regarded as the pathognomonic feature for the distinction of inflammatory breast carcinoma from non-inflammatory breast carcinoma.

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1 Hello. I am Dr. Krishnamurthy, Professor of Pathology from the University of Texas MD Anderson Cancer Center. Today, I ll be talking to you about the pathology of inflammatory breast cancer. The objectives of this program are: Upon completion of this lecture, participants will be able to identify the diagnostic criteria to establish a diagnosis of inflammatory breast cancer; to recognize the pathological features in skin and breast in inflammatory breast cancer; and to understand the differential diagnosis of inflammatory breast cancer; and finally, to be familiar with the distribution of standard and potentially useful biomarkers in inflammatory breast So, I start with the talk. Inflammatory breast carcinoma is a rare and aggressive type of breast cancer that comprises from 1 percent to 5 percent of all newly diagnosed breast cancers. This entity is characterized by rapid progression, aggressive behavior, and an overall survival that is lower than other breast cancers. This entity is characterized by diffuse erythema, edema and/or peau d orange and/or warmth with or without a palpable mass in the breast. It should be noted that the erythema occupying the breast should cover at least one-third of the entire breast. And, the duration of clinical history should not be more than six months. Finally, there should be a pathological confirmation of the presence of invasive breast carcinoma in the affected breast. Inflammatory breast carcinoma is comprised of two clinical entities, what we call as primary inflammatory breast carcinoma and secondary inflammatory breast By primary inflammatory breast carcinoma, we refer to the development of de novo breast carcinoma in a previously normal breast. On the other hand, the term, secondary inflammatory breast carcinoma is given to the development of inflammatory skin changes associated with invasive breast carcinoma in a breast that already had cancer or there was carcinoma in the chest wall that developed after a mastectomy for non-inflammatory breast There are several differential diagnoses to the entity of inflammatory breast carcinoma, particularly bacterial infection of the breast, such as mastitis or even collection of pus in the breast that is an abscess could mimic inflammatory breast Other cancers involving the breast could also look like inflammatory breast Postradiation dermatitis with redness and edema of the breast can very closely look like inflammatory breast Congestive heart failure with edema of the breast can also look like inflammatory breast So, to come to a good diagnosis which is accurate, it is very important to get an accurate medical history from the patient. And, particularly, there should be a tissue diagnosis, that is, confirmation of the presence of breast carcinoma in the affected breast. Inflammatory breast carcinoma is characterized by the presence of numerous dermal tumor emboli in papillary and reticular dermis of the skin overlying breast. This is

2 regarded as the pathognomonic feature for the distinction of inflammatory breast carcinoma from non-inflammatory breast Here is an example of a skin punch biopsy from a patient with inflammatory breast You can see the numerous lymphovascular tumor emboli in the superficial dermis. Now, the dermal tumor emboli in inflammatory breast carcinoma are generally numerous and often larger in size than non-inflammatory breast However, it is to be noted that there is no direct relation between the number of lymphovascular tumor emboli or vascular distension and the skin manifestations in patients with inflammatory breast The tumor cells comprising the lymphovascular tumor emboli are generally high grade with large nucleus. And, here is a Ki67 immunostain which labels the proliferative index of the tumor. And, you can see that many of the tumor cells are labeled with this immunomarker, indicating that the proliferative index of the tumor vascular emboli is really high. So, how do we recognize the skin changes in inflammatory breast carcinoma? It is recommended that two skin pun --- punch biopsies be performed of either 2 mm to 8 mm in width from the most prominent area of breast skin discoloration. It is to be noted that tumor emboli in dermal lymphovascular spaces may not, however, be demonstrable in every patient with inflammatory breast On the average, dermal tumor emboli may be demonstrated in up to 75% of the patients with inflammatory breast It is well understood that wider is the skin punch biopsy, more is the probability of detecting the changes in the dermis. As you can see here, a 4-mm punch has larger blue areas indicating the sites of probable changes in the skin than a 2-mm smaller skin punch biopsy with just one blue area, which is probably the site of action in the skin. The skin changes in inflammatory breast carcinoma, apart from the presence of lymphovascular tumor emboli, can also be comprised of other changes, such as mild to moderate lymphoplasmacytic infiltration around the lymphovascular tumor emboli. And, generally, the skin may show increased thickness due to edema and collagen deposition in the dermis. It is to be noted that there is no evidence of skin ulceration or Paget s disease in the skin overlying the affected breast. Here is an example of a skin punch biopsy showing moderate lymphoplasmacytic infiltration around the lymphovascular tumor emboli in the skin in a patient with inflammatory breast So, with respect to lymphovascular tumor emboli, it is to be recognized that while lymphovascular tumor emboli are useful for confirming the clinical diagnosis of inflammatory breast carcinoma, their absence does not negate a diagnosis of

