Transcript A. Breast CA at AKS

Updates on Breast Diseases:
What clinicians need to know from pathologists
Preah Bat Norodom Sihanouk Hopsital, 22 April 2009
Monirath Hav, MD, Ph.D. fellow (VLIR project)
Pathology Department, Ghent University Hospital
Ghent University, Belgium
Benign breast lesions
Richard J et al. The New England Journal of Medicine. Volume 353:275-285 (July 2005)
Benign breast lesions: standard pathology report
1. Histologic type + type of proliferation
2. Maximum diameter
3. Nuclear grade (for DCIS only)
4. Resection margin (for DCIS & pleomorphic LCIS only)
5. Presence/absence of micro-invasion (for DCIS only)
6. Areas of involvement (unifocal, multifocal, multicentric)
VAN NUYS Prognostic Index for the
management of DCIS
Size (measured on histology exam)
 Score 1: size < or = 1.5 cm
 Score 2: size 1.6 – 4 cm
 Score 3: size > or = 4.1 cm
Age of patient
 Score 1: > 60 y.o
 Score 2: 40 – 60 y.o
 Score 3: < 40 y.o
Nuclear grade
 Score 1: DCIS nuclear grade 1
 Score 2: DCIS nuclear grade 2
 Score 3: DCIS nuclear grade 3
Surgical margin
Management
 Score 4 – 6 : lumpectomy
 Score 7 – 9 : lumpectomy + radiation Th.
 Score 10 – 12 : mastectomy
 Score 1: tumor-free margin < or = 1 cm
 Score 2: tumor-free margin 0.1 – 0.9 cm
 Score 3: tumor-free margin < 0.1 cm
Silverstein MJ, Lagios MD, Craig PH, et al. Cancer 77(11): 2267-2274, 1996
Malignant lesions
Malignant lesions
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Secretory/Juvenile carcinoma (<0.15%)
Tubular carcinoma (<2%)- so low recurrence that some centers
consider adjuvant th. unnecessary.
Invasive cribriform carcinoma (0.8-3.5%)
Metaplastic carcinoma (<1%)
Invasive papillary carcinoma (1-2%)
Mucinous carcinoma (~2%)
Neuroendocrine carcinoma (2-5%)
Medullary carcinoma (1-7%)
Invasive lobular carcinoma (5-15%)
Invasive ductal carcinoma (75%)
Invasive carcinoma –
standard pathology report
1. Histologic type
2. Histologic grade (Bloom-Richardson)
3. TNM (size, node, distant metastasis)
4. Ki-67 index
5. Lympho-vascular invasion
6. Necrosis
7. Tumour border
8. Status of resection margins
9. ER, PR, HER2/neu status
10. In situ components, if present
Histologic type: different prognosis
Darius Dian et al . Arch Gynecol Obstet (2009) 279:23–28
Histologic type
Gives pathologists and clinicians the ideas of:
1. Tumour’s aggressiveness
2. Patients’ overall prognosis
3. Tumour’s origin
(i.e. basal-like + family history of breast CA  highly suggestive for
hereditary origin of BRCA1 mutation*)
4. Response to chemotherapy
(i.e. basal-like  45% pCR after neoadjuvant therapy using
anthracycline and taxane**)
*
Turner NC & Reis-Filho JS (2006). Oncogene 25:5846–5853
**
Rouzier R et al. (2005). Clin Cancer Res 11:5678–585
Basal-like?
Features of basal-like breast CA
Histology:
• Solid growth pattern
• High nuclear grade
• < 5% DCIS
• Lympho-vascular invasion
• Central scar
• Pushing border
• Marked lymphocytic infiltrates
Immunohistochemical profile:
CK5 + or CK14 + or CK17 + or EGFR +
Mamatha Chivukula
Appl Immunohistochem Mol Morphol Volume 16, Number 5, October 2008
1. Histologic type
2. Histologic grade (Bloom-Richardson)
3. TNM (size, node, distant metastasis)
4. Ki-67 index
5. Lympho-vascular invasion
6. Necrosis
7. Tumour border
8. Status of resection margins
9. ER, PR, HER2/neu status
10. In situ components, if present
Modifed Bloom-Richardson grade
Tubule Formation
score 1: >75% of tumor has tubules
score 2: 10%-75% of tumor has tubules
score 3: <10% tubule formation
Nuclear Size
score 1: tumor nuclei similar to normal duct cell nuclei (2-3÷ rbc)
score 2: intermediate size nuclei
score 3: very large nuclei, usually vesicular with prominent nucleoli
Mitotic Count
(per 10 hpf with 40÷ objective and field area of 0.196 mm2)
score 1: 0-7 mitoses
score 2: 8-14 mitoses
score 3: 15 or more mitoses
rbc, red blood cells; hpf, high power field
From Robbins P, Pinder S, de Klerk N, et al. Histological grading of breast carcinomas: A study of
interobserver agreement. Hum Pathol 1995;26:873-879, with permission.
