Case 5 -

Substantial But Incomplete Pathologic Response to Neoadjuvant Chemotherapy with Residual Invasive Carcinoma in Breast and Lymph Nodes Gelareh Farshid BreastScreen SA Adelaide, SA, Australia

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Clinical History: A 54 year old women presented with an inoperable 10.5cm mass in the left breast. Core biopsy showed an infiltrating ductal carcinoma, ER+ve, PR +ve, HER2 not amplified. Staging investigations were clear. She was treated with neoadjuvant chemotherapy, an aromatase inhibitor and radiation therapy. Proceeded to mastectomy, axillary clearance and a TRAM reconstruction. She made an uneventful recovery with a good cosmetic result. Pertinent Laboratory Data: No discrete mass found on gross inspection. An ill defined, diffusely edematous region with prominent ducts,140x70x25mm, merges with the central breast disc. The axillary clearance specimen showed very small lymph nodes, largest 5mm. Case 5 - Figure 1 Fibrotic breast parenchyma with a sprinkling of inflammatory cells. Case 5 - Figure 2 Rare enlarged atypical cells admixed with inflammatory cells. Case 5 - Figure 3 Small groups of larger, atypical cells. Note absence of normal breast ducts and lobules. Case 5 - Figure 4 A breast duct showing enlargement and atypia of its lining epithelium. Case 5 - Figure 5 Atrophic axillary lymph node showing capsular edema and fibrosis. Case 5 - Figure 6 Treatment effect in an axillary lymph node. Case 5 - Figure 7 Immunohistochemistry for CD68, demonstrating reactivity of histiocytes, but not the scattered larger, suspicious tumour cells. Case 5 - Figure 8 Immunohistochemistry for the cytokeratins AE1/3, highlighting small numbers of residual cancer cells. Introduction: This is a typical case of breast carcinoma showing response to treatment with neoadjuvant chemotherapy (NAC). The main considerations include an assessment of the presence of residual disease, and if residual disease is identified, classification of the extent of the response in the breast and the lymph nodes. Microscopic Findings In sections from the breast, paucicellular, edematous fibrous tissue, with scattered inflammatory cells is the main finding. Plasma cells, lymphocytes and histiocytes are scattered in this tissue, accompanied by siderophages in areas. There is a notable diminution of breast ducts and lobules. Focally, larger cells are admixed with the inflammatory elements. These occur singly and although they show nuclear enlargement and atypia, they are mitotically inactive. They show no tendency to duct formation. The residual breast ducts and lobules show a variable lining which in areas consists of cells with enlarged nuclei. The lymph nodes are atrophic. Some exhibit fibrosis and myxoid change, particularly at their capsule. Aggregates of foamy histiocytes are found in the subcapsular region of some nodes. Cholesterol clefts and edema are also seen in some nodes. One node contained an aggregate of tumour cells. Differential Diagnoses: Residual invasive carcinoma vs. a histiocytic stromal response In cases where there has been a significant response to NAC, breast carcinoma, regardless of subtype shows marked reduction of cellularity. The cells may exhibit a greater tendency to dissociation, occurring singly or in single file. These features may lead to mimicry of the ubiquitous histiocytes. The greater degree of nuclear atypia and chromatin disturbances in cancer cells are usually helpful in making this distinction, but the retention of their respective immunohistochemical profiles (CD68 in histiocyes, cytokeratins in carcinoma cells) provides confirmatory support. The difficulty in distinguishing cancer cells from histiocytes in cases where a substantial response to NAC has been achieved impacts accurate assessment of the size of the area involved residual tumour as well as reducing confidence in the status of surgical margins, particularly when breast conserving surgery is used. Residual DCIS vs. LCIS, vs. therapy induced atypia in ducts and lobules Chemotherapy may induce changes in the lining cells of normal ducts and lobules so that they appear larger and more pleomorphic and thus simulate in situ carcinoma. Furthermore, pre-existing LCIS, when subjected to NAC may assume greater nuclear pleomorphism and resemble DCIS. Attention to the widespread extent of the changes and absence of the architectural features of in situ carcinoma assists in recognizing treatment effect in normal parenchymal structures. The distinction between DCIS versus LCIS compounded by treatment effect is also assisted by attention to the architectural features and awareness of the necessity to make allowances for the cytomorphology of LCIS post therapy. The loss of E-Cadherin in LCIS will assist in such cases. Reactive nodes, vs. remission of nodal metastases vs. residual nodal metastasis Regression of nodal metastases as a result of NAC is associated with recognizable morphologic changes, including nodal fibrosis, formation of mucin pools and aggregates of foamy histiocytes in the absence of viable carcinoma. Because the disease free survival for these patients is better than those with residual disease in the nodes, but not as good as those with no nodal metastases and no evidence of regression it is important that "treatment effect" in lymph nodes be recognized and mentioned in pathology reports. The total number of nodes harvested and their status should be reported. Unless sentinel node biopsy has been performed the use of levels, immunohistochemical stains or CPR are not standard of care for the evaluation of lymph nodes post NAC. In practice, broad-spectrum cytokeratins or low molecular