but we think it’s an improvement on other such studies, and more generalized,” says Dr. Smyrk. “We found that the method worked very well and is easy to use. As proof of that easiness, we had a variety of different pathologists count buds for us, some with an interest in colon cancer, others who are not necessarily specialists, and we had very good correlation between all the different counters.”
Beside the method being a very powerful prognosticator, its user-friendliness makes it easily reproducible in general practice. Hence, Dr. Smyrk and his colleagues deem the method ready to go.
“I don’t think it needs any more tweaking,” he says. “The method we used in the paper is the method we should use, and I think it’s just a matter of getting the word out and getting everyone to agree with it.”
This method, if implemented, won’t necessarily change treatment regimes for CRC patients. Tumor budding does not appear to be a marker for a specific mutation that could be a target for therapy. But because of the method’s powerful prognostic merit, it could help change the way patients are managed. For example, most pathologists in the U.S. are not currently reporting tumor budding in cancer found in a polyp, but there is evidence suggesting that such a finding indicates the need for additional surgery.
Another possible application may be in patients with resected stage II CRC (those without positive lymph nodes). These patients don’t generally receive adjuvant chemotherapy, but the presence of tumor budding could be a push in the direction for more aggressive clinical management.