Letters
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July 2008
The story by William Check, PhD, in the May issue provided a balanced view of how some institutions are using (or not using) the GeneSearch BLN assay for detecting metastasis in sentinel lymph nodes of patients with invasive breast carcinoma (“Amazing Mets Test? Sizing Up a New Assay”). However, it omits any discussion of the lack of specificity of the test in its current form. The RT-PCR that is done assays for cytokeratin-19 and mammoglobin, two markers which, in this context, are specific for breast epithelial cells but not for malignant cells, let alone those having a metastatic phenotype. It is well known that benign breast epithelium can be present in axillary lymph nodes, most frequently in fact in the sentinel node(s), occasionally in sizable quantities. Furthermore, smaller foci of epithelial cells (both benign and/or malignant) can be physiologically transported to the first draining lymph node(s), that is, the sentinel node(s) after iatrogenic displacement. These situations would at least theoretically cause a false-positive PCR reaction using the markers currently available. Of most concern, however, is the fact that it is impossible to determine when such a false-positive exists since the exact tissue submitted for PCR is completely consumed by it and cannot be examined histologically. As any surgical pathologist knows, in this context, such lesions vary tremendously in their extent within nodes, even in serial sections. The view that eventually we may be homogenizing sentinel lymph nodes intraoperatively and foregoing histologic examination is entirely premature and should await the day when we have markers that are specific to the metastatic phenotype. False-positives caused by benign cells would cause unnecessary axillary dissection and, more alarmingly, might lead to unnecessary chemotherapy. The problem is, however, that the very nature of the test prevents one from knowing when this is occurring. The decision for completion axillary dissection can be approached differently, by using published nomograms for predicting non-sentinel node positivity and by tailoring surgery after evaluating the clinical information available on each case preoperatively, namely radiologic size (most accurate sonographically) and core-biopsy–determined characteristics (tumor type and grade and lymphatic invasion, if present). This combined with intraoperative touch prep for grossly negative lymph nodes and minimal non-sentinel node sampling are examples of useful techniques that can achieve the same goals for which RT-PCR has been applied, namely avoiding bringing patients back for completion axillary dissections, with the advantage that one knows when the lymph node is truly positive and to what extent. In our view, at least in its current form, the potential for harm with RT-PCR of sentinel lymph nodes far outweighs any benefit. Before adapting a new assay, pathologists need to be cognizant of the inherent limitations of the test itself, not just the reimbursement and logistical issues, which your article rightly addressed. Ira J. Bleiweiss, MD Juan P. Palazzo, MD, professor of pathology, anatomy, and cell biology, Thomas Jefferson University, Philadelphia, replies: I was one of three pathologists who participated in the review of all the H&E slides from the clinical trial that was conducted to validate the BLN assay. As all pathologists know, there is no specific immunohistochemical marker available today for breast cancer or, for that matter, for most epithelial neoplasms. The two markers used in the study were selected from a large pool of markers and represented the most sensitive markers for breast cancer. As most surgical pathologists also know, there are no specific markers that identify metastatic tumor cells. The markers that are emerging as more specific are not detected by H&E or immunohistochemistry but by molecular analysis (gene profiling, among others). In practice, the vast majority of markers we use in diagnostic pathology cross-react between benign and malignant cells. The BLN test will not detect a few epithelial cells transported to the lymph nodes, whether they are benign or malignant (isolated tumor cells). The number of cells required for the test to be positive (cutoff value) far exceeds the number of cells present in misplaced glands in the lymph nodes. If the cells are malignant, it remains to be seen whether they are of significance for the management of the patient. In the clinical trial of 722 patients we did not see a single case of benign glands in the lymph nodes while specifically looking for them. We concluded that it is an extremely uncommon phenomenon that, unfortunately, has been reported and published in such a manner that gives the false impression of representing a significant problem in surgical pathology when, in reality, it is not. From Dr. Bleiweiss’ argument, it is not possible to verify if the BLN assay is truly positive or false-positive because it cannot be verified histologically. Regarding this issue, it is important to remember that the current approach analyzes approximately five percent to 10 percent of the entire lymph node. The rest of the lymph node is either wasted while cutting sections in the cryostat or remains in the paraffin block. Multiple studies have shown that the more sections taken from sentinel lymph nodes, the more metastases are diagnosed, and these metastases have prognostic significance. The studies that have included the evaluation of the entire sentinel lymph node have shown there is a survival difference for those patients whose lymph nodes are truly negative. The current approach to studying lymph nodes falls short of the aim of studying the entire lymph node to stage the patients properly and denies these patients proper care and staging. Dr. Bleiweiss also fails to recognize the value of a negative BLN assay. When both the assay and the H&E slides are negative, it is reassuring for the surgeon that the patient is highly unlikely to have a metastasis in the sentinel lymph node, and that much more of the lymph node has been analyzed. The BLN assay has been used at Morton Plant Hospital, Clearwater, Fla., and applied in 193 patients since FDA approval. There are excellent examples of the appropriate setting of CT values for the two markers in which a sentinel node positive on H&E is positive on molecular analysis, but a sentinel node positive only for isolated tumor cells is negative on molecular analysis in the same patient. Trying to deny the potential value of nonmorphologic clinical tests, when performed in the right setting and in specific circumstances, leads to missed opportunities for surgical pathologists to provide better patient care. Indeed, the only way to truly assess the significance of molecular findings is to do more, not fewer, clinical trials incorporating the molecular data along with known morphologic parameters. Following Dr. Bleiweiss’ recommendations, a number of breast cancer patients, certainly many more than the patients with “misplaced glands” (not detected by the BLN assay anyway), would be undertreated, since their metastasis would have been missed by the current approach.
The “President’s Desk” column in the April issue was right on target (“What It Means To Be a Physician”). When I entered practice over 40 years ago, I followed the example of my mentors and essentially hid behind the paraffin curtain. Although I interacted with clinicians, I almost never saw or spoke with a patient. I have been practicing in an independent laboratory setting for about 24 years. I speak with patients who call me about interpretation of clinical lab tests. Often their physicians either don’t fully understand the test or don’t want to spend the time to discuss it with their patient. It’s very gratifying to get a heartfelt thanks from a patient who had a great deal of anxiety over a minimally abnormal test result that most likely was not clinically significant. Conversely, clarifying the possible causes and implications of significantly abnormal test results gives the inquiring patient correct information and direction. Some of the most gratifying experiences that I have had come through a program that our laboratory offers allowing patients to order a limited menu of tests themselves. I call the patients who have significant abnormal results and an occasional critical value and introduce myself as a pathologist. I refer them all to their family doctor if they have one or recommend contacting a physician when they don’t. It makes me feel like a family practitioner when the patients share information about themselves, their family, and their own medical history. Of course, they are extremely appreciative that a physician took the time to call them and explain the possible causes of their abnormal test results. The pathologist used to be known as the “doctor’s doctor.” It’s time that we regained that title by making ourselves and our expertise known to patients and clinicians. Herman Hurwitz, MD |
Breast Lymph Node assay