1. Histologic type
2. Histologic grade (Bloom-Richardson)
3. TNM (size, node, distant metastasis)
4. Ki-67 index
5. Lympho-vascular invasion
6. Necrosis
7. Tumour border
8. Status of resection margins
9. ER, PR, HER2/neu status
10. In situ components, if present
1. Histologic type
2. Histologic grade (Bloom-Richardson)
3. TNM (size, node, distant metastasis)
4. Ki-67 index
5. Lympho-vascular invasion
6. Necrosis
7. Tumour border
8. Status of resection margins
9. ER, PR, HER2/neu status
10. In situ components, if present
Ki-67 index
-
Ki-67  recurrence rate
-
Ki-67 < 10%  no benefit from chemotherapy (2)
-
Ki-67 > 25%  sensitive to chemotherapy (2)
-
Ki-67 between 10 to 25%?  other factors (Bloom-richardson grade,
TNM stage, resection margin etc) (2)
; overall survival
(1)
(1) E de Azambuja et al. British Journal of Cancer (2007) 96, 1504-1513
(2) Frédérique Spyratos et al. Cancer 2002 Apr 15;94(8):2151-9
1. Histologic type
2. Histologic grade (Bloom-Richardson)
3. TNM (size, node, distant metastasis)
4. Ki-67 index
5. Lympho-vascular invasion
6. Necrosis
7. Tumour border
8. Status of resection margins
9. ER, PR, HER2/neu status
10. In situ components, if present
Sebastian F et al. Ann Surg.
2004 August; 240(2): 306–312.
How about peri-neural invasion?
Present in ~10% of high-grade tumours
No study has yet proven
its independent
prognostic significance
1. Histologic type
2. Histologic grade (Bloom-Richardson)
3. TNM (size, node, distant metastasis)
4. Ki-67 index
5. Lympho-vascular invasion
6. Necrosis
7. Tumour border
8. Status of resection margins
9. ER, PR, HER2/neu status
10. In situ components, if present
Prognostic value of Tumor necrosis & Tumor border
Carter D et al. Am J Surg Pathol 1978;2:39–46
1. Histologic type
2. Histologic grade (Bloom-Richardson)
3. TNM (size, node, distant metastasis)
4. Ki-67 index
5. Lympho-vascular invasion
6. Necrosis
7. Tumour border
8. Status of resection margins
9. ER, PR, HER2/neu status
10. In situ components, if present
1. Histologic type
2. Histologic grade (Bloom-Richardson)
3. TNM (size, node, distant metastasis)
4. Ki-67 index
5. Lympho-vascular invasion
6. Necrosis
7. Tumour border
8. Status of resection margins
9. ER, PR, HER2/neu status
10. In situ components, if present
Survival analysis: DCIS in invasive breast CA
Rosemary R. Millis et al. Breast Cancer Research and Treatment 84: 197–198, 2004.
1. Histologic type
2. Histologic grade (Bloom-Richardson)
3. TNM (size, node, distant metastasis)
4. Ki-67 index
5. Lympho-vascular invasion
Estogen receptor
6. Necrosis
7. Tumour border
8. Status of resection margins
9. ER, PR, HER2/neu status
10. In situ components, if present
HER2/neu
Overview on ER, PR, HER2 status in breast cancer
HER2/neu  overexpressed in 25 – 30%
ER, PR, HER2 status (con’t)
Molecular sub-types of breast CA:
•
•
•
•
Luminal A (ER/PR +, HER2 -)
Luminal B (ER/PR +, HER2 +)
HER2 sub-type (ER/PR -, HER2 +)
Basal-like (ER -, PR -, HER2 -)
Perou CM, Sorlie T, Eisen MB et al (2000). Nature 406:747–752
Prognosis of each sub-type of breast CA
Hiroo Nakajima et al. World J Surg (2008) 32:2477–2482
ER, PR, HER2 status (con’t)
Therapeutic implication :
•
•
•
•
Luminal A (ER/PR +, HER2 -)  Hormonal therapy
Luminal B (ER/PR +, HER2 +)  Hormonal therapy? + anti-HER2
HER2 sub-type (ER/PR -, HER2 +)  anti-HER2
Basal-like (ER -, PR -, HER2 -)  No benefit from either therapy
“Quickscore” for ER-PR IHC
Staining intensity
- Negative (no staining of any nuclei at high magnification)= 0
- Weak (only visible at high magnification) = 1
- Moderate (readily visible at low magnification) = 2
- Strong (strikingly positive at low magnification) = 3
Quickscore:
08
Proportion of positive cells (nuclei)
- 0% = 0
- <1% = 1
- 1–10% = 2
- 11–33% = 3
- 34–66% = 4
- 67–100% = 5
Quickscore : What should be the cut off?
Harvey JM et al. J Clin Oncol. 1999 May;17(5):1474-81.
Quickscore in ER, PR IHC
 Score 0 : no response to endocrine treatment
 Score 2 - 3 : 20% response to endocrine treatment
 Score 4 - 6 : 50% response to endocrine treatment
 Score 7 - 8 : 75% response to endocrine treatment
But many labs use
the 10% cut off rule!
HER2/neu Immunohistochemistry
What is known about HER2
and response to Trastuzumab?
