Problems in staging breast carcinoma Primary systemic therapy (PST) of breast carcinoma pathologists tasks Dr. Janina Kulka, 2nd Department of Pathology, Semmelweis University Budapest Austro-Hungarian Pathology Congress 1-3 October 2009
PST or neoadjuvant therapy Systemic oncological treatment prior to surgical intervention Formerly used only in T4, inflammatory carcinoma In recent years used in earlier stage disease to achieve Tumor size reduction, thus the possibility of breast conserving surgery Longer disease free survival Longer overall survival
Effect of 6 cycles of FEC100 treatment
New problems Preoperative pathological diagnosis and staging Breast: most prefer CORE biopsy Regional lymph nodes: FNAB Close and continous communication between the specialities: pre-treatment, pre-operative and postoperative multidisciplinary consultation. How to handle the specimens? How many blocks to submit? How to identify the histological signs of the treatment? Which system to use for the classification of tumor regression? Is the TNM system is good enough for staging in this new situation? The whole setting is not included in the EU guideline as yet.
Recent comprehensive literature Pinder SE, et al Histopathology 2007;50:409-17 Laboratory handling and histology reporting of breast specimens from patients who have received neoadjuvant chemotherapy Sahoo S, Lester SC. Arch Pathol Lab Med 2009;133:633-642 Pathology of breast carcinoma after neoadjuvant chemotherapy Pusztai L POR 2008;14:169-171 Preoperative systemic chemotherapy and pathologic assessment of response
Alvarado-Cabrero I et al Ann Diagn Pathol 2009;13:151-157 Incidence of pathologic complete response in women treated with preoperative chemotherapy for locally advanced breast cancer: correlation of histology, hormone receptor status, Her2/neu, and gross pathologic findings Jeruss JJ et al. Cancer Res 2008;68:6477 Staging of breast cancer in the neoadjuvant setting ( Clinical-Pathological Scoring System CPS) Kurosumi M Breast Cancer 2006;13:254 Significance and problems in evaluations of pathological responses to neoadjuvant therapy for breast cancer EU guideline next edition will include a chapter on this subject, the draft by Prof. Angelika Reiner-Concin now available only for the EWBSP members http://www3.mdanderson.org/app/medcalc/index.cfm?pagena me=jsconvert3 calculator of residual cancer burden (RCB)
Clinical Imaging Diagnosis & Staging Core biopsy diagnosis and predictive factors FNAB of sentinel LN or pathological LN Pathological staging Marking tumor edges TREATMENT Clinical staging SURGERY Preoperative localisation if necessary (if BCS is feasible) Intraoperative control: Specimen mammography or ultrasound
MACROSCOPY Identification of the residual tumor or the fibrotic area SLICE SPECIMEN MAMMOGRAPHY Submission of representative areas and axillary nodes MICROSCOPY No residual tumor at all Residual tumor found In the breast In the nodes pcr ypt0/tis N0 Sataloff T-A, N-A,B EU: T 1(i)(ii) N1-2 ypt1-4 N0 Sataloff T-B,C,D N-A,B EU: T2-4 N1-2 In either ypt0/tis N1-3 ypt1-4 N1-3 Sataloff T-A N-C,D EU: T1(i)(ii) N3-4 Sataloff T-B,C,D N-C,D EU: T2-4 N3-4
Macroscopical examination The tumor bed may be Rubbery fibrous tissue Fleshy nodule(s) Bright yellow circumscribed area May not be recognisable Sampling If tumor is visible: 1block/cm If residual tumor is small: embed the entire area No tumor found initially: further extensive sampling of tumor bed may be necessary Thorough sampling of margins
Lymph nodes Presence of grossly visible scar may indicate complete response in the LN
Microscopic examination Tumor bed Hyalinised, fibro-elastotic, vascular stroma Aggregates of foamy histiocytes and lymphocytes Haemosiderin pigment Cholesterol clefts Residual tumor cells May look identical to that seen in the core biopsy Enlargement, vacuolisation of the cytoplasm Pleiomorphic, bizarr nuclei Decreased mitotic activity CK immunohistochemistry may be necessary to identify them (both breast and LNs)
COLLAGENE IV IMMUNOHISTOCHEMISTRY
TENASCIN IMMUNOHISTOCHEMISTRY
