Sentinel Lymph Nodes for Breast Carcinoma: A Paradigm Shift Edi Brogi MD PhD Attending Pathologist Director of Breast Pathology
Sentinel Lymph Nodes 2014 • AJCC 2010 staging • Micrometastases • Occult metastases • Z0011 and B-32: implications for SLN evaluation • Routine • Intraoperative review of MSKCC current protocols
Assessing LN status of patients with breast carcinoma used to be simple …
Today, LN involvement comes in 3 different flavors… • pN1 • pN0 pN0(i-) MACROMETASTASIS pN0(i+) size >2 mm ISOLATED TUMOR CELLS (ITCs) • pN1mic single cells and clusters MICROMETASTASIS <0.2 mm, even in H/E- size >0.2 mm and <2 mm stained slides >200 cells in one LN section pN0(mol-) and pN0(mol+) AJCC 2010
Micrometastases (<2 mm) Annals Surgery 1971 • First defined by Huvos et al. in 1971 • 75% 8-y OS for 63 pts with mets only in level I LNs – 94% 8-y OS for pts with micromets – 64% 8-y OS for pts with macromets
practical approach to measuring size of LN met 1/5 of 200X 100X FOV FOV = 0.2 mm = 2 mm 100X final magnification 200X final magnification • The diameter of a 100X • The diameter of a 200X field of vision (FOV) FOV (20X objective and (10X objective and 10X 10X ocular piece) is about ocular piece) is about 2 1 mm mm • One fifth of a 200X FOV diameter is about 0.2 mm
SEER micrometastasis study • 209,720 patients (SEER) 1992-2003 – pN0 – pN1mi (0.3-2 mm) – pN1 (>2 mm) • N1mi significant at multivariate analysis (p<0.0001) – vs N0 (HR1.35) – vs N1 (HR 0.82) Chen SL et al Ann Surg Oncol. 2007, 12:3378-84
SENTINEL LYMPH NODE 1 st LN draining tumor bed 1 st site of local mets SLN identification Tc 99 -radiotracer “hot” and/or 0 isosulphane blue dye “blue” and/or or palpable intraoperatively Usually 1-3 SLNs identified
Histologic evaluation of SLNs • SLN site of first local metastasis AND • Only 1-3 SLNs per patient • More extensive evaluation of SLNs aimed to identify occult metastases
Occult metastases An occult metastasis is any metastasis that is either missed or not identified on initial examination using a “standard” evaluation protocol
Section through plane A LN is diagnosed as negative all mets are occult A A
Section through plane B LN is diagnosed as positive for met larger mets are still occult B B
“ENHANCED PATHOLOGY” ADDITIONAL EVALUATION OF SLNs NEGATIVE IN THE INITIAL H/E-STAINED SECTION DEEPER H/E LEVELS +/- CYTOKERATIN STAINS PATHOLOGIST
ENHANCED PATHOLOGY OF SLN Many different protocols have been used to identify occult metastases in SLNs
What is the clinical significance of occult metastases? MSKCC retrospective study NASBP B-32
Significance of occult metastases MSKCC retrospective study • 368 LN-neg women treated between 1976-78 • all had MRM and axillary dissection • no systemic rx • All LNs blocks retrieved and re-evaluated using same enhanced pathology protocol H&E and IHC 50 µ H&E and IHC 1 H&E and 1 AE1:AE3 stained section from each of two levels 50 µ apart
Significance of occult metastases MSKCC retrospective study • Patient median age: 57 y (24-83) • Tumor Type DUCTAL 319 (87%) LOBULAR 49 (13%) • Tumor size cm – <1.0 64 (17%) – 1.1- 2.0 180 (49%) – >2.0 123 (34%) – missing 1 (<1%) Tan, L. K. et al. J Clin Oncol; 26:1803-1809 2008
Significance of occult metastases MSKCC retrospective study 83/368 (23%) with occult metastases IHC+/HE- 50 (14%) IHC+/HE+ 33 (9%) pN0i+ ( < 0.2 mm): 61 (73.5%) pN1mic (0.3-2 mm): 17 (20.5%) pN1a (>2mm): 5 (6%) Tan, L. K. et al. J Clin Oncol; 26:1803-1809 2008
DFS by pattern of LN staining IHC-/H&E- IHC+/H&E- IHC+/H&E+ Tan, L. K. et al. J Clin Oncol; 26:1803-1809 2008
DFS by largest cluster size Negative <0.2 mm 0.3-2.0 mm Tan, L. K. et al. J Clin Oncol; 26:1803-1809 2008
MSKCC retrospective study Strenght Limitation • Patients received no • Nowadays most patients adjuvant therapy receive some form of adjuvant therapy (chemo-tx + hormone-tx data informative of the + radio-tx + immuno-tx) biologic significance of small tumor deposits in LNs data NOT informative in the greatest majority of cases
NSABP B-32 Clinically Negative Axillary Nodes (n=5,611) Randomization GROUP 2 GROUP 1 SLNB SLNB and ALND SLN+ on H&E SLN- on H&E No ALND ALND
NASBP-32 study QUESTION Is SLN biopsy equivalent to ALND for axillary staging of patients with cN0 LNs?
