Stray 'micrometastases' could be missed, harming long-term survival, study suggests
WEDNESDAY, April 9 (HealthDay News) -- A new long-term analysis of breast cancer patient survival suggests it might be time to update the way pathologists test lymph node biopsies.
A team of New York City physicians found about one in four patients originally declared to be free of cancerous cells in their sentinel lymph nodes were actually not cancer-free, and that tiny cancer remnants called micrometastases reduced the women's survival over a 20-year period.
These findings address a long-standing question among breast cancer researchers: Are such micrometastases prognostically significant?
"This is the first study to show that there is a survival impact for the detection of micrometastases," said Dr. Stephen F. Sener, a professor of surgery at Northwestern University Feinberg School of Medicine in Chicago.
The results are published in the April 10 issue of the Journal of Clinical Oncology.
In the study, a team led by Dr. Hiram S. Cody III, a professor of clinical surgery at Memorial Sloan-Kettering Cancer Center in New York City, analyzed a population of 368 patients who were originally diagnosed with breast cancer in the 1970s. At the time, these patients were judged to be free of cancerous cells on the basis of a single tissue slice (standard procedure at that time). As a result of that diagnosis, these patients received no follow-up treatment for their disease.
Each of these patients was then monitored over the following 20 years or so. Cody and his team retrospectively reanalyzed the decades-old tissue samples using modern techniques. They then assessed how many of the slices did, in fact, contain cancerous cells, and whether those stray cancerous cells had affected the women's survival.
"What we found was that among these patients, 23 percent were converted to node-positive [cancer status], and among those who were converted, their survival was worse than among patients who remained node-negative," said Cody.
"The 23 percent number is very significant, because it argues that if pathologists just do one section, you may want to ask them to do more," he explained. "We think the information you get by doing more is significant."
According to Cody, 30 years ago the standard of care for breast cancer patients was complete dissection of the axillary lymph nodes (those found under the armpit) followed by cell-shape analysis using a single tissue slice from each node. Such a surgery would typically collect 15 to 20 nodes, on average. Today, however, a different, less traumatic approach called sentinel node biopsy is used.
In sentinel lymph node (SLN) biopsy, a patient's tumor is injected with a combination of dye and radioactive tracer molecules. The following day, only those lymph nodes to which the tracer molecules migrated (the SLNs) are biopsied and analyzed. So, instead of harvesting 15 to 20 nodes, on average only two are three are collected using the new technique.
That reduction in work per node has a real payoff, because pathologists can delve much deeper into each sample, Cody explained.
"Because you remove fewer nodes, you can study them more carefully, and we argue that the information you get by doing that is prognostically significant," he said.
Current guidelines from the College of American Pathologists recommend analyzing one tissue slice per biopsied lymph node, Cody noted. Yet for years, he said, physicians have known that the more carefully one looks, the more cancerous cells one can find. The problem has always been one of balancing the additional work and expense required against the likelihood of success -- some studies have suggested a pathologist would need to analyze as many as 1,600 additional sections to find a single additional node-positive case.
In the current study, Cody's team took four sections per node, analyzing two each for cell shape (morphology) and the presence of a molecular marker of cancer. Nine percent of patients were found to be node-positive using morphological criteria alone; the other 14 percent were detected using molecular markers. In both cases, survival was poorer than in patients who remained node-negative.
"What we are suggesting is that perhaps the staging system for lymph node metastases should be reevaluated in the next edition of the AJCC [American Joint Committee on Cancer] staging," he said.
Many sites already analyze more than one slice per node, he added. Sener's facility, for instance, uses 10.
According to Sener, the current findings underscore the need for additional systemic therapy, such as chemotherapy, in patients with SLN micrometastases. But he also noted that SLN micrometastases do not necessarily require surgical excision, as most patients with positive lymph nodes do not develop cancer under the arm.
Sener hypothesized that could be because each metastasizing cancer cell has a sort of molecular ZIP code, which governs where it can go. Under this hypothesis, the decreased survivability associated with micrometastases has less to do with the lymph nodes per se, than with what those positive nodes say about metastases elsewhere in the body.
"It may be that the presence of micrometastases in these lymph nodes may be a bystander phenomenon," Sener said, "a surrogate marker for the presence of the lung or liver ZIP code in these cells."
Cody noted one "significant caveat" to this study: Because breast cancer survival and treatment regimens have changed so dramatically over the past 30 years, this study says nothing about the prognostic implication of micrometastases discovered today. That will require prospective studies, several of which are ongoing.
Nevertheless, he said, "because we don't know the results of those studies yet, studies like our own may be the best available evidence at present, and our study suggests these micrometastases are prognostically significant."
For more on breast cancer, visit the U.S. National Cancer Institute.
SOURCES: Hiram S. Cody III, M.D., attending surgeon, professor, clinical surgery, Breast Service, department of surgery, Memorial Sloan-Kettering Cancer Center, New York City; Stephen F. Sener, M.D., professor, surgery, Northwestern University Feinberg School of Medicine, Chicago; April 10, 2008, Journal of Clinical Oncology
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