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Sentinel Lymph Node Biopsy: Detection of Micrometastases Leads to More Precise Staging of Breast and Melanoma Tumorsby Katie Prout Matias
Like detectives tracking clues that a suspect leaves behind, surgical oncologists use a technique called sentinel lymph node biopsy to find cancer cells that have escaped the tumor and threaten to infiltrate other parts of the body. The sentinel node, or the first lymph node to which extracellular fluid from a tumor drains, acts as the gateway to the lymphatic system and beyond. Thus, the presence or absence of tumor cells in the sentinel node provides a wealth of information about the nature of a cancer and how best to treat it. The current standard of care for melanoma and breast cancer, sentinel lymph node biopsy spares patients who have no trace of disease in their sentinel nodes from the sometimes severe complications of having an entire nodal basin removed: chronic swelling, discomfort, infection, and reduced mobility. The procedure also allows for more thorough pathologic analysis and more accurate staging, perhaps even improving survival rates in patients with certain cancers. As researchers at The University of Texas M. D. Anderson Cancer Center work to maximize the benefits of sentinel lymph node biopsy, however, two issues remain unresolved: What is the best way to find and manage micrometastatic disease, and how important are alternative lymphatic drainage patterns? Finding the sentinel node Surgical oncologists hunt for the sentinel lymph node armed with a radioactive tracer and blue dye. The radioactive tracer is used first to illuminate the route of the tumor’s drainage. During lymphoscintigraphy, the tracer is injected around the tumor or biopsy site, and a gamma camera captures its final destination. In an operating room, the surgeons use a hand-held gamma probe to find the “hot spot” or area of high concentration of radiation. This is where the sentinel node, packed full of radioactive tracer, lies. They next inject the bright blue dye around the tumor site and massage it to encourage the dye to migrate quickly to the sentinel node. After a few minutes of massaging, the surgeons cut a small opening in the skin at the hot spot and look for one or more bean-like nodules dyed bright blue. Once the surgeons have identified any suspicious nodes, they remove them and pass them on to the pathologist. The presence and number of tumor cells in the lymph nodes are strong prognostic factors. “The amount of disease within that lymph node is a very good predictor of the likelihood that a patient will remain cancer free,” said Jeffrey Lee, M.D., a professor in the Department of Surgical Oncology. “Patients with larger amounts of cancer are more likely to suffer a relapse.” Identifying micrometastatic disease In the past, when completion dissections were routinely performed on all patients, pathologists would have to scrutinize 15 to 30 lymph nodes, a time-consuming and expensive task, according to Ebrahim Delpassand, M.D., an associate professor in the Department of Nuclear Medicine. Now, they usually inspect one or two sentinel nodes, which allows them to more meticulously examine each node for micrometastases. Finding pathology assays that can quickly and accurately identify micrometastasis is now the most important goal for sentinel lymph node biopsy because it is the key to managing tumors, according to Merrick Ross, M.D., a professor in the Department of Surgical Oncology. In the Sunbelt Melanoma Trial, Drs. Lee and Ross are investigating the use of polymerase chain reaction (PCR) to detect cancer cells at the molecular level. Using PCR, which could be sensitive enough to detect one melanoma cell among a million normal cells, they are looking in lymph nodes for the presence of genes that are typically expressed in melanoma. “We’re hopeful that some of these techniques may help us to identify small amounts of cancer that are not apparent looking under the microscope with our best techniques,” said Dr. Lee. For patients with breast cancer, researchers have not yet identified which markers could be used with PCR. Instead, they are focusing on ways to intraoperatively examine lymph nodes for micrometastases so that if a positive node is discovered, the surgeons will not have to operate a second time to remove the rest of the nodes. Currently, in examining the nodes of patients with breast cancer, pathologists at M. D. Anderson use touch preparations in which they slice the node, pat the two halves onto slides, and examine the cells that stick to the slides. The accurate staging made possible by such painstaking pathology allows oncologists to choose the most appropriate therapies. “I think it really helps us to get a little bit closer to identifying the patients at high risk for metastatic disease so that we can be more careful with our treatments,” said Kelly Hunt, M.D., an associate professor in the Department of Surgical Oncology. “Certainly, we help a lot of people with chemotherapy, but there are some people that we’re not helping.” Too much of a good thing?
Using these highly sensitive techniques, pathologists are uncovering more micrometastases than they have in the past. “We found that the more you look, the more you find. Sometimes we’re actually finding just single cells that look like they’re probably malignant cells,” said Dr. Hunt. “The question is, are those cells just passing through the lymphatic system and would normally be cleared out by the lymphatics, or are they truly an important biologic event that we then need to treat with more surgery or chemotherapy?” One of the biggest controversies in sentinel lymph node biopsy is whether surgeons should remove all of the nodes when micrometastatic disease is found. To answer this question, researchers are developing prediction models. In a study of 160 patients with breast cancer who had positive sentinel nodes, Dr. Hunt and others found that using additional parameters—such as the size of the metastasis in the lymph node, the presence or absence of lymphovascular invasion in the primary tumor, the number of lymph nodes that were removed, and the size of the primary tumor—they could predict which patients were going to have additional nodal metastases and which were not. “I think the challenge for sentinel lymph node biopsy is to continue to refine the groups of patients who will most benefit from the technique,” said Dr. Lee. “Most important, it will be helpful to identify patients who may not need completion lymph node dissection.” Which way do they go?
No two lymphatic systems are exactly the same, so it is not always possible to predict clinically or anatomically where a tumor will drain. Furthermore, certain areas of the body, such as the head, neck, and trunk, have ambiguous drainage patterns. In the trunk, for example, about 5% to 10% of tumors migrate to ectopic or interval node groups in addition to the usual inguinal and axillary nodes, said Dr. Ross. In breast cancers, while most tumors drain to the axilla, there are some that drain to the internal mammary nodes, the supraclavicular nodes, and the intramammary nodes. Even using sentinel lymph node biopsy, surgeons sometimes overlook or ignore these unexpected nodal basins. “What we’re doing with sentinel node mapping is trying to be very focused. We’re trying to be more accurate with our staging system. So why would we want to ignore potential alternative drainage sites?” asked Dr. Hunt. Drs. Hunt and Delpassand have found that the site of the tracer injection influences where it will drain. Injections to the skin almost never drain to the internal mammary nodes, but injections to the breast parenchyma drain to the internal mammary nodes in about 15% to 20% of patients. Preoperative chemotherapy for breast cancer can potentially obfuscate drainage patterns because the chemotherapy often shrinks tumors, leaving scar tissue and fibrosis that make it hard for surgeons to inject a tracer or dye into the tumor. In melanomas, wide local excisions of the trunk, which has an ambiguous drainage pattern to begin with, can throw the drainage off its normal path. Surgical oncologists at M. D. Anderson see these and other challenges as part of a learning curve to be overcome with practice and knowledge. “I think this is just an amazing opportunity to…look at the anatomy and the drainage of each individual tumor very carefully,” said Dr. Hunt. For more information on this topic or for questions about M. D. Anderson’s treatments, programs, or services, call askMDAnderson at (877) MDA-6789. Other articles in OncoLog, September 2003 issue:
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