Sentinel Nodes - breast ca

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United States and Canadian Academy of PathologyUnited States and Canadian Academy of Pathology

Breast Pathology Long CourseBreast Pathology Long Course11 March 200911 March 2009

Pathology Evaluation of Sentinel NodesPathology Evaluation of Sentinel Nodes::Protocol recommendations and rationaleProtocol recommendations and rationale

Donald L. Weaver, MDDonald L. Weaver, MDProfessor of PathologyProfessor of Pathology

University of Vermont College of MedicineUniversity of Vermont College of Medicine

Burlington, VermontBurlington, VermontUSAUSA


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ObjectivesObjectives

To understand the prognostic continuum for nodaltumor burden

To understand how sentinel node evaluation enhancesidentification of micrometastases

To understand survival impact of micrometastasesrelative to macrometastases

To understand limitations of pathologic analysis of

sentinel nodes To discuss evaluation and sampling strategies for

sentinel nodes


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Basic recommendationsBasic recommendations

Thin gross sections (2 mm)

Embed and examine each slice

Examine one section from each block

If levels used, evenly space sections through the block

0.5 mm or 0.2 mm intervals may be rational

IHC not required If used must explain it is for rapid screening, highlights

smallest metastases, still miss metastases under 0.1 mm


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Number of positive axillary nodes

is a continuous variable

emoto: Cancer 1980 45:2917-24.

0

1020

30

40

50

60

70

80

%

0 1 2 3 4 5 6-10 11-15 16-20 21+

number of positive axillary nodes

5-year overall and disease free survival

OS

DFS

VolumetVolumetr

TumorTumor

BurdenBurden


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Important AJCC/UICC 6th edition concepts

Codify quantitative nodal tumor burden 10 or more positive nodes (pN3)

4-9 positive nodes (pN2)

1-3 positive nodes (pN1)*

Micrometastases (pN1mi)

Metastases larger than 0.2mm but none larger than 2.0mm

Isolated tumor cells and cell clusters (pN0(i+))

No metastasis larger than 0.2mm

Clinical

Significance

*nodes with ITC only do not increase node co


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Defining a micrometastasis

No single tumor deposit larger than 2.0 millimeters

Huvos: Ann Surg 1971; 173: 44-6.

Fisher: Cancer 1978; 42: 2032-8.

No difference in survival between

node negative and micrometastase


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Tumor volume for varying numbers of spherical metastatic foc

Number Diameter (mm) Volume (mm3)

1 cell 0.02 0.00000421000 cells 0.02 0.004188

1 cluster (ITC) 0.2 0.004188

1,000,000 cells 0.02 4.188

8000 clusters 0.1 4.188

1000 clusters 0.2 4.188125 clusters 0.4 4.188

1 micrometastasis** 2.0 4.188

**Volume estimates assume a spherical metastasis 2 x 2 mm. An ellipsoid micrometastasis

2 x1 mm will occupy one half the volume (2.1 mm3) of a spherical micrometastasis. ITC =

isolated tumor cell cluster.


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1

1 or 22

3

The effect of tumor size and lymph node status

on breast carcinoma lethality. Michaelson et al.

15-yr survival

2.0-2.9 cm tumors

Mortality estimate1% per 1mm size

6% per each +LN

In none of the size

groups examined di

women with one

positive lymph nodehave a statistically

significantly greater

death rate comparedwith lymph node

negative women wit

tumors of the samesize


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The prognostic significance of micrometastases in breast cancer:

A SEER population-based analysis. Chen et al. Ann Surg Oncol

2007; 14:3378-3384. (1992-2003)

pN0 = 154,569

pN1mi = 11,405pN1a = 43,746

% pN0 pN1mi pN

T1 75.9 61.0 49

T2 21.8 33.7 43

T3 1.8 4.2 5.

T4 0.5 1.1 2.

p =


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pN0 = 154,569

pN1mi = 11,405pN1a = 43,746

The prognostic significance of micrometastases in breast cancer:

A SEER population-based analysis. Chen et al. Ann Surg Oncol

2007; 14:3378-3384. (1992-2003)

% pN0 pN1mi pN

T1 75.9 61.0 49

T2 21.8 33.7 43

T3 1.8 4.2 5.

T4 0.5 1.1 2.

p =


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Stage II Breast Cancer Rates

U.S. Women (50-64 yrs), 1992-2000

0

20

40

60

80

100120

140

1985

1992

1993

1994

1995

1996

1997

1998

1999

2000

Year

rate

per

100,0

00

Stage 2

Stage 2, N

Stage 2, N+

Stage 2 unSLNB


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UVM-NSABP sampling strategyProtocol B-32 (experimental)

Sectioning

strategy

Thinly slice 2-3 mm

Formalin and embed

Evaluate initial section at

participating site Used for treatment

Blinded analysis of occult

metastases at UVM Correlate with outcome

H&E and CK IHC at 0.45

and 0.96 mmTarget accrual: 5600Protocol closed: met accrual


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Recommended SLN Protocol

Thinly slice gross lymphnode at intervals no

thicker than 2.0 mm

Examine one H&Esection from the surface

of the faced block

CK IHC for suspicious

findings

A1

A1

Correct

Facing

Wrong


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Xx

xxxx

xx

xx

xx

xxxxx

Xxx

xxx

xxx

x

xxx

xxxx

Patterns of missed and detected micrometastases

X

xxxxx

x

xxx

x

xxxxxx

X

xxxxx

xxxx

xxxxxxx

pN0(i+)

pN1mi

pN0(i-)

pN0(i-)


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Patterns of missed micrometastases for various strategie

Three levels

200 micron intervals

Two levels1.0 mm interval

Four levels through block

500 micron (0.5 mm) intervals

Multiple levels through block200 micron intervals


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Alternative SLN Protocol #1

Thinly slice gross lymph

node at intervals no thicker

than 2.0 mm

Embed all slices Face block

Set microtome at 5 micronsand mount levels: 1, 100,

200, and 300

Four levels through block

500 micron (0.5 mm) intervals

This protocol can be linked to NSABP B-32 outcome results for occult metastase


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Alternative SLN Protocol #2

Thinly slice gross lymph

node at intervals no thicker

than 2.0 mm

Embed all slices Face block

Set microtome at 5 micronsand mount levels: 1, 40, 80,

120, 160, 200, 240 etc

Multiple levels through block

200 micron intervals

This protocol has approximately 96% efficiency for detecting all ITCs present


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Cytokeratin Immunohistochemistry

DOES NOT

guarantee the pathologist wont missisolated tumor cells and clusters


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Occult SLN metastases identified by pathologist (LM) and comput

assisted cell detection with image analysis (CACD)

0

1

2

3

4

5

6

78

9

10

0.0

1

0.0

2

0.0

3

0.0

4

0.0

5

0.0

6

0.0

7

0.0

8

0.0

90

.10

.20

.30

.40

.50

.60

.70

.80

.9 1

largest occult metastasis (mm)

num

ber

ofcases

CACD only

LM

Cancer 2006; 107:661

Pathologists will

miss isolated CKpositive tumor cel

clusters that are n

larger than 100microns (0.1 mm)

B-32

236 cases screened

34/236 (14.4%) pos by L

30/202 (14.9%) pos by CA


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IHC disproportionately identifies the

smallest category of metastases (ITC)

Systematic sectioning proportionately

identifies metastases


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The practical solution

Agree on a:statistically sound,

rational,and economically efficient

protocol for screening sentinel nodes. Accept we will miss metastases.

Reproducibly document what we find.

Sentinel Nodes - breast ca

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