Sentinel Lymph Nodes in Breast Cancer:

Histology, reporting, andclinical implications!"#$%&'(&)"*+,

Sentinel Lymph Nodes in Breast Cancer:

Histology, reporting, andclinical implications!"#$%&'(&)"*+,

!"#$%&'"%()*+&,*(&!"#$%&'"%()*+&,*(&-).)/,*0)&!$&-).)/,*0)&!$&$!1)%&$!1)%&2323 4),5"%)54),5"%)5

Sentinel Lymph Node

First node in regional nodal basin that drains a primary tumor and reflects the tumor status of the entire nodal basin

Surgical aspects per Dr. Morrow

Gold Standard, before sentinel methodology accepted

• Axillary lymph node dissection (although minimal cases missed)

• Histopathologic study of nodes

• report # of positive nodes/ # nodes

present

Sentinel Lymph Node

• Gross examination

• Frozen section

• Touch prep

• Immunohistochemistry

• PCR[not indicated, high false +]

SEER Staging Trends (1983-1998)

• Stage 0 – increase

• Stage 1 - increase

• Stage 2 node negative – stable

• Stage 3, 4 – stable

• Stage 2, node positive - increase of as much as 30%,most minimal involvement

Metastasis in SLN

SLND ALND

no. patients 162 134

% positive 42% 29%

% <2mm) 38% 10%

Giuliano, Ann Surg 1995

Outcome and Node AnalysisEarly,1999,espouse conservative

“IHC metastases do not appear to adversely affect prognosis”

“IHC should not be routinely performed” on SLN, “nor should treatment decisions be made”[recall that average size is T1c, and grades

are mostly low.]

Turner, et al., Am J Surg Pathol, 23: 263-7, 1999

CO$T CON$IDERATIONDon Weaver,MD

• In order to detect single cells:– Section at 10 micron (0.01 mm) intervals

– One paraffin block (2 mm) results in 200 slides

• $12 per slide = $4800 per case

• Newly diagnosed breast cancer in US = $900 million annually

• 77 million slides

Significance of isolated tumor cells and

Cell Clusters (ITCs)

?X

xx

xx

x

xxxx

xxxxxxx

Xx

xx

xx

xxxx

xxxxxxx

Patterns: missed & detected micrometastasesPatterns: missed & detected Patterns: missed & detected micrometastasesmicrometastases

Xx

xx

xx

xxxx

xxxxxxx

Xx

xx

xx

xxxx

xxxxxxx

pN0(i+)

pN1mi

pN0(i-)

pN0(i-)

Don Weaver

Patterns of missed micrometastases for various strategies

Three levels

200 micron intervals

Two levels

1.0 mm interval

Four levels through block

500 micron (0.5 mm) intervals

Multiple levels through block

200 micron intervals

Don WeaverPathologistsPathologists’’ chargecharge

Minimal epithelial cells need to be examined and analyzed without

the assumption that they represent relevant node involvement by

cancerQuantitatively and Qualitatively

False Positive Nodal Involvement

CK staining of dendritic macrophages, and

plasmablasts as well as degenerating cell debris

Benign inclusions

Viable fragments of papillomas

Benign transport: usually fragments of hyperplasia

as seen in the displaced clusters in granulation

tissue of biopsy site

or papilloma(s)

Artifactual keratinocytes in plane above node

Benign Transport

• 15 cases from breast consult files

• Node dissection 15 days after biopsy

• 7 of 15 with DCIS

• Cluster (<100!m) of epithelial cells in subcapsular sinus accompanied by hemosiderin-laden macrophages, giant cells, and altered RBC’s

Carter et al, Am J Clin Pathol, 2000

Nl. Glands at Bx. SiteCLUSTER OF 3 DEGENERATING CELLS IN SINUS

WITH SURROUNDING MACROPHAGE REAXN.

AJCC Cancer Staging2002

• Micromets distinguished from ITC

• Identifiers added to indicate SLN and IHC

• Major classification of lymph node status designated according to number of involved axillary nodes

AJCC/UICC Cancer Staging

6th edition

Isolated tumor cells (ITCs)

defined as single tumor cells or small clusters not greater than 0.2 mm

pN0 (it)

Modified by Singletary,et al,

Cancer; 2003

ITC = Isolated tumor cells and cell clustersAJCC Cancer Staging

2003

• Micrometastasis (greater than 0.2 mm, none greater than 2.0 mm)

pN1mi

Dense small cell groups, probably significant

= < 2mm.

