6/5/2010. Neoadjuvant Treated Breast Cancer. Outline of Talk. Problems in Grossing, Diagnosing & Staging

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1 Neoadjuvant Treated Breast Cancer Problems in Grossing, Diagnosing & Staging Outline of Talk Goals of Evaluating Neoadjuvant Treated Specimens Grossing Microscopic Alterations Joseph Rabban MD MPH Effects on Determining: Margins AJCC Staging Lymph Node Staging Purpose of Neoadjuvant Treatment of Breast Cancer Sequence of Neoadjuvant Therapy Indications: Radiologic Staging Goals: Locally advanced cancer Bulky cancer Shrink tumor to enable conservation surgery Test response to specific chemotherapy Core Biopsy (ER,PR,HER2) 4 cycles Chemotherapy Clinical / radiologic exam Response Lumpectomy / SLN 1

2 Sequence of Neoadjuvant Therapy Responses to Therapy Radiologic Staging Core Biopsy (ER,PR,HER2) 4 cycles Chemotherapy Clinical (exam/imaging) Complete Response Partial Response Stable Progressive Response Clinical / radiologic exam No response Pathologic Residual Cancer No Residual Cancer Lumpectomy / SLN Mastectomy / Nodes Clinical Complete Response Pathologic Complete Response Before Neoadjuvant TX After 4 Chemo Cycles 2

3 Clinical Partial Response Before Neoadjuvant TX After 4 Chemo Cycles Clinical Response X Pathologic Response Complete response 2/3 residual cancer on pathology 1/3 no residual on pathology Cancer 2002; 95: 681 Pathology of Complete Response Pathology of Partial Response No residual invasive tumor in breast stage as ypt0 (or yptis if residual DCIS) may still have nodal metastases Residual invasive tumor reduced size and/or cellularity altered cytologic appearance Changes in stroma of tumor bed necrosis granulation tissue Changes in normal breast tissue atrophy / fibrosis Changes in stroma of tumor bed necrosis granulation tissue Changes in normal breast tissue atrophy / fibrosis 3

4 Goals of Pathologist in Evaluating Neoadjuvant Treated Breast Specimens Outline of Talk Identify residual disease in breast (none, in situ, invasive?) in nodes (negative, positive?) Define stage ypt ypn Define margin status Goals of Evaluating Neoadjuvant Treated Specimens Grossing Microscopic Alterations Effects on Determining: Margins AJCC Staging Lymph Node Staging Gross findings: Gross Findings Don t Always Correlate with Microscopic Findings Patterns of Residual Tumor Pre-treatment Tumor May over-estimate residual tumor size due to gross stromal fibrosis May under-estimate residual tumor size due to occult residual cancer Concentric Reduction Single Residual Mass Grossly Visible Patchy Reduction Multifocal Residual Mass Grossly Visible Patchy Reduction Sparse Residual Cells Grossly Invisible May be confusing to interpret tumor size due to patchy drop out of cancer 4

5 Residual Gross Mass Grossly Unremarkable No residual cancer Residual invasive cancer, 12 cm Positive margins Grossly Altered Stroma Grossly Altered Stroma No residual cancer Organizing granulation tissue Residual invasive cancer, 5 cm Negative margins No residual cancer Organizing granulation tissue Residual DCIS, 9 cm Negative margins 5

6 Grossing a Post-treatment Breast Example Determine the pre-treatment radiologic tumor size Thoroughly sample an area equal to original tumor size regardless of gross findings Pre-treatment 5 cm mass Post-treatment No residual mass Sample representative areas of gross fibrosis Thoroughly sample margins Regardless of gross findings Sample across a minimum of 5 cm Outline of Talk Cytologic Alterations in Residual Cancer Cells Due to Neoadjuvant Chemotherapy Goals of Evaluating Neoadjuvant Treated Specimens Grossing Microscopic Alterations Effects on Determining: Margins AJCC Staging Lymph Node Staging Alteration Reduced Cellularity Reduced Atypia Histiocyte-like Changes Lobular-like Changes Mucinous Changes Potential Problem Under-estimate tumor size Under-diagnose margins Under-diagnose margins Under-diagnose tumor size, margins Under-diagnose lymph nodes Mis-classify tumor type Mis-classify tumor type 6