Guido Sauter et al
J Clin Oncol 29. 2009 by American Society of Clinical Oncology
HER2 gene amplication detected by In Situ Hybridization
is superior to HER2 protein overexpression detected by IHC in predicting
Response to Trastuzumab.
Mass R et al. Clinical Breast Cancer 6:240-246, 2005
Does HER2 over- expression defined by
IHC predict response to Trastuzumab?
YES! If not false-positive
Inexperience
interpreter
Poor fixation
Artifact
Antigen retrieval
techniques
Correlation between HER2 FISH and IHC
FISH result
IHC score
0
1+
2+
3+
Total
Amplified
4.5%
3.27%
8.6%
83.6%
244 cases
Not amplified
49.5%
23.74%
17.22%
9.53%
598 cases
Guido Sauter et al
J Clin Oncol 29. 2009 by American Society of Clinical Oncology
How about HER2 status
and response to Tamoxifen?
HER2 overexpression is correlated with resistance
to Tamoxifen in metastastic breast cancers
ER, PR IHC tests are no longer important in
metastatic setting
De Laurentiis M et al. Clin Cancer Res. 2005 Jul 1;11(13):4741-8
Does HER2 overexpression predict resistance
to Tamoxifen in early breast cancers?
Controversial studies: no conclusion yet
Why
don’twe
we
Should
conduct
trust allstudies
these
on our own
studies?
population?
Standard pathology report for benign breast lesions:
•
•
•
•
•
•
Histologic type of lesion + type of proliferation
Diameter
Areas of involvement (unifocal, multifocal, multicentric)
Nuclear grade and growth pattern (for carcinoma in situ)
Presence/absence of micro-invasion (for carcinoma in situ)
Status of resection margin (for carcinoma in situ > 2mm  safe)
Sample of a standard report
Conclusion:
1.
2.
3.
4.
5.
6.
7.
Lumpectomy: Atypical Ductal Hyperplasia (Proliferative lesion with
atypia)
Nuclear grade: 3
Growth pattern: solid type
Areas of involvement: multifocal (3 foci)
Overall size: 0.8 cm
Microinvasion: absent
Resection margins: not involved / negative (6 mm)
Standard pathology report for invasive breast carcinoma
1.
2.
3.
4.
5.
6.
7.
8.
Histologic type
Histologic grade (Bloom-Richardson)
TNM (size, extension, node, distant meta.)
Ki-67 index
Lympho-vascular/perineural invasion
Status of resection margin (> 1 mm  safe)
ER, PR, HER2/neu status
In situ component, if present
Sample of a standard report
Conclusion:
Tumorectomy – left breast :
 Invasive component:
1.
Type: Invasive ductal adenocarcinoma
2.
Poorly differentiated, Bloom score 8
3.
Maximal diameter : 1.8 cm
4.
Lymphovascular invasion: present
5.
Resection margins: minimally safe (3 mm from dorsal margin)
6.
Left axillary lymph nodes: 5 lymph nodes found, 2 lymph nodes invaded by carcinoma (2/5)
7.
Ki-67 index : approximately 30% of the tumor
8.
Receptor status:



ER negative (quickscore 0)
PR negative (quickscore 2)
HER2/neu score 2+
TNM (6th edition, 2002) : pT1c pN1a p Mx
 In situ component : absent
References and suggested readings
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2.
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7.
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10.
Richard J et al. Benign Breast Disorders. The New England Journal of Medicine. Volume 353:275-285
(July 2005)
Turner NC & Reis-Filho JS (2006). Basal-like breast cancer and the BRCA1 phenotype. Oncogene
25:5846–5853
Rouzier R et al. (2005). Breast cancer molecular subtypes respond differently to preoperative
chemotherapy. Clin Cancer Res 11:5678–585
Mamatha Chivukula. Evaluation of Morphologic Features to Identify ‘‘Basal-like Phenotype’’ on Core
Needle Biopsies of Breast. Appl Immunohistochem Mol Morphol Volume 16, Number 5, October 2008
E de Azambuja et al. Ki-67 as prognostic marker in early breast cancer: a meta-analysis of published
studies involving 12 155 patients. British Journal of Cancer (2007) 96, 1504-1513
Frédérique Spyratos et al. Correlation between MIB-1 and Other Proliferation Markers: Clinical
Implications of the MIB-1 Cutoff Value. Cancer 2002 Apr 15;94(8):2151-9
Perou CM, Sorlie T, Eisen MB et al (2000). Molecular portraits of human breast tumors. Nature 406:747–
752
Hiroo Nakajima et al. Prognosis of Japanese Breast Cancer Based on Hormone Receptor and HER2
Expression Determined by Immunohistochemical Staining. World J Surg (2008) 32:2477–2482
Sebastian F et al. Prognostic Value of Lymphangiogenesis and Lymphovascular Invasion in Invasive
Breast Cancer. Ann Surg. 2004 August; 240(2): 306–312.
Rosemary R. Millis et al. Ductal in situ component and prognosis in invasive mammary carcinoma.
Breast Cancer Research and Treatment 84: 197–198, 2004.