Individual Tumor Cells and Clusters, = ITC

Some more “real” than others. Still small

Individual Tumor Cells and Clusters, = ITCIndividual Tumor Cells and Clusters, = ITC

Some more Some more ““realreal”” than others. Still smallthan others. Still small

Normal glandular inclusions in capsuleNormal glandular inclusions in capsuleNormal glandular inclusions in capsule Benign Inclusion, in capsule substanceBenign Inclusion, in capsule substanceBenign Inclusion, in capsule substance

Nodal Inclusion, nl. polarized cellsNodal Inclusion, Nodal Inclusion, nlnl. polarized cells. polarized cells ITC or Benign transportITC or Benign transportITC or Benign transport

Lymph Node Sinusoid, Nl. Gland & giant cellLymph Node Sinusoid, Lymph Node Sinusoid, NlNl. Gland & giant cell. Gland & giant cell

CK, B9 transport & CK, B9 transport & squamoussquamous metaplasiametaplasia

Sinusoid

Individual tumor cells and clustersITCITC

Benign Benign papillomapapilloma ““inclusioninclusion”” in nodein node Benign transport, Benign transport, subcapsularsubcapsular sinussinus

AnucleateAnucleate squamessquames in in subcapsularsubcapsular sinussinus

Occult Cells in Lymph Nodes

Does the finding change the prognosis from that already indicated by other information?

Implication of minimal cells in other nodesother nodes not = survival survival predictionprediction

But may indicate other nodes But may indicate other nodes with tumorwith tumor

Viale et al, Ann. Surg;2005

further axillary involvement was significantly

associated with the type and size of SLN metastases, the number of affected SLNs, and the occurrence of peritumoral vascular invasion. A predictive model was able to identify subgroups of patients at significantly different risk for further axillary involvement. CONCLUSIONS: Patients with the most favorable combination of predictive factors still have no less than 13% risk for nonsentinel lymph node metastases and should be offered completion ALND outside of clinical trials of SLN biopsy without back-up axillary dissection.

further further axillaryaxillary involvement was significantlyinvolvement was significantly

associated with the type and size of SLN associated with the type and size of SLN metastases, the number of affected metastases, the number of affected SLNsSLNs, and , and the occurrence of the occurrence of peritumoralperitumoral vascular vascular invasion. A predictive model was able to invasion. A predictive model was able to identify subgroups of patients at identify subgroups of patients at significantly different risk for further significantly different risk for further axillaryaxillary involvement. CONCLUSIONS: Patients involvement. CONCLUSIONS: Patients with the most favorable combination of with the most favorable combination of predictive factors still have no less than predictive factors still have no less than 13% risk for 13% risk for nonsentinelnonsentinel lymph node lymph node metastases and should be offered completion metastases and should be offered completion ALND outside of clinical trials of SLN biopsy ALND outside of clinical trials of SLN biopsy without backwithout back--upup axillaryaxillary dissection.dissection.

Pinder et al, Br.J.Cancer;2005• Metastatic deposits were classified as macrometastasis (>2.0

mm), micrometastasis (0.2-2.0 mm) or isolated tumour cells (ITC, <0.2 mm). Of the 216 patients, 56 (26%) had metastasis as identified by H&E. IHC detected metastatic deposits in a further nine patients (4%), of whom four (2%) had micrometastasis and five (2%) had ITC only. Those with micrometastases were all, on review, visible on the H&E sections. IHC detects few SLNs, of which were either micrometastasis or ITC. Until the prognostic significance of these deposits has been determined, IHC may be of limited value in the histopathological examination of SLNs

