Dr. Misialek currently serves as Associate Chair of Pathology at Newton-Wellesley Hospital, Newton, MA. He is the Medical Director of the Vernon Cancer Center, Chemistry Laboratory and Point of Care Testing. Holding an academic appointment at Tufts University School of Medicine as a clinical assistant professor of pathology, he regularly instructs medical students and pathology residents. Dr. Misialek is a strong advocate for pathology and is very active in the College of American Pathologists.
Dr. Misialek graciously agreed to answer questions on pathology and metaplastic breast cancer.Q:Can you describe the tests and process a pathologist will use to arrive at a metaplastic diagnosis? What would you say is the hallmark of a metaplastic tumor? Could you give us a good working definition of “Metaplastic Carcinoma” in layman’s terms?
A: A pathologist will make the diagnosis of metaplastic breast carcinoma (MpBC) if there are any cell types seen under the microscope other than the glandular cells of typical breast cancer. This is done by staining thin slices of paraffin embedded formalin fixed tumor tissue with the standard hematoxylin and eosin stain. Sometimes special stains (immunohistochemical antibody tagged) will be used to highlight these other cell types. This change from one cell type to another is termed “metaplasia”, thus the name MpBC. Metaplasia though is a common finding in breast cancer. Simply finding metaplasia does not qualify for a diagnosis of MpBC.
The hallmark of MpBC is an adenocarcinoma in which a variable proportion of the glandular epithelial elements (i.e. typical breast cancer) has transformed into a nonglandular epithelium (i.e. squamous cell) or a mesenchymal cell (i.e. spindle cell, cartilage, bone, muscle). Simply put, a breast cancer composed of other cell types in addition to the malignant glands seen in typical breast cancers defines MpBC.
MpBC has only been recognized by the WHO as a distinct entity since 2000. It represents less than 1% of all breast cancers. As such, only small case series have been published. MpBC comprises a heterogenous group of breast cancers due to the wide variations in appearance and lack of a universally accepted classification system. Because of this, it has likely been underreported or even misclassified in the past.
Q: What about the mixed nature of the tumors? What percentage of a tumor must be metaplastic to qualify as a metaplastic tumor? Knowing that metaplastic tumors can be a combination of different cell types how do you insure you have all of the relevant types identified in one tumor? Is there a standard protocol for making this diagnosis?
A: There is no accepted cutoff for what percentage of a non-epithelial cell type that must be present to qualify for the diagnosis of MpBC. Currently, the presence of any amount of non-epithelial cell type is enough for the diagnosis. The more thoroughly a tumor is sectioned, the greater the likelihood of finding tissue heterogeneity.
Q: Is a metaplastic diagnosis difficult to make? Some of us have been mis-diagnosed initially. We are not sure if this is common. Does a metaplastic tumor look or react similarly to other kinds of breast cancer, making it more difficult to identify?
A: Due to its relative rarity and heterogeneous microscopic appearance, the diagnosis of MpBC can be difficult. Since the non-epithelial elements that define MpBC can be sparsely distributed throughout a tumor, there is the possibility of these areas not being sampled. Typically a pathologist will carefully go through the tissue, taking sections for slides. However, it is technically unrealistic to microscopically examine every micron of tissue, especially for large tumors. Adding to the difficulty of the diagnosis is the evolving classification system, which contributes to variations in reporting.
Q: Can you explain what information we should be able to find on our pathology reports?
A:In addition to the diagnosis, the pathology report should contain several pertinent tumor characteristics which are important in determining prognosis and next steps in care, i.e. size, stage, grade, margins, vascular invasion, hormone status, etc. The College of American Pathologists publishes recommended reporting templates that include all relevant tumor features. For an example of the most current guidelines, follow this link.
Q: Through our discussions some women have found that their pathology reports contain less information than others. For example some women will have a sub-type listed on their report or a more specific description of the type of metaplastic breast cancer, while others will simply have “metaplastic carcinoma” listed on theirs. Can you explain why?
A: The College of American Pathologists publishes recommended reporting guidelines for all tumor types (see above question). At a minimum, each of these items should be present in a pathology report. Although the WHO terminology is recommended, it does not preclude the use of other classifications.
Q: Is there a way for us to find additional information about the pathology of our tumors? For example, if the only information we were given is that the tumor is “metaplastic carcinoma” can we ask for more detail? Can we request information on what testing was done to come to that diagnosis? Can we ask about the sub-type, even if it wasn’t noted in the report? Would that information possibly still exist in the pathologist’s notes?
A: You can start by asking your physician for a copy of your pathology report, if not already available. Ask them to explain anything which you do not understand. Better yet, ask if you can meet with the pathologist who diagnosed your tumor. At my facility, patients are offered the opportunity to meet with a pathologist and review their slides. It is a relatively new concept, not universally offered, but in my opinion, pathologists are eager to take on this role. We are happy to meet with you.
Your pathologist can help you understand your report and show you the slides. This is a great opportunity for deeper insight and understanding of your particular disease. I am a firm believer that patients should learn as much as they can about their health, ask questions and be your own advocate.
Q: With the advent of targeted treatments many of us are more concerned with our sub-types and yet there doesn’t seem to be an agreement in the medical community on how to definitively classify different types of metaplastic breast cancer. The Wargotz and Norris definitions are most commonly used but not always. Why is this?
