SPECIMEN HANDLING & PATHOLOGY REPORT BEFORE AND AFTER BREAST CANCER NEOADJUVANT TREATMENT

1. SPECIMEN HANDLING & PATHOLOGY REPORT BEFORE AND AFTER BREAST CANCER NEOADJUVANT TREATMENT . DR. Mervat Mohamed Fouad Assistant Lecturer, Pathology Department NCI

2. European Congress of Pathology September 2005 held in Paris(update in pathology) Consensus conference was convened in Philadelphia in April 2003, discuss issues related to routine application of neoadjuvant chemotherapy & establish more formal guidelines for its use in patients with all stages of breast carcinoma. The full proceedings of the conference was published inCancer 2004,100: 2512-2532 The panel recognized the major role of the pathologist in providing essential tumor parameters necessary to tailor this type of treatment

3. MAGNITUDE OF THE PROBLEM OF BREAST CANCER The breast cancer is more prevalent in well developed countries USA: -1.15 million new cases 2002 -Accounting for 23 % of all female cancers -Highest mortality 411.000 death /year 2002 -99.6 /100.000 population (Globcan) Egypt : -NCI 10.000 new cancer cases are diagnosed each year -Breast cancer constitutes 19.1% in both sexes & 37.6% in females. -According to population based registry El-Gharbih incidence of breast cancer is 49.6 /100.000

4. Neoadjuvant chemotherapy (NAC) is also termed primary, preoperative or induction chemotherapy. NAC or hormonal therapy is used before surgery in breast cancer to down stage the tumor so that less extensive resection is needed & breast conservation becomes increasingly feasible. Although it is the standard therapy for patients with locally advanced breast cancer it is increasingly used for early stage operable disease. NAC prevent changes in metastatic cells such as acceleration of growth & development of drug resistance subclones upon resection of the primary tumor. Furthermore micrometastasis that may be present are thus treated at the earliest possible moment. Third rapid assessment of tumor sensitivity to chemotherapy within 3-4 months.

5. Essential tumor parameters to tailor this treatment & Predictive parameters for treatment response on pretreatment biopsy • 1-Confirm the diagnosis by true cut or core biopsy, in cases diagnosed by fine needle aspiration cytology (FNAC) as cytologic examination can not differentiate between in situ and invasive tumors . but palpable regional lymph nodes with detection of malignant cells in L.N denote invasive cancer.

6. 2-Histological type , nuclear grade & mitotic index (MI)

9. -Histologic type lobular carcinoma is a low responder High tumor grade, high nuclear grade & high MI all exhibits high response rate. Grade 1 tumors &/ or lobular carcinomas are not responding

10. -Immunohistochemical evaluation of ER ,PR & HER-2/neu predictors for targeted therapy -ER & PR proved to be necessary to predict response to NHT tamoxifen & antiaromatse. -Her-2/neu trials of preoperative trastuzumab show very high level of complete response rate among Her-2/neu amplified & overexpressed tumors (up to 70%)

11. -ER & PR negative tumors respond to certain chemotherapeutics as high grade poorly differentiated tumors are more likely to be ER & PR negative. -HER-2 predict response to NAC anthracycline based. -Proliferative markers…… cell proliferation correlate with response of breast carcinomas to preoperative chemotherapy & disease outcome but it is not used to select patients . There is no consensus on method used SPF, MI & KI-67 may indicate possibility of obtaining pCR

14. Topoisomerase II œ is a vital DNA binding enzyme. It helps DNA repair following strand cleavage. Topo II œ is the specific target of several chemotherapeutic agents including anthracyclins. Topo II œ gene is located at 17q 12-21 close to HER-2/neu gene , coamplification of HER-2/neu gene & Topo II œ gene was observed in 44% of breast cancer whereas the Topo II œ gene was deleted in another 42%. This complex relationship between the two genes may explain the altered sensitivity to anthracyclins of HER/-2/ amplified breast carcinomas.