The Milan Studies involve complete analysis of each node

There are varieties of epithelial presence

other than benign transport in lymph nodes

There are also instances of cytokeration staining of

other than epithelial cells, particularly of

dendritic macrophages

Micrometastasis <2 mm

Recorded: N1

Prognostically: N0

AJCC Staging Manual 5th edition

Minimal Occult Metastasis

author method survival impact

De Mascarel IHC none

Cote IHC none overall, postmenopausal only

References for D.Page- Pathology of Sentinel Lymph Nodes in Breast Cancer. Feb. 2006. AJCC reporting and CAP Guidelines: 7,9,13,14

Pathology and prediction10-12

1-6,8,15-24

1. Carter BA, Jensen RA, Simpson JF, et al.: Benign transport of breast

epithelium into axillary lymph nodes after biopsy. Am J Clin Pathol 2000, 113:259-65

2. Chagpar A, Middleton LP, Sahin AA, et al.: Clinical outcome of patients with lymph node-negative breast carcinoma who have sentinel lymph node micrometastases detected by immunohistochemistry. Cancer 2005, 103:1581-6

3. Cibull ML: Handling sentinel lymph node biopsy specimens.A work in progress. Arch Pathol Lab Med 1999, 123:620-1

4. de Mascarel I, Bonichon F, Coindre JM, et al.: Prognostic significance of breast cancer axillary lymph node micrometastases assessed by two special techniques: reevaluation with longer follow-up. Br J Cancer 1992, 66:523-7

5. de Mascarel I, MacGrogan G: [Strategies for management of axillary lymph nodes in breast cancer. Point of view of the Institut Bergonie.]. Ann Pathol 2003, 23:518-33

6. Diaz LK, Hunt K, Ames F, et al.: Histologic localization of sentinel lymph node metastases in breast cancer. Am J Surg Pathol 2003, 27:385-9

7. Fitzgibbons PL, Page DL, Weaver D, et al.: Prognostic factors in breast cancer. College of American Pathologists Consensus Statement 1999. Arch Pathol Lab Med 2000, 124:966-78

8. Goyal A, Douglas-Jones A, Newcombe RG, et al.: Predictors of non-sentinel lymph node metastasis in breast cancer patients. Eur J Cancer 2004, 40:1731-7

9. Greene FL, Page DL, Fleming ID, et al. (editors): AJCC Staging Manual. New York, Springer-Verlag, 2002

10. Intra M, Zurrida S, Maffini F, et al.: Sentinel lymph node metastasis in microinvasive breast cancer. Ann Surg Oncol 2003, 10:1160-5

11. Klevesath MB, Bobrow LG, Pinder SE, et al.: The value of immunohistochemistry in sentinel lymph node histopathology in breast cancer. Br J Cancer 2005, 92:2201-5

12. Koscielny S, Le MG, Tubiana M: The natural history of human breast cancer. The relationship between involvement of axillary lymph nodes and the initiation of distant metastases. Br J Cancer 1989, 59:775-82

13. Singletary SE, Greene FL: Revision of breast cancer staging: the 6th edition of the TNM Classification. Semin Surg Oncol 2003, 21:53-9

14. Singletary SE, Greene FL, Sobin LH: Classification of isolated tumor cells: clarification of the 6th edition of the American Joint Committee on Cancer Staging Manual. Cancer 2003, 98:2740-1

15. Trojani M, de Mascarel I, Bonichon F, et al.: Micrometastases to axillary lymph nodes from carcinoma of breast: detection by immunohistochemistry and prognostic significance. Br J Cancer 1987, 55:303-6

16. Trojani M, de Mascarel I, Coindre JM, et al.: Micrometastases to axillary lymph nodes from invasive lobular carcinoma of breast: detection by immunohistochemistry and prognostic significance. Br J Cancer 1987, 56:838-9

17. Veronesi U, Galimberti V, Mariani L, et al.: Sentinel node biopsy in breast cancer: early results in 953 patients with negative sentinel node biopsy and no axillary dissection. Eur J Cancer 2005, 41:231-7

18. Veronesi U, Paganelli G, Viale G, et al.: A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. N Engl J Med 2003, 349:546-53

19. Viale G, Maiorano E, Pruneri G, et al.: Predicting the risk for additional axillary metastases in patients with breast carcinoma and positive sentinel lymph node biopsy. Ann Surg 2005, 241:319-25