NSABP B-32 SLN negative patients OS similar for SLN&ALND and SLN w/o ALND 100 * 300 deaths triggered the definitive 80 analysis * 309 reported as of 12/31/2009 % Surviving 60 84.6% of pts in the study received systemic therapy 40 Treatment N Deaths 20 SNR and AD 1975 140 SNR only 2011 169 HR=1.20 p=0.117 0 Data as of December 31, 2009 0 2 4 6 8 Years After Entry
NSABP B-32 SLN negative patients DFS similar for SLN&ALND and SLN w/o ALND 100 80 % Disease-Free 60 84.6% of pts in the study received systemic therapy 40 Treatment N Deaths 20 SNR and AD 1975 315 SNR only 2011 336 HR=1.05 p=0.542 0 Data as of December 31, 2009 0 2 4 6 8 Years After Entry
NASBP-32 study QUESTION 1 Is SLN biopsy equivalent to ALND for axillary staging of patients with cN0 LNs? ANSWER: YES
NASBP-32 study QUESTION 2 What is the significance of a false negative SLN biopsy in clinically LN-negative patients? in other words, What is the significance of occult mets in patients with clinically negative LNs? Or: What is the best method for histologic evaluation of SLNs?
NSABP B-32 Pathology Methods • SLNs sliced at 2.0 mm intervals • All slices paraffin-embedded • Original lab examined only one H&E-stained slide from each block • All SLN-negative blocks were sent to Univ. of VT lab for additional evaluation Weaver D et al. AJSP 2009;33:1583-1589
NASBP B-32 additional pathology evaluation at the central lab 1 surface H&E B32 protocol 1 H&E and 1 CK-IHC at 2 levels 0.5 mm apart to identify mets >1 mm comprehensive protocol 1CK IHC every 0.18 mm to identify mets >0.2 mm Weaver D et al. AJSP 2009;33:1583-1589
NASBP B-32 pathologic evaluation Weaver D Am J Surg Pathol. 2009;11:1583-9 Micro mets N1mic 0.2 mm ITCs N0i+
ITCs or MICROMETASTASIS pN1mi: >0.2mm pN0i+: <0.2mm
Deeper section shows MICROMETASTASIS pN1mi: 0.4mm
NSABP B-32 Occult metastases SLN biopsy and ALND SLN biopsy alone 1924 SLN neg pts with F/U info 1960 SLN neg pts with F/U info 1608 had no occult mets 1660 had no occult mets 316 had occult mets 300 had occult mets Weaver D. et al. NEJM , 2011;364:412-21
NSABP B-32 Occult metastases SLN biopsy and ALND SLN biopsy alone 1924 SLN neg pts with F/U info 1960 SLN neg pts with F/U info 1608 had no occult mets 1660 had no occult mets 316 had occult mets 300 had occult mets 15.9% of pts had occult mets Weaver D. et al. NEJM , 2011;364:412-21
Occult mets more likely in younger pts, larger tumors, and mastectomy All patients (N=3887) Characteristics P value number/total number (%) Age 0.03 <49 172/947 (18.2%) >50 445/2940 (15.1%) Clinical tumor size <0.001 <2.0 cm 481/3260 (14.8%) 2.1-4.0 cm 123/567 (21.7%) >4.1 cm 13/60 (21.7%) Planned surgical treatment <0.001 Lumpectomy 510/3399 (15.0%) Mastectomy 107/488 (21.9%) Weaver D. et al. NEJM , 2011;364:412-21
Occult metastases and adjuvant therapy All patients (N=3887) Adjuvant therapy P value number/total number (%) Chemotherapy Yes 305/1548 (19.7%) <0.001 No 309/2319 (13.3%) Endocrine therapy Yes 454/2648 (17.1%) <0.001 no 160/1217 (13.1%) Weaver D. et al. NEJM , 2011;364:412-21
Occult mets slightly worse regional/ distant recurrence Recurrence No Occult Mets Occult Mets Total Cohort Site (n=3268) (n=616) (n=3884) Local 86 (2.6%) 16 (2.6%) 102 (2.6%) Regional 14 (0.4%) 7 (1.1%) 21 (0.5%) Distant 94 (2.9%) 23 (3.7%) 117 (3.0%) Contralateral 83 (2.5%) 16 (2.6%) 99 (2.6%) Weaver D. et al. NEJM , 2011;364:412-21
Occult Metastases and Survival Distant Disease Free Interval slightly but significantly shorter Weaver D. et al. NEJM , 2011;364:412-21
Occult Metastases and Survival Disease Free Survival slightly but significantly shorter Weaver D. et al. NEJM , 2011;364:412-21
Occult Metastases and Survival Overall Survival slightly but significantly worse 95.8% 94.6% Difference only 1.2% To achieve survival benefit in 1.2% of patients, 98.8% patients would have to be overtreated Weaver D. et al. NEJM , 2011;364:412-21
NASBP-32 Results Summary • 15.9% prevalence of occult metastases • 3.5% overall regional or distant recurrence • 1.2% reduction in 5-years survival in women with occult metastases – 0.6% reduction with ITC – 2.4% reduction with micrometastasis
Recommend
More recommend