15. Because most tumors respond well to treatment tumor localization is important. This is can be performed using either externally visible or radioopaque marker or metal coil simple mean to provide landmark for localization & excision when the breast lump become impalpable & radiologically undetected. Sentinel node if the tumor is small , it is likely to be lymph node negative therefore SLNB result will guide subsequent treatment . In addition number of positive lymph nodes indicates necessity of postoperative radiotherapy.

16. Criteria for evaluating response to systemic treatment according to WHO IUAC: 1-Complete response………complete disappearance of all clinically detectable disease 2-Partial response……….more than 50% reduction in the sum of the products of the 2 longest perpendicular diameters of measurable tumor deposits. 3-Progressive disease ……25% -30% increase in the sum of products of the 2 longest perpendicular diameters of tumors or appearance of new lesions Combined clinical & radiological examination is needed to detect extent & sites of residual cancer in order to determine geography of the tumor and to plan surgery. Although clinical response is often selected as the primary endpoint in trials of NAC ,main goal of therapy should be a pathological complete response (pCR). The most objective information concerning effectiveness of NAC is provided by microscopic assessment of the extent & type of residual tumor.

17. Gross examination of breast specimen -Inspection- palpation & X-ray appearance 1-Fresh-fixed (state of the specimen) 2-Type ……….excision biopsy or mastectomy 3-Side, size 3 dimensional 4-Dominant lesion…… site & size (maximum diameter is most important), texture (consistency), color, outlines & relationship to surrounding tissues. 5-Margins …. Proximity to specimen margin 6-X-ray appearance ( when relevant)

18. If a complete clinical remission is achieved, resection of area surrounding marker is performed to detect the presence of microscopic residual disease as complete clinical regression does not imply completepathological regression Excision biopsy -Mark tumor -Orient specimen -Margins inked or marked -Radiograph & / or ultrasound image of the specimen -Section at 3-5 mm thick if the specimen is too large. Step sectioning aid in Semi quantitative estimation for residual tumor size based on the number of positive histological slides.

19. In mastectomy specimens -Laterality -Site of tumor -Size before therapy -residual tumor --tumor bed -Margins -Imaging

20. Pathology report: -Residual tumor –ve or +ve , invasive or intraductal component . No evidence that residual DCIS confer either distant recurrence liability or difference in long term survival. So that if no invasive cancer in breast & axilla this denote complete pathological response. -Histological type, histologic grade, nuclear grade , MI Many studies conducted to assess pathologic response to chemotherapy described 2 characteristic histologic features associated with chemotherapy exposure namely fibrosis & cytonuclear changes. -Defined fibrosis as scar-like tissue , appeared as hyaline- rich , cell deprived desmoplastic stroma only if located at peripheral edge of the tumor. - Regressive cytonuclear alterations scored if marked anisocytosis, vacuolization & increase in the nuclear size.

26. - Pathological complete remission (pCR): No residual carcinoma macroscpically or microscopically - Microscopic residual disease (pMRD) : minimal tumor residues were found in the breast or in the axilla. Histopathological changes in a macroscopic residualtumor (pH RTM): Histopathological characteristic of NAC exposure but as macroscopic residual tumor mass. No response (p NR): No quantitative or qualitative histopathological evidence of tumor response. Sataloff et al., Grading of the therapeutic effect related to the primary tumor site & ALNs as defined by microscopic changes: T-A= total/near total therapeutic effect T-B=subjectively > 50% therapeutic effect but < total/near total therapeutic effect T-C=< 50% therapeutic effect, but effect evident • T-D= no therapeutic effect

27. ALNs response classification N-A=evidence of therapeutic effect , no metastasis N-B=no therapeutic effect, no nodal metastasis N-C=evidence of therapeutic effect, nodal metastasis present N-D=no therapeutic effect, viable metastatic disease Factors predictive for response to NAC: -ER status -LN involvement - p53 -Tumor size -Ki-67 -HER-2/NEU

28. Thank you Thank you Thank You Thank You