20. Viale G, Sonzogni A, Pruneri G, et al.: Histopathologic examination of axillary sentinel lymph nodes in breast carcinoma patients. J Surg Oncol 2004, 85:123-8

21. Viale G, Zurrida S, Maiorano E, et al.: Predicting the status of axillary sentinel lymph nodes in 4351 patients with invasive breast carcinoma treated in a single institution. Cancer 2005, 103:492-500

22. Weaver DL: Sentinel lymph node biopsy in breast cancer: creating controversy and defining new standards. Adv Anat Pathol 2001, 8:65-73

23. Weaver DL: Occult "micrometastases" in ductal carcinoma in situ: investigative implications for sentinel lymph node biopsy. Cancer 2003, 98:2083-7

24. Weaver DL: Sentinel lymph nodes and breast carcinoma: which micrometastases are clinically significant? Am J Surg Pathol 2003, 27:842-5

Monica Morrow, M.D.Monica Morrow, M.D.

Chairman, Department of Chairman, Department of

Surgical OncologySurgical Oncology

G. Willing Pepper Chair in Cancer ResearchG. Willing Pepper Chair in Cancer Research

Sentinel Node Biopsy and Clinical

Decision Making

The Evolving Role of Axillary Dissection

Therapy

Prognosis

Need for Adjuvant Rx

Local Control

1900’s 1970’s 1980’s 1990’s

Re-Examining Axillary Dissection

• Increased frequency of small

mammographically detected tumors

• Systemic therapy of N+ and N0

Cancers

• Neoadjuvant Chemotherapy

AuthorAuthor nn % SN identified% SN identified % False negative% False negative

GiulianoGiuliano 107107 9494 00

BorgsteinBorgstein 130130 9494 22

VeronesiVeronesi 376376 9999 6.76.7

DeCiccoDeCicco 250250 9696 2.52.5

ZervosZervos 149149 8989 44

CoxCox 186186 9393 0.80.8

Results of SN Biopsy: Single Institution TrialsResults of SN Biopsy: Single Institution Trials Is SN Biopsy the Standard of Care?Is SN Biopsy the Standard of Care?

• Can the results of single institution studies be generalized?

• What is an acceptable false negative rate?

• Long-term outcomesLocal controlMorbidity

NSABP B32NSABP B32

Clinical NO

SN Biopsy + Axillary Dissection

SN Biopsy

RANDOMIZE

SN- SN+

No Further

SurgeryAxillary

Dissection

ACOSOG Sentinel Node Study

T1 -T2

Candidate for BCT

SN Biopsy

N+ N -

Axillary No Axillary

Dissection DissectionRT to Breast IHC

+ Adjuvant Rx SN

+

Marrow

RT to Breast

Adjuvant Rx

ACOSOG Z10ACOSOG Z10 NSABP B32NSABP B32

# Cases# Cases 53275327 52105210

# Surgeons# Surgeons 198 198 233233

TechniqueTechnique AnyAny combinedcombined

TrainingTraining 2020--30 cases +ALND Proctor, 5 cases + ALND30 cases +ALND Proctor, 5 cases + ALND

PatientsPatients TT11 TT22, N, N00 + BCT+ BCT TT11 TT22 NN00, any surgery, any surgery

Comparison of NSABP B32 and Comparison of NSABP B32 and

ACOSOG Z10ACOSOG Z10Comparison of NSABP B32 and Comparison of NSABP B32 and

ACOSOG Z10ACOSOG Z10

ACOSOG Z10 NSABP B32

SN ID 98.6% 97%

SN positive 24% 26%

BMI p BMI p !! 0.0001 0.0001

Age p Age p !! 0.00010.0001

Cases accrued p Cases accrued p !! 0.00010.0001

Not SignificantNot Significant

Nodal statusNodal status

T sizeT size

Tumor locationTumor location

HistologyHistology

Biopsy TypeBiopsy Type

Factors Associated with SN Factors Associated with SN

IdentificationIdentificationResults of SN Biopsy: Collaborative StudiesResults of SN Biopsy: Collaborative Studies

No. of Technique (%) SN False -

Author Patients Localization Identification Rate(%)