3 inflammatory breast carcinoma in patients with invasive cancer and the characteristic clinical findings of the entity of inflammatory breast Now, how do we make a diagnosis of the carcinoma in the underlying breast parenchyma? We can do two techniques. The first is called fine needle aspiration biopsy. This can be performed with or without image guidance. And, it can be used to document the presence of carcinoma in the affected breast. However, fine needle aspiration biopsy cannot distinguish the presence of carcinoma in situ from invasive Also, this technique is not considered to be optimal for the recognition and evaluation of the prognostic and predictive markers in the breast. Here is an example of fine needle aspiration biopsy findings in a patient with inflammatory breast You can see the loose sheet of carcinoma cells which are high grade. And, they show a large nucleus with scant to moderate amounts of cytoplasm. What is the role of fine needle aspiration of local regional lymph nodes in the staging of patients with inflammatory breast carcinoma? We all have to recognize that sonographic findings of the lymph nodes with or without additional fine needle aspiration of indeterminate and suspicious lymph nodes helps in preoperative staging of patients with inflammatory breast Here, you can see a very large lymph node which is very suspicious for the presence of metastatic And, fine needle aspiration of this lymph node clearly shows the presence of metastatic carcinoma as is shown in this image. The optimal method for making a diagnosis of the presence of carcinoma in the affected breast is performing an image-guided core needle biopsy of the affected breast. And, different width of the core needle biopsies can be performed, ranging from 9 gauge to up to 14 gauge cores can be obtained from the breast of --- in patients with inflammatory breast Now, what is the real pathology in the affected breast in inflammatory breast carcinoma? The invasive tumor in inflammatory breast carcinoma is distributed as foci of variable sizes with adjacent parenchyma studded with medium and large-sized lymphovascular tumor emboli. It is to be noted that there may or may not be the presence of a distinct tumor mass in the breast. And, also, there may or may not be a distinct in situ component with the invasive Generally, inflammatory breast carcinoma infiltrates the stroma very diffusely. Here is an example of a very low magnification of a tissue section from the affected breast. You can see that in this entire section, there are several blue areas with some lighter areas, and there is really no big tumor mass. Instead, there are these very small areas interspersed with these normal areas. And, at a higher magnification, those blue areas correspond to the presence of invasive breast As you can see here, these are the collection of tumor cells loosely

4 arranged invading the stroma. And, here is the unaffected breast tissue around these foci of invasive breast Around such foci of invasive breast carcinoma, it is very common to see lymphovascular tumor emboli, such as is demonstrated here, and you can see that there are medium to large sized emboli that contain collection of the tumor cells. The tumor cells are usually high grade, as is shown here, with a high nuclear to cytoplasmic ratio. They do not form glands and they are loosely clustered together. There are some single cells. And, see how loosely they are arranged in the breast parenchyma. It is also common to see tumor cells with spaces around them and we believe that these are tumor cells arranged as lymphovascular tumor emboli that are closely packed together, almost mimicking like artifactual retraction of the tumor cells from the surrounding parenchyma. In the invasive ductal carcinoma, is usually the not otherwise specified type of breast It is a ductal type of high nuclear grade, high histologic grade. Although invasive ductal carcinoma, not otherwise specified type, is the common type of breast carcinoma to be encountered in patients with inflammatory breast Other types of breast carcinoma can be seen. But these are less common, such as invasive lobular carcinoma, invasive mucinous carcinoma, or invasive micropapillary So, different types can be seen, although they are not that common. Here is an example of large lymphovascular tumor emboli with pooling of blood around them, which is a very dramatic finding and can be seen in many patients with inflammatory breast And, these large tumor emboli many times mimic carcinoma in situ. Here is a p63 immunostain that highlights the myoepithelial cells at the adjacent duct, but notes that the large lymphovascular tumor emboli that almost looks like a ductal carcinoma in situ does not have even a single p63 marked myoepithelial cell around it. Also, here is a CD34 immunostain which highlights some of the endothelial cells around this lymphovascular tumor emboli, thereby confirming that this is a lymphovascular tumor emboli and not carcinoma in situ. As mentioned, carcinoma in situ can be encountered in patients with inflammatory breast They could be of any type, with or without necrosis. Here is an example of ductal carcinoma in situ that is not associated with necrosis. On the other hand, here is another image that shows nice comedonecrosis associated with micropapillary type of high grade ductal carcinoma in situ.