weight cytokeratins may be helpful in problematic cases. Final Diagnosis: Substantial But Incomplete Pathologic Response to Neoadjuvant Chemotherapy with Residual Invasive Carcinoma in Breast and Lymph Nodes. Case Discussion The Appeal of Neoadjuvant Chemotherapy Neo-adjuvant chemotherapy (NAC) also referred to as pre-operative chemotherapy or primary chemotherapy was used initially in the setting of locally advanced or inoperable breast cancer. Clinical trials evaluating this therapy in patients with operable breast cancer have demonstrated that overall survival (OS) and disease free survival (DFS) after NAC are similar to those achieved with postoperative (adjuvant) chemotherapy [17]. However, NAC offers several benefits: i) For the subset of patients who achieve a pathologic complete response (CPR) the outlook improves markedly. ii) Because pre-op chemotherapy results in tumour shrinkage in some patients, more patients may be rendered eligible for breast conservation. iii) NAC offers a unique opportunity to assess the impact of systemic therapies on breast cancer biology within a short timeframe and in vivo. Issues for Consideration Tumours respond to NAC in different, partly predictable ways [21] (Table 1). A small subset of patients, 10-25% for most chemotherapeutic regimens, achieves a complete response. Others tumours are less responsive. Each scenario raises points for discussion. For patients without residual invasive carcinoma in the breast after NAC, the significance of residual DCIS and also that of residual nodal disease are debated. Among patients with residual disease post NAC, the development of validated systems of classifying the extent of response and the prediction of their long-term outlook are of interest. The fact that some patients have only a limited response to NAC focuses attention on the desirability of improved prediction of tumour response to various NAC regimens, so as to avoid delays in initiating alternative treatment options. 1. Complete Pathologic Response While all response classification systems agree that the essential feature of this state is the absence of invasive carcinoma in the breast, the significance attributed to residual DCIS and residual nodal disease is more variable. 1a. Residual DCIS While the NSABP trials allow the presence of residual DCIS and nodal disease in the CPR group, other investigators insist on the absence of invasive cancer from the nodes as well as the breast but DCIS is still considered CPR. A 2006 consensus statement suggested that CPR must not include and residual invasive or in situ disease in breast or axilla [10]. Limited data are available showing that the 5 yr and 10 yr OS for patients with no residual DCIS or invasive cancer in the breast or nodes (CPR) was not significantly different from the group of CPR+DCIS [13] and was significantly better than for patients with any residual invasive cancer. About 5-15% of DCIS only residual disease patients developed local recurrence, similar to the local recurrence rate in the group who had no residual disease at all. These data are in agreement with the findings of smaller prior series [5, 9]. 1b. Response in Lymph Nodes Axillary nodes may atrophy and be difficult to identify. Node counts are reduced in some studies [1]. Most investigators advocate the use of one H&E section for the microscopic examination of lymph nodes in the NAC setting. The use of levels, immunohistochemical stains or PCR are not standard of care, unless sentinel node biopsy has been performed where the usual, local protocols are to be used. There are data showing that CPR in axillary nodes in response to NAC is important prognostically, independent of the response in the primary tumour. In Hennessy's study, patients who achieve CPR in previously documented positive axillary nodes had considerably better outcomes than patients who did not, regardless of response in the primary tumour [7]. Indeed, the 5 yr overall survival (OS) was not significantly different between those with axillary CPR who did or did not achieve a breast CPR. However the study is not powered adequately to assess this. As well as OS, recurrence free survival (DFS) was better in patients with axillary CPR, since loco-regional recurrence was reduced significantly. Furthermore, there is some evidence that features of tumour regression observed in axillary nodes that no longer contain metastatic tumour are of prognostic value. Newman et al [15] found that patients with tumour regression defined as the presence of nodal fibrosis, mucin pools or aggregates of foamy histiocytes in negative nodes had a better DFS than those with residual disease in the nodes, but not as good as those with no nodal metastases and no evidence of regression. Therefore "treatment effect" in lymph nodes should be mentioned in pathology reports. The number of nodes that bear metastatic carcinoma remains of prognostic value post NAC. 2. Outlook for Patients with Less Than a Complete Response 2a. Response Classification Systems Patients in whom a pathologic complete response (CPR) is achieved have a vastly improved prognosis compared to patients who retain residual disease after NAC and the extent of residual breast cancer after NAC has also been shown to be predictive of future local and distant relapse and long term survival [4, 11]. At present there is no consensus on a standardised response classification system. Table 1 outlines some of the systems employed to categorize the extent of residual tumour [2, 3, 5, 6, 14, 18, 19, 20]. These methods vary in the variables included and in the granularity of the predictive information they provide. Regardless of the system in use at any