A: Because of the rarity of MpBC and the multitude of appearances, pathologists have had difficulty in reaching a consensus on the subtypes of MpBC. In order to create uniformity in reporting, the WHO in 2011 subclassified MpBC into 5 categories: squamous cell carcinoma, metaplastic carcinoma with mesenchymal differentiation, low-grade adenosquamous carcinoma, spindle cell carcinoma and fibromatosis-like metaplastic carcinoma. Hopefully this will standardize reporting and help in future research into the biology of the different subtypes.
Q: Do you think the sub-type is relevant? With targeted therapies will there be more important information we should look for like gene mutations and pathway activations? With targeted therapies in mind, what information should we be concerned with?
A: More work needs to be done into whether there is prognostic and biologic significance of the different subtypes. Hopefully better treatment regimens will be developed specific to subtypes. In order to do so, there needs to be uniformity in reporting. Personally, I feel the WHO terminology should be used so that data can be gathered and compared in clinical studies.
There is some data to suggest that low-grade adenosquamous carcinoma and low-grade fibromatosis-like metaplastic carcinoma are associated with a good prognosis, while the others have a worse prognosis. However, more work needs to be done.
Currently MpBC should be approached in the same fashion as that of any other breast cancer, i.e. determination of estrogen and progesterone receptors and HER2 status. Biomarker array tests, such as Oncotype Dx, when appropriate, should be utilized.
We aren’t yet routinely profiling or sequencing tumors beyond these tests, but most likely will in the near future. So, with MpBC there is no specific additional testing that must be requested beyond that which is standard of care for the more common breast cancer types.
Q: What is your opinion, should we pursue molecular profiling of our tumors? Can our local pathologist provide this information? Can you discuss a little more about tumor profiling? What is important information? What do you think will be important one day? Also, we often hear competing information metaplastic tumors. Some studies suggest these tumors are basal-like and others claudin-low. What do these designations mean and how can we determine if our tumors are either? We often run across studies that suggest basal-like tumors do one thing or another but we don’t know if these studies apply to us or not.
A: Traditionally prognosis and the probability of breast cancer recurrence has been estimated using clinical pathologic features such as tumor size, grade, and lymph node status. A pathologist will use immunohistochemical (IHC) stains to determine estrogen and progesterone receptor expression levels. HER2 is determined by IHC or in situ hybridization (FISH).
More recently the expression pattern of a panel of specific tumor-related genes can be analyzed to predict recurrence and prognosis. These biomarkers can be identified with such tests as Oncotype DX (Genomic Health Inc., San Francisco, CA), PAM50 (Nanostring Technolo¬gies Inc., Seattle, WA) and MammaPrint (Agendia, Inc., Irvine, CA). These tests are designed to help patients with early stage breast cancer by selecting those who would benefit most from chemotherapy, while sparing those who would derive little or no benefit.
These biomarker arrays look at dozens of genes but not all tumor genes. Sequencing (profiling) of the entire tumor genome is slowly replacing these biomarker arrays and will likely become standard of care. Out of the information gathered from these studies, we have been able to identify specific molecular subtypes of breast cancer. These include luminal A, luminal B, luminal C, HER2-enriched, basal-like, claudin-low, and normal breast-like.
In 2011, the St. Gallen International Breast Cancer Conference defined breast cancer subtypes using IHC stains as a surrogate for molecular profiling. A combination of estrogen (ER), progesterone (PR), Ki67 (a proliferation marker) and HER2 are used to define these and include: luminal A (ER + and/or PR+, Ki67 low and HER2-), luminal B (ER + and/or PR+, Ki67 high and/or HER2+), HER2-positive (ER-, PR- and HER2+) and triple negative (ER-, PR-, HER2-).
The most recently recognized subtype is claudin-low breast cancer which is characterized by overexpression of genes associated with epithelial-to-mesenchymal transition. This includes genes that are involved in metaplasia of one cell type to another. The majority of claudin-low breast cancers have a profile different than that of the luminal subtypes. They are HER2 and hormone receptor negative by IHC (triple negative), frequently diagnosed as MpBC and medullary breast cancer, and are often part of the basal-like subgroup. Cytogenetic studies show MpBC to often contain complex genetic karyotypes with frequent p53 mutations.
We are in an exciting new era in breast cancer research where the very definition of breast cancer is evolving. Recent research is focused on the biological differences between MpBC and typical breast cancer and potential novel targets and agents.
We have learned that MpBC contains factors important in epithelial to mesenchymal transition (metaplasia). It appears that tumor infiltrating cells play a role in the development of MpBC. There is even evidence that MpBC acquires breast cancer stem cell markers. Current and future research will test the hypothesis that blocking metaplasia on the molecular level and/or tumor stem cells may improve outcomes in MpBC. Clinical trials are needed in MpBC to further characterize the biology and therapy of this disease.
Q: How likely is it with metaplastic breast cancer to have METS with a change in hormone expression and/or mutation from the primary tumor and what do you do when those new METS can’t reasonably be biopsied?
Recent studies support the idea of re-evaluating ER, PR, and HER2 expression in distant metastasis, lymph node metastasis and local recurrences for all breast cancer types. The College of American Pathologists and American Society of Clinical Oncologists recommends testing the primary tumor and metastases for HER2.
Not only can these biomarkers change over time, but there is evidence that the molecular subtype can also evolve. The St. Gallen molecular subtype in the primary tumor can shift to a more aggressive subtype in synchronous lymph node metastases. This might impact the selection of systemic adjuvant therapy.
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