Krag 443 R 91 11

McMasters 806 Any 88 7.2

Shivers 560 B&R 85 4.0

Tafra 535 B&R 87 13

Bergkvist 498 B&R 90 11

NSABP 5210 B&R 97 9.7

R - radioactivity

B - blue dye

SN Biopsy Reliably Stages the SN Biopsy Reliably Stages the AxillaAxilla

SN BiopsySN Biopsy

ManselMansel

N = 1031N = 103124.8%24.8%

% Nodal Metastases

VeronesiVeronesi

N = 516N = 51635.5%35.5%

AxillaryAxillary DissectionDissection

23.8%23.8%

32.3%32.3%

Local Control After SN Biopsy AloneLocal Control After SN Biopsy Alone

Author n

no. AxillaryFailures

RoumenShiversDessureaultChungHansenLozaBadgwellVeronesiCody

100309890206238168159259

2,222

000101003

Mean Follow-up(months)

2416202639213246*31*

* median

Total 4,551 5 (0.001%)

Initial Results: ACOSOG Z10Initial Results: ACOSOG Z10n=5327n=5327

•• 16 16 axillaryaxillary LRsLRs (0.3%) at a median of (0.3%) at a median of 31 mo follow31 mo follow--upup

•• 3/16 1+SN, no ALND3/16 1+SN, no ALND1/16 3+ SN, ALND done1/16 3+ SN, ALND done12/16 SN negative, no ALND12/16 SN negative, no ALND

•• Median to recurrence 16 mo Median to recurrence 16 mo (4.2 (4.2 –– 40.1 mo)40.1 mo)

Is SN Biopsy the standard of care?Is SN Biopsy the standard of care?

•• SN biopsy reliably identifies SN biopsy reliably identifies axillaryaxillarynodal metastases with low morbidity.nodal metastases with low morbidity.

•• Long term local control rates after SN Long term local control rates after SN biopsy are excellent.biopsy are excellent.

•• SN biopsy is the procedure of choice for SN biopsy is the procedure of choice for managing the clinically node negative managing the clinically node negative axillaaxilla today.today.

Rationale for Rationale for AxillaryAxillary Surgery in DCISSurgery in DCIS

• Incomplete sampling

• Diagnosis by core bx

• DCIS has the ability tometastasize

How Common is Undiagnosed Invasive Cancer?How Common is Undiagnosed Invasive Cancer?

• Cause specific survival rates of 97% - 100% NOT

compatible with high rates of invasive cancer

• Smaller mammographic DCIS seen today less

likely to have undiagnosed invasion

• Pathologic sampling more extensive

Author # Patients % Invasive

Kestin 2000 130 7.7

Rosenfeld Darling 2000 289 14

Cox 2001 240 12.5

Cox 2003 499 9.4

Morrow 238 13.3

DCIS Diagnosed by Core Biopsy:

How Common is Sampling Error?

Does DCIS Have The Capacity To

Metastasize?

Pendas Klauber-DeMore

n=87 n=76

SN+ 5 (6%) 9 (12%)

IHC only 3 7

Addl. + nodes 0 1/6

Invasion in primary 1 18 “suspicious”

What do IHC Positive Cells in DCIS Mean?

• Retrospective review

• 79 DCIS patients F/U > 10 years

• Axillary Dissection performed

• Nodes recut, IHC performed

4 IHC positive patients (5.1%)

Outcome: 8/79 patients recurred, NONE with IHC+

Cox, Moffit

When Should Sentinel Node Biopsy

Be Performed in DCIS

• Microinvasive carcinoma

Metastases in 3% - 20% of cases

• DCIS treated by mastectomy

opportunity lost if invasion found

• Done as a second procedure if invasion

found after lumpectomy

Prior biopsy does not interfere with mapping

Contraindications to SN BiopsyContraindications to SN Biopsy

• Locally advanced breast cancer

• Pregnancy and Lactation

• Prior axillary surgery

Is a Repeat SN Biopsy Feasible?Is a Repeat SN Biopsy Feasible?

Intra, et al n=18

100% SN identification

2/18 positive

No axillary recurrence at 12.7 mo median

Ann Surg Oncol 2005

ControversiesControversies

• Multicentricity

• Internal Mammary Nodes

• Neoadjuvant Therapy

SN Biopsy for SN Biopsy for MulticentricMulticentric CancerCancer

• Original hypothesis: Unique drainage pathway for each cancer.