7 Treatment Effects on Tumor Cytology Nuclear Atypia May be Severe or Mild Apocrine / squamoid change Vacuolization Histiocytoid changes Histiocytoid changes 7

8 6/5/2010 Histiocytoid changes Keratin Keratin is Useful if Occult Tumor Cells are Suspected Granulation Tissue May Harbor Occult Tumor Cells Lobular appearance of Treated Ductal Carcinoma E-cadherin 8

9 True Residual Lobular Carcinoma Reduced Atypia and Cellularity Makes Margin Evaluation Challenging Reduced Atypia and Cellularity Makes Margin Evaluation Challenging Keratin May Assist in Margin Evaluation 9

10 Margins Are Frequently Involved in Neoadjuvant Treated Specimens Mucin pools can appear following treatment in non-mucinous carcinomas Gross Findings % Positive Margins None 33 % Altered Stroma 13% Residual Mass 24% Rabban et al. Mod Pathol 2007; 2: 46a Mucin pools can appear following treatment in non-mucinous carcinomas Mucin pools can appear following treatment in non-mucinous carcinomas Presence of mucin alone is not diagnostic of tumor type High nuclear grade and non-mucinous architecture should trump presence of mucin in terms of typing Re-examine pre-treatment core biopsy before diagnosing residual mucinous carcinoma Hint: Classic mucinous carcinoma is rarely treated with neoadjuvant approach 10

11 Residual DCIS Can be Difficult to Identify Minimal DCIS with treatment effect Minimally involved ducts / lobules with treated DCIS may go undetected. Because tumor cells are too scant Because they may be interpreted as reactive Problem for margin evaluation Minimal DCIS with treatment effect Minimal DCIS with treatment effect 11

12 Minimal DCIS with treatment effect HER2 Minimal DCIS with treatment effect HER2 Minimal DCIS with treatment effect HER2 Healing DCIS 12

13 Healing DCIS Healing DCIS Healing DCIS Residual Minimal DCIS: Diagnostic Clues Large Nuclei Macronucleoli Irregular Nuclear Contours Attention: Healing ducts Margins 13

14 Staging Residual Tumor Patterns of Residual Tumor AJCC criteria No residual invasive or in situ tumor Residual DCIS only Residual invasive cancer ypt0 yptis ypt1 or more Pre-treatment Tumor Method to determine residual tumor size An unresolved problem Largest single focus of invasive tumor Do not include fibrotic tumor bed nests of tumor cells in fibrotic stroma the T should be determined based on the largest contiguous area of invasive carcinoma, excluding Recommendation: report 2 sizes 1) AJCC method. Best attempt at single largest focus 2) Total maximal span of all residual cancer. surrounding areas of fibrosis 14

15 Tumor Grading after Neoadjuvant Treatment Biomarker Testing after Neoadjuvant Treatment Use Modified Scarff-Bloom-Richardson grade Still applicable after treatment Generally, lower the grade = lower the response Best to determine on pre-treatment core biopsy No need to repeat on post-treatment specimen ER / PR / HER2 are relatively stable Outline of Talk Lymph Nodes and Neoadjuvant Treatment Goals of Evaluating Neoadjuvant Treated Specimens Grossing Microscopic Alterations Nodal metastasis is common in this population prior to neoadjuvant TX since it is a treatment indication Response of nodal metastases to neoadjuvant TX Effects on Determining: Margins AJCC Staging Lymph Node Staging No response Partial response* Complete response* ypn1 or more ypn1 or more ypn0 * Stromal fibrosis, hemorrhage, granulation tissue is common 15

16 Post-treatment node with fibrosis Post-treatment node with fibrosis No metastases, ypn0 Post-treatment node with fibrosis Residual metastases, ypn1 keratin Residual nodal metastasis with stromal reaction Hemorrhagic Fibrotic 16

17 Keratin Necrosis in node = suspicious for occult metastases Acellular mucin in treated node = ypn0 17

18 Lymph Nodes and Neoadjuvant Treatment Outline of Talk Introduction of ITC in post-treatment nodes Rules for pn0i+ now apply for post-treatment New category of ypn0i+ * Stromal fibrosis can be used in measuring size! Goals of Evaluating Neoadjuvant Treated Specimens Grossing Microscopic Alterations Effects on Determining: Margins AJCC Staging Lymph Node Staging 18

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