09/11/2013 1 Breast Cancer Staging Ian Ellis Molecular Medical Sciences, University of Nottingham Department of Histopathology, Nottingham University Hospitals NHS Trust Breast Cancer Staging Pathology Issues • Tumour Size • Vascular Invasion • Lymph Node Status 0 50 100 150 200 250 300 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Maximum diameter (mm) No. of pathologists Case No. 8 Submitted - size range 8-20 - median 13 Measured size range on first, middle and last section, 13, 13 and 13mm Circulation 2001/1 Case 8 Invasive Ca, grade 1, NST 0 50 100 150 200 250 300 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Maximum diameter (mm) No. of pathologists Case No. 11 Submitted - size range 7-26 - median 20 Measured size range on first, middle and last section, 21, 21 and 19mm Circulation 2001/1 Case 11 Invasive Ca, grade 2, Lobular
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09/11/2013
1
Breast Cancer Staging
Ian Ellis
Molecular Medical Sciences, University of Nottingham
Department of Histopathology, Nottingham University Hospitals NHS Trust
Breast Cancer StagingPathology Issues
• Tumour Size
• Vascular Invasion
• Lymph Node Status
0
50
100
150
200
250
300
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Maximum diameter (mm)
No
.o
fp
ath
olo
gis
ts
Case No. 8
Submitted - size range 8-20 - median 13Measured size range on first, middle and last section, 13, 13 and 13mm
Circulation 2001/1 Case 8Invasive Ca, grade 1, NST
0
50
100
150
200
250
300
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Maximum diameter (mm)
No
.o
fpa
tho
log
ists
Case No. 11
Submitted - size range 7-26 - median 20Measured size range on first, middle and last section, 21, 21 and 19mm
Circulation 2001/1 Case 11Invasive Ca, grade 2, Lobular
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0
30
60
90
120
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32
Maximum diameter (mm)
No
.o
fp
ath
olo
gis
ts
Case No. 7
Submitted - size range 2-26, median 21Measured size range 1st, 35th and 70th sections, 24, 23 and 22mm
Circulation 2001/1 Case 7 Low grade DCIS
Distribution of measures of agreement for NHSBSP pathologists
• This means the assessment of microscopiclevels at specified distances from each other(complete or incomplete assessment of theblocks).
• Terms: - Step sectioning
Tissue block withembedded LN(piece) in it
Sectioning with amicrotome(microscopic) at stepsof … mm.
1 2 3 4
Multilevel assessment III.
• This means the assessment of microscopiclevels separated by the thickness of one (or afew) sections (complete or incompleteassessment of the blocks).
• Terms: - Serial sectioning, microscopic serialsectioning
Tissue block withembedded LN(piece) in it
Sectioning with amicrotome(microscopic) at stepsof 3-5 um.
1 2 3 …
Multilevel assessment IV.A combination of slicing and step sectioning
4 slices of an obviously positive SN, not requiring stepsectioning
3 slices step sectioned at 250 mm
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CAM5.2
Immunohistochemistry
• Increases detection of metastasesby 10 to 30%
• Quicker for technician andpathologist
• Can assess morphology
• Pitfalls
sentinel node trial
• ACOSOG Z0010
• 5539 patients
• BCT and SNB (AxCl if LN+(H&E))
• 5 year OS not related to nodal metsdiscovered with immuno (trend for BMmets) on multivariate analysis
Trends and possibilities in SNassessment
SLN assessment
Standard histopathology Enhanced histopathology
Limited sampling with or without IHC Thorough (systematic) sampling
Limited sampling with or withoutIHC
• A few levels separated by a givendistance.
• Results in upstaging but leaves aproportion of the SN unexplored
• E.g. the Santa Monica protocol
The Santa Monica protocol(2004)
Halving of the lymph node in its hilar plane, which they claimto be the most likely site of metastases.
Hilum Efferent lymphatics
• 1 HE frozen• 1 HE paraffin• 1 CK IHC
separated by 200 mmfrom the initiallyassessed level (perhalf)
Rather large proportion of theSN not investigated
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Trends and possibilities in SNassessment
SLN assessment
Standard histopathology Enhanced histopathology
Limited sampling with or without IHC Thorough (systematic) sampling
Thorough (complete)sampling
• The whole thickness of the SN isinvestigated at given distances,depending on the size of the metastaseswe are looking for.
• Complete (?) investigation of the lymphnode. (Loss of diagnostic material)
2a = 2[r2-(d/2)2]1/2
Complete step sectioning ofSNs at 250 mm + IHC /750
mm
Number of levels assessed for identification of metastases
%
0
20
40
60
80
100
1 2 3 4 5 6 7 8 9 >9
J Clin Pathol 2002; 55:926-931.
Thorough sampling (Model)
• To detect a spherical metastasis of 2 mm indiameter as a metastasis of 2 mm, levelsseparated by 1 mm should be examined.
J Clin Pathol 2004; 57:467-471.
2a = 2[r2-(d/2)2]1/2d: distance between sectioning levels
Statements on handling
• Thorough (systematic) sampling mayyield the best results.
• The largest metastases are generallydetected by limited sampling.
• IHC may sometimes be of help inidentifying larger metastases, but itgenerally helps detectingmicrometastases and ITCs.
• All SLN assessed separately
• Management of– Nodes <4mm
– Nodes >4mm
• Standardised reporting
Pathology assessment ofSLN:
National guidelines
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Single H & E section
• Suspicious or metastatic cells seen?