• Concordance studies indicate the majority of breast tumors drain via central collecting system.

• Reasonable to do a subareolar injection or separate peritumoral injections.

SN Biopsy for SN Biopsy for MulticentricMulticentric CancerCancer

Author Number of Cases % SLN identified % Sensitivity

Kumar, et al 10 100 100

Tousimis, et al 70 96 92

Kumar, et al 59 93 100

Ozmen, et al 21 86 89

Fernandez, et al 53 98 100

Jin Kim, et al 5 100 100

Schrenk, et al 19 100 100

Total 237 95.4 96.9

Internal Mammary Node Metastases

7070 Patients

22.4% I.M. node positive

4.9% I.M. node were only site

of metastases

Morrow and Foster, Arch Surg 1981

How Common are Isolated IM How Common are Isolated IM

Metastases?Metastases?

• Dupont, et al Vander Ent, et al ALMANAC

3/1273 3/256 5/1139

0.2% 1.2% 0.4%

Nodal Response to Neoadjuvant Therapy?

Tumor SN

Non-SN

SN Biopsy After SN Biopsy After NeoadjuvantNeoadjuvant RXRX

Studies Since 2002Studies Since 2002% SN % False

Author n Identified NegativeStearns 2002 34 85 14Brady 2002 14 93 0Miller 2002 35 86 0Reitsamer 2003 30 87 7Balch 2003 32 97 5Vigario 2003 37 94 39Piato 2003 42 98 17Schwartz 2003 21 100 9Kang 2004 80 76 7Patel 2004 42 95 0Shimazu 2004 47 94 12

SN Biopsy After SN Biopsy After NeoadjuvantNeoadjuvant RXRX

HIGHLY VARIABLE RESULTS DUE TO:

– SMALL NUMBERS 2/17 STUDIES > 50 PTS

– DIVERSE POPULATIONS

T1 – T4

N0, N+

– ? CLASSIFICATION PALPABLE, ABNORMAL

NODES

T1C - T3, N0 or N1

NSABP B27NSABP B27

Randomize

AC x 4

Surgery

Docetaxol x 4

AC x 4

Surgery

AC x 4

Surgery

Docetaxol x 4

Accuracy of SN BiopsyAccuracy of SN Biopsy

NEOADJUVANT RX PRIMARY SURGERY

NSABP B27 Metaanalysis, 2002

69 Studies

n=428/2365 n=10,000

SN identified 85% 90%

False negative 11% 8.4%

Relationship Between SN False Relationship Between SN False

Negative Rate and ResponseNegative Rate and Response

RESPONSE % FALSE NEGATIVE

Clinical

CR 8.7

Other 11.6

p=ns

Accuracy of SN Biopsy by Accuracy of SN Biopsy by

Pathologic ResponsePathologic Response

RESPONSE % ACCURACY

CR 98.4

CCR, Residual tumor 96.0

PR/Stable 94.9

p=ns

Unresolved ProblemsUnresolved Problems

• Is Completion Axillary Dissection

Necessary After a Positive SN

Biopsy?

• Significance of Micrometastases

Management of the Positive SNManagement of the Positive SN

Is Axillary Dissection Indicated?

" Small primary tumors

" Small metastatic deposits not seen intraop

Risk of Additional Metastases: Risk of Additional Metastases:

T1b CancerT1b Cancer

Author n % Cases

Chu - 13

Wong 41 22

Nos 61 12

Viale* 200 34

Van Zee 171 26

*T1a+b

Risk of Additional Metastases by Risk of Additional Metastases by

Size of Size of MetastaticMetastatic DepositDeposit

Author n Size % Cases

Viale 116 <0.2 mm 14.5

212 0.2 – 1 mm 16.9

Leidenius 39 <0.2 mm 20.5

35 0.2 – 1 mm 34.3

Risk of Additional Metastases by Risk of Additional Metastases by

Size/Detection Method: Size/Detection Method:

MicrometastasesMicrometastases

Author n Method % Cases

Mignotte 44 IHC 15.9

24 H&E 33.2

Kamath 26 IHC 7.6

20 H&E 25.0

Multivariate Analyses of Factors Multivariate Analyses of Factors

Predictive of Involvement of Predictive of Involvement of

NonNon--Sentinel NodesSentinel Nodes

n=4017 Patients, 10 Studies

Tumor Size : 5/10 Tumor Grade : 0

Metastases Size: 7/10 # SN involved : 6/9

LVI : 4/10 # SN removed : 3/4

AxillaryAxillary Dissection?Dissection?