particular centre, the pathology report should provide a minimum data set including diameter, cellularity, grade, proportion of DCIS component, nodal disease and usual biomarkers to permit assessment of the nature of the response. The residual cancer burden index, proposed by the MD Anderson group [20] has the advantage of being a continuous rather than dichotomous measurement of response. On line assistance in deriving this index is provided at www.mdanderson.org/breastcancer_RCB. Local recurrence occurs in approximately 10% of patients. The pathologic predictors of locoregional recurrence in the setting of locally advanced breast cancer treated with NAC, mastectomy and radiation therapy include the number of positive nodes, dissection of <10 nodes, multifocal/multicentric disease, extracapsular extension, vascular invasion, skin/nipple involvement and ER negativity [8]. These features should be included in the pathology report. 2b. Determination of Tumour Size (Multifocality vs. Heterogeneous Response) Tumour response is frequently not uniform, resulting in variable islands of residual cancer with intervening fibrotic zones. This pattern of response raises problems in determining tumour size. Should pathologists treat this as multifocal carcinoma or as one large fragmented cancer? Correlation with the pre-therapy imaging and clinical information is used in this situation to determine the size of the tumour bed and distinguish multifocality from heterogeneous response. If pre-therapy data indicated a single mass, one generally would report the largest dimensions of the entire tumour bed. 2c. Status of Surgical Margins When there has been a significant response and particularly when the tumour fragments and shows a marked reduction in cellularity (5%), even when margins appear clear of disease, tumour may remain in the adjacent breast beyond the margin. Pinder et al suggest that it may be prudent to indicate that the completeness of excision of the carcinoma cannot be confirmed with any degree of reliability [16]. 2d. Biomarkers Post NAC Limited data are available on the correlation of ER, PR & HER2 between the pre-treatment core biopsy and the post-treatment resection specimens and various authors have interpreted the data differently. Pinder et al conclude that there are insufficient data to state definitively whether hormone receptors status and HER2 should be re-examined on the excised tumour [16]. They also believe that there is no sound evidence base as to which assessment (pre or post NAC) provides the more accurate prediction of response to hormone therapy and or Herceptin of any subsequent metastatic disease. By contrast, the 7th edition of the AJCC TNM staging manual recommends re-testing of these biomarkers in the residual carcinoma [12]. Our own pragmatic approach is to repeat these markers after NAC since our oncologists ask for this information. Table 1: Summary of some predictors of complete pathologic response (CPR) to neoadjuvant chemotherapy. Variable Consensus Tumour size (T) CPR less likely if larger, higher stage ER status ER -ve respond more (24% vs 8%) Nuclear grade 3 Some data suggest grade 3 more apt to respond Tumour subtype Ductal > lobular (15% vs 3%) HER2 positive Good response with Transtuzumab Topoisomerase IIa Better response to AC Ki-67 ?Better response if >20% Molecular subgroups Basal-like & HER2 > luminal Apoptosis genes p53, BAX, Bcl2 - significance unclear Age, menopause status ?More CPR if <50yrs. Most find no effect Table 2: Summary of selected response classification systems used in the setting of neoadjuvant chemotherapy in breast cancer. Study Basis Chevallier 4 tier system: 1) tumour disappearance, 2) only residual DCIS, 3) therapy effect (sclerosis) in breast, 4) no change Chollet Modified NPI. Residual tumour size, modified breast grading index NSABP CPR defined as no residual invasive cancer (gross/micro) in the breast, versus residual invasive cancer Miller/Payne 5 tier system based on reduction in cellularity. No change, <30%, 30-90%, >90%, 100% Sataloff Therapy effect in breast & nodes. 4 tiers each. Breast: total or near total effect, >50%, <50% but some effect, no effect. Bonadonna 5 tier system based on reduction in cellularity: None, mild loss, moderate up to 90%, marked (tiny cell clusters), NRT or DCIS Smith Bonadonna with assessment of nodal therapy effect added Symmans RCB: Bidirectional diameter tumour bed, % celluarity, number of positive nodes, diameter of the largest nodal metastasis. Abbreviations: NPI (Nottingham Prognostic Index). CPR (Complete Apthologic Response). NRT (No Residual Tumour). RCB (Residual Cancer Burden). Opportunities for Future Advances Areas where pathologists may contribute to this evolving field include the development of evidence based and validated response classification systems that allow consensus in: 1) Identifying patients who have had a complete pathologic response after NAC since this group has an improved prognosis. 2) Quantifying the extent of response of patients who have achieved a less than a complete response. 3) Determination of more robust predictors of response to various NAC regimens, so as to foreshadow lack of response in individual cases and avoid delay in initiating alternative treatment options while NAC is being administered. Conclusions NAC is used most often for patients with locally advanced breast cancer. While NAC does not improve the overall survival rates beyond those achieved by adjuvant chemotherapy, this therapy down stages some patients, rendering their disease operable or providing the opportunity for breast conserving surgery. 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