• Further levels and/or ICC to establish natureand size (classification) of deposit
• IHC may be helpful but not mandatory
• Identification of ITC not the aim ofassessment
Pathology assessment ofSLN:
National guidelines
12
1
2
Group of metastatic cells2 mm diameter
Lymph node <4mm
Pathology assessment ofSLN:
National guidelines
2mm
1 2 3 4 5
1 2
3
4
5
Lymph node >4mm
Pathology assessment of SLN:National guidelines
Micrometasis vs ITC
?
Micrometastasis
• Term introduced by Andrew Huvos;<2mm, as this was felt the size thatgenerally needed microscopy fordetection. Larger metastases couldmore often be picked up by experiencednaked eye examination.
• However the term is used differentlyby different authors.
The current definitions ofITC
(and micrometastasis)
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• TNM categories are arbitrarily chosen(have some evidence in support), but areused on the basis of a consensus. Theyhave DEFINITIONS, but these are notsufficient to assure an acceptablereproducibility.
Micrometastasis (UICC)pN1mi
• Larger than 0.2 mm, but none largerthan 2 mm in greatest dimension
Sobin LH, Wittekind C (eds).
TNM Classification of Malignant Tumours,6th edition, 2002.
pN0 & isolated tumor cell clusters (ITC)• ! Approximately 1,000 tumor cells are contained in a three-
dimensional 0.2-mm cluster. Thus, if more than 200 individual tumorcells are identified as single dispersed tumor cells or as a nearlyconfluent elliptical or spherical focus in a single histologic section ofa lymph node there is a high probability that more than 1,000 cellsare present in the lymph node. In these situations, the node shouldbe classified as containing a micrometastasis (pN1mi).
• ! … the 200 cells must be in a single node profile even if the node hasbeen thinly sectioned into multiple slices.
• It is recognized that there is substantial overlap between the upperlimit of the ITC and the lower limit of the micrometastasiscategories due to inherent limitations in pathologic nodal evaluationand detection of minimal tumor burden in lymph nodes. Thus, thethreshold of 200 cells in a single cross-section is a guideline to helppathologists distinguish between these two categories. Thepathologist should use judgment regarding whether it is likely thatthe cluster of cells represents a true micrometastasis or is simply asmall group of isolated tumor cells.
• ! Metastatic characteristics no longer considered in the distinctionbetween micrometastasis and ITC.
Studies of occultmetastases with at least40 events or 150 patients
Weaver et al. Effect of OccultMetastases on Survival
in Node-Negative Breast Cancer.N Engl J Med 2011;364:412-21
3887 women (NSABP-B32), median follow up 95 monthsSentinel node (+/- Axillary Clearance)2mm slices, H&E negativeImmuno at 0.5mm and 1mm, but clinicians not informedOccult metastases 16%5 year overall survival:Occult metastases present 94.6%Occult metastases not seen 95.8%Multivariate analysis (with size and grade, but no VI):Occult metastases RR 1.4 (95% 1.05 – 1.86)Conclusion: ‘do not indicate a clinical benefit of additionalevaluation, including immunohistochemical analysis’
Pathology evaluation of sentinel lymphnodes in breast cancer: protocolrecommendations and rationale.
Weaver. Mod Pathol 2010
“All protocols that use serial sectionsand IHC must be consideredexperimental until validated withoutcome data”
Sectioning nodes at 2mm intervals
Embedding all the sections
Examine one section
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Intraoperative Assessment
• Frozen section
• Imprint cytology
• Intraoperative immunohistochemistry
• Molecular asessment
Background and rationale including theresults from clinical trials
Optimal handing of the specimen andanalysis
Role of Immunohistochemical analysis?Role of Intraoperative Examination?
Alternatives and future directions
Sentinel lymph node biopsy
Imaging modalities forassessing the axilla
• Mammography
• CT
• MRI
• PET
• Scintimammography
• Ultrasound
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Cortex
Benign Malignant
• Normal 94% 10%
• Abnormal 6% 90%P<0.0001
In vitro high Resolution Helical CT of small axillary LymphNodes in Patients with Breast Cancer. Uematsu et al AJR2001;176:1069-1074
Pre-operative Biopsyof Axillary Lymph
Nodes
Study Total no. ofpts
No. with LNmets (%)
FNA/ Core Criteria used pre-opdiagnosis rate(%)
Bonnema et al(1997)
150 62 (41) FNA No 63
de Kanter et al(1997)
185 87 (47) FNA No 36
Kuenen-Boomeester(2002)
183 85 (46) FNA No 44
Duerloo et al(2003)
268 121(45) FNA Yes 31
Sapino et al(2003)
267 88 (33) FNA Yes 55
Damera et al(2003)
166 64 (39) Core Yes 42
Ciatto et al
(2006) **
491 298 (61) FNA Yes 73
Britton et al
(2009)
139 73 (53) Core No 53
Pre-operative biopsy of axillary nodes
Node positive patients
No. of positivenodes
No. of patients % diagnosed bypre-op biopsy
1 26 15
2 12 17
3 5 60
3 or more 26 77
4 or more 20 90
Nottingham data
STUDY CONCLUSIONS
• A pre-operative diagnosis of nodalmetastases can be made in 42% ofnode positive patients
• US guided core biopsy is moresensitive in patients with extensivenodal involvement