5 There are several histologic mimickers, or in other words, differential diagnosis for the histologic findings of inflammatory breast And, they are involvement of the breast by any non-mammary poorly differentiated malignant neoplasm that is associated with extensive lymphovascular invasion in breast and overlying skin. So, what could those be? Metastatic poorly differentiated carcinoma from other organs; non-hodgkin lymphoma, high grade; melanoma; acute leukemia; angiosarcoma. Any of these malignant neoplasms can mimic and present like inflammatory breast Once a diagnosis of invasive breast carcinoma is made, the next step is to do evaluation for the prognostic and predictive markers. The commonly done prognostic and predictive markers as standard of care is estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, or HER2. The testing and reporting of these prognostic and predictive markers should be done according to the standard ASCO-CAP guidelines. Here is an example of an invasive breast carcinoma in a patient with inflammatory breast carcinoma that shows strong and diffuse positivity for estrogen receptor. Now, with respect to inflammatory breast carcinoma, there is usually a higher frequency of estrogen receptor and progesterone receptor negative status. And this can happen to a tune of 83 percent in patients with inflammatory breast It is also reported that lack of expression of hormone receptors is associated with a more aggressive clinical course and also is associated with decreased overall and breast cancer-specific survival in inflammatory breast Here is an example of inflammatory breast carcinoma showing strong protein overexpression at 3+ immunostaining for HER2/neu. And here is a FISH finding showing marked HER2 gene amplification in a patient with inflammatory breast With respect to HER2 status in inflammatory breast carcinoma, it is to be recognized that there is higher incidence of HER2 protein overexpression and gene amplification. While the prognostic role of HER2 status in inflammatory breast carcinoma is not yet accurately defined, the predictive role, however, is well proven in inflammatory breast There are other biomarkers that have been described to have some role in the biology of inflammatory breast These are p53 mutations; the overexpression of epidermal growth factor receptor; the expression of chemokine receptor, such as CXCR4 and CCR7; presence of Notch-1, VEGFR-3, prox-1, lymphatic vessel endothelial receptor 1; COX 2 and its enzymatic product PGE2 in inflammatory breast Here is an example of inflammatory breast carcinoma showing strong staining and diffuse positive for p53 as well as diffuse strong positivity membranous positivity for EGFR immunostain.