Predictive factors Must be examined in the pretreatment corebiopsy Yet uncertain if re-testing is necessary in the Yet uncertain if re-testing is necessary in the excision specimen contradictory data published
28 year old woman with no family history of breast or any other cancer ER/PR Ki67 CB11 1,5 Her2 signal/chr.17 CK5/6 Assessed as ER/PR/HER2 negative tumor
Assessment of tumor response
Kurosumi M. Breast Cancer Vol. 13 No. 3 July 2006
Sahoo S and Lester C Arch Pathol Lab Med Vol 133, April 2009
Suggested assessment of tumor response 1. Complete pathological response i) no residual carcinoma ii) DCIS present (no invasive carcinoma) 2. Partial response to therapy i) minimal residual disease: <10% of tumor remained ii) evidence of response, but 10-50% of tumor remained iii) >50% of tumor remained, cellularity similar to that seen in the core biopsy, some features of response present 3. No evidence of response Pinder S et al. Histopathology 2007
Assessment of residual tumor size Apple SK, Suthar F. The Breast 2006;15:370 Macroscopically: in three dimensions May considerably under- or overestimate the microscopic size Microscopically this is the gold standard: By mapping, based on the serial slices mandatory to record the thickness of the slices Record the size and extent of the invasive and the in situ component Question of multifocality
Suggested assessment of nodal response 1. No evidence of metastatic disease, no evidence of change in the LN-s 2. Metastatic tumor not detected but evidence of response (partial or complete fibrosis) 3. Metastatic tumor detected, but evidence of response (fibrosis) 4. Metastatic tumor detected and no evidence of response Pinder S et al. Histopathology 2007
Sentinel nodes in this setting Sentinel lymph node biopsy after preoperative chemotherapy for breast cancer: findings from the Austrian Sentinel Node Study Group. Tausch C et al. Ann Surg Oncol 2008 Dec;15(12):3378-83. The results of SLNB after PC are comparable to the results of SLNB without PC. Further investigation in a prospective setting is warranted to confirm these promising results. Accuracy of sentinel node biopsy after neoadjuvant chemotherapy in breast cancer patients: A systematic review. van Deurzen C et al. Eur J Cancer 2009 Aug 26. [Epub ahead of print] There is a potential role for SN biopsy following NAC which could be considered on an individual basis. However, there is insufficient evidence to recommend this as a standard procedure. Further research with subgroup analysis using variables reported to be associated with decreased SN accuracy is required in order to clearly define its value in the subgroups of breast cancer patients.
Towards rational axillary treatment in relation to neoadjuvant therapy in breast cancer Straver ME et al Eur J Cancer 2009 Sep,45:2284 20% of the patients with proven (axillary) metastasis by cytology prior to neoadjuvant chemotherapy have an axillary pcr. The axillary pcr rate is very high in certain subgroups (triple negative cancers). Identification of those patients could result in more axilla-conserving surgery. Axillary-conserving surgery is facilitated by neoadjuvant chemotherapy of breast cancer Beatty JD et al Am J Surg 2009 May, 197:637 Pathological complete response of ALN was documented in 36% of patients NCT downstages primary breast cancer and ALN metastasis. ALN and SLN byopsy following, rather than before, neoadjuvant chemotherapy facilitate both breast- and axillary-conserving surgery.
Pathologic staging (i.e. AJCC) has not been validated for patients receiving neoadjuvant chemotherapy. and It is unclear, whether the initial clinical stage or the final pathological stage is more meaningful in terms of prognosis and there is no current methodology for incorporating the information on clinical and pathologic response to the chemotherapy into the stage grouping. Jeruss JS et al. Cancer Res 2008:68:6477
CPS-EG: Clinical-pathological scoring system Combines tumor stage at presentation, tumor stage following PST, and ER status and nuclear grade All patients who achieve pcr are not the same biologically and cannot be expected to have similar outcomes Jeruss JS et al. Cancer Res 2008:68:6477
Acknowledgements