Problems in staging breast carcinoma

Primary systemic therapy (PST)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 carcinomacarcinoma

• 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 post-operative multidisciplinary consultation.

• How to handle the specimens? How many blocks to • 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 • 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• 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?pagename=jsconvert3 –calculator of residual cancer burden (RCB)

ClinicalImaging

Diagnosis &Staging

Core biopsydiagnosis and

predictive factors

TREATMENT Clinicalstaging

Marking tumor edges

FNAB of sentinel LN

or pathological LN

Pathologicalstaging

SURGERY Preoperative localisation

if necessary (if BCS is feasible)

staging

Intraoperative control:

Specimen mammography or ultrasound

MACROSCOPYIdentification

of the residual tumor or thefibrotic area

SLICE SPECIMEN MAMMOGRAPHY

Submission of representative areasand axillary nodes

MICROSCOPY

No residual tumorat all

Residual tumor found

pCRypT0/Tis N0

In the breast In the nodes

In either ypT0/Tis N1-3ypT1-4 N0

ypT1-4 N1-3

Sataloff T-A, N-A,BEU: T 1(i)(ii) N1-2

Sataloff T-B,C,DN-A,B

EU: T2-4 N1-2

Sataloff T-B,C,DN-C,D

EU: T2-4 N3-4

Sataloff T-AN-C,D

EU: T1(i)(ii) N3-4

Macroscopical examination

• The tumor bed may be– Rubbery fibrous tissue– Fleshy nodule(s)– Bright yellow circumscribed area– May not be recognisable– 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– 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 core-

biopsy– Yet uncertain if re-testing is necessary in the – Yet uncertain if re-testing is necessary in the

excision specimen – contradictory data published

ER/PR Ki67

28 year old woman with no family history of breast or any other cancer

CB11 CK5/61,5 Her2 signal/Chr.17

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 CArch 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 – 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 sizemicroscopic 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 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 chemo therapy 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.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,45:228420% 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 • Axillary -conserving surgery is facilitated by neoadjuvant chemotherapy of breast cancer

Beatty JD et al Am J Surg 2009 May, 197:637Pathological 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 „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