Pros:Pros:

• Significant risk of additional nodal disease

• Small survival benefit for dissection cannot be

excluded

• Information on the status of remaining nodes

may help clarify decisions about adjuvant rx

Unresolved QuestionsUnresolved Questions

• Significance of micrometastases

Pathologic Analysis of Lymph NodesPathologic Analysis of Lymph Nodes

• Pre-SLND

– Bivalve lymph nodes

– Half of lymph node discarded

– Section from 1/2 lymph node evaluated with H&E

• Post-SLND

– Serial sections of sentinel node

– Evaluation with H&E and IHC

IHC DetectedIHC Detected MicrometastasisMicrometastasis

Micrometastases

• Present in 7% - 32% H & E negative nodes

• Heterogeneous - ranging from missed tumors greater than 2mm to single cells in subcapsular sinus

• Prognostic significance uncertain

no benefit

important in postmenopausal women

DFS differences 2% - 14%

Significance of Significance of MicrometastasesMicrometastases: :

Ludwig TrialLudwig Trial

• Method: Retrospective analysis of a prospectivetrial

736 of 921 patients included

Serial sections

Single section from first level of node stained for AE-1 and CAM5-2

Median follow-up 12 yrs

Cote, Lancet 1999

Detection of Detection of MicrometastasesMicrometastases::

Ludwig TrialLudwig Trial

H&E

Serial Selection IHC

7% 20%

Cote, Lancet 1999

!""#$%&'()*&'*+,%-.*!""#$%&'()*&/(0-%-.*

12&345

6-0*,0*&78**&9#8.-.,$&:;<

0 2 4 6 8 10 12 14

100

80

60

40

20

0

0 2 4 6 8 10 12 14

Hematoxylin and eosin

12&344=

6-0*,0*&78**&9#8.-.,$&:;<

>-?*&9-'"*&@,')(?-A,%-('&:B*,80<

100

80

60

40

20

0

Prognostic Significance of

MicrometastasesImmunohistochemistry

Cote, Lancet 1999

Time Since Randomization (years)

John Wayne Prospective Study of

Micrometastases

n = 683

• Stage I and II cancer 1/92 - 4/99

• SN Step Sectioned, H & E stained

If H & E – IHC

• Stratified by SN met size

Hansen et al

Results

Group Definition

NegNeg SN (SN (--) H&E & IHC) H&E & IHC

IHCIHC SN (+) IHCSN (+) IHC

MicroMicro SN (+) H&E SN (+) H&E Mets Mets << 2 mm2 mm

MacroMacro

n

419

56

76

132 SN (+) H&E SN (+) H&E Mets > 2 mmMets > 2 mm

Mean Age

5858

5858

5858

56560 20 40 60 80 100

Su

rviv

al (%

)

0

20

40

60

80

100

Disease Free Survival

Time (mos)

IHC 96.67Neg 98.01

Macro 73.56Micro 97.09

5-yr DFS (%)

P=0.0001

Median F/U: 44 mos

IHC Should NOT be used routinely

Decisions regarding Stage and the

need

for adjuvant therapy should be made

on the basis of H & E staining

CAP Consensus

Phila Concensus

ConclusionsConclusions

• SN Biopsy is the procedure of choice for managing the clinically node negative axilla

• Axillary dissection remains standard management for the SN+ patient

• Routine use of IHC awaits results of prospective trials

Sentinel Node Biopsy and Clinical Decision Making

Monica Morrow, M.D.

USCAP, February 12, 2005

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Morrow M, Wilke LG, Herndon JE 2nd

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CB, Walker AP, Mikkelson WM, Stauffer JS, Robidoux A, Theoret H, Soran A, Fisher

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