6 There are other potential biomarkers that may have a role in inflammatory breast It is recognized that ER-negative inflammatory breast tumors are characterized by overexpression of multiple nuclear factor kappa beta, that is NFκB target genes. Also, RHO C GTPase, which is an oncogene that encodes a member of ras homology GTPase family of proteins, is upregulated in up to 90 percent of inflammatory breast Loss of wnt-inducible signaling protein 3, which is a breast tumor suppressor gene, is also noted in patients with inflammatory breast E-cadherin expression in inflammatory breast carcinoma is another finding that is considered as a hallmark of inflammatory breast This marker, which is a calcium dependent transmembrane glycoprotein, is responsible for cell adhesion. Overactive E-cadherin, beta-catenin axis with loss of sialyl-lewis moieties is critical for the genesis of lymphovascular tumor emboli in patients with inflammatory breast E-cadherin overexpression is regarded as a hallmark of the invasive tumor and also the lymphovascular tumor emboli in patients with inflammatory breast Here is an example of E-cadherin expression in invasive tumor and lymphovascular tumor emboli. Notice the strong, diffuse membranous positivity in the invasive tumor as well as in the lymphovascular emboli in the skin in a patient with inflammatory breast With respect to overexpression of genes --- other genes, it is to be noted that genes associated with angiogenesis and lymphangiogenesis are overexpressed in inflammatory breast In addition, there is also increased levels of angiogenic growth factors and receptors. There is generally increased lymphatic endothelial cell proliferation and lymphangiogenesis. In addition, vasculogenesis, that is, ability of tumor cells to form vessel-like structures, what is called as vascular mimicry, can also be encountered in inflammatory breast Overall, inflammatory breast tumors are more angiogenic, lymphangiogenic, and vasculogenic than non-inflammatory breast carcinomas. With respect to cancer stem cells and inflammatory breast carcinoma, it is now recognized that inflammatory breast tumors are enriched for cancer stem cells. Increased cancer stem cells may have a potential role in creating an aggressive phenotype for inflammatory breast These stem cells are linked to tumor progression through their ability to undergo the process of epithelial - mesenchymal transition, or EMT. So, overall, with respect to biomarker evaluation in inflammatory breast carcinoma, there is insufficient evidence to define the prognostic and predictive role of all biomarkers other than the standard biomarkers including estrogen receptor, progesterone receptor, and HER2/neu. Routine testing of other biomarkers is currently not recommended in patients with inflammatory breast

7 What is the role of gene expression profiling in inflammatory breast carcinoma? With gene expression profiling, we clearly know that all molecular subtypes that occur in noninflammatory breast carcinoma occur similarly with inflammatory breast However, some types, such as the basal-like and HER2 positive type, occur more frequently in inflammatory breast carcinoma than non-inflammatory breast Generally, there is marked transcriptional heterogeneity in inflammatory breast carcinoma with differences in gene expression levels between IBC and non-ibc very variable across different studies. There is no gene overlap between reported gene signatures specific to inflammatory breast So, the bottom line is, there is no signature predictive of therapeutic response or clinical outcome that has been identified specifically to inflammatory breast carcinoma or that has been specifically validated for inflammatory breast So, we move on to the role of surgery in inflammatory breast Definitive surgery is performed in selected patients with partial or complete response to primary systemic treatment of inflammatory breast And, a modified radical mastectomy and complete axillary dissection is generally performed. So, how do we evaluate the mastectomy specimen in a patient with inflammatory breast carcinoma? The approach has to be standard, like what is done for any patient with non-inflammatory breast carcinoma undergoing radical mastectomy. A thorough examination of the specimen slices for accurate sampling of the affected areas is mandatory. Sections of nipple and skin to evaluate the lymphovascular tumor emboli should also be performed. There has to be accurate evaluation of the margins and also, optimal and thorough evaluation of the axillary lymph nodes for the presence of metastatic tumor. Here are examples one could encounter: complete response to chemotherapy with no residual tumor, or there may be some amount of residual tumor. The lymphovascular tumor emboli may persist or may be totally gone. So, in the final reporting of the mastectomy specimen, the extent of residual disease, particularly the cellularity of the tumor in the tumor bed, the status of the axillary lymph nodes with respect to the size of metastatic tumor, presence or absence of extranodal extension, documentation of the margin status, and documentation of the lymphovascular tumor emboli and extent of skin thickening has to be recorded in the final diagnosis. So, in summary, inflammatory breast carcinoma is not a specific histological subtype of mammary Pertinent histopathological findings in mammary parenchyma and overlying skin in association with the characteristic clinical history can help a pathologist to suggest a diagnosis of inflammatory breast It is to be recognized that inflammatory breast carcinoma is a distinct entity of breast cancer. The etiology and risk factors of this variant of breast carcinoma is not fully identified.

8 There is a need for discovery of unique biomarkers and targets for diagnosis and treatment of this variant of breast Research is needed to understand the biology of the disease and also for the recognition of the other aspects, particularly the biomarkers of this particular type of breast So, finally, recognition of inflammatory breast carcinoma by physicians and awareness of the public is definitely essential for accurate diagnosis and optimal clinical management of the patients. This is the end of my presentation. Thank you for listening to this talk. We welcome any feedback from you with respect to this presentation. Thank you again.