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![Page 1: 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.](https://reader036.fdocuments.in/reader036/viewer/2022081518/55144b4e5503462d4e8b4e45/html5/thumbnails/1.jpg)
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
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Benign breast lesions
Richard J et al. The New England Journal of Medicine. Volume 353:275-285 (July 2005)
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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)
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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
Nuclear grade
Score 1: DCIS nuclear grade 1 Score 2: DCIS nuclear grade 2 Score 3: DCIS nuclear grade 3
Surgical margin
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
Age of patient
Score 1: > 60 y.o Score 2: 40 – 60 y.o Score 3: < 40 y.o
Management
Score 4 – 6 : lumpectomy Score 7 – 9 : lumpectomy + radiation Th. Score 10 – 12 : mastectomy
Silverstein MJ, Lagios MD, Craig PH, et al. Cancer 77(11): 2267-2274, 1996
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Malignant lesions1. Secretory/Juvenile carcinoma (<0.15%)2. Tubular carcinoma (<2%)- so low recurrence that some centers
consider adjuvant th. unnecessary.3. Invasive cribriform carcinoma (0.8-3.5%)4. Metaplastic carcinoma (<1%)5. Invasive papillary carcinoma (1-2%)6. Mucinous carcinoma (~2%)7. Neuroendocrine carcinoma (2-5%)8. Medullary carcinoma (1-7%)9. Invasive lobular carcinoma (5-15%)10. Invasive ductal carcinoma (75%)
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1. Histologic type
2. Histologic grade (Bloom-Richardson)
3. TNM (size, node, distant metastasis)
4. Ki-67 index
5. Lympho-vascular invasion
8. Status of resection margins
9. ER, PR, HER2/neu status
10. In situ components, if present
6. Necrosis
7. Tumour border
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Histologic type: different prognosis
Darius Dian et al . Arch Gynecol Obstet (2009) 279:23–28
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Histologic typeGives pathologists and clinicians the ideas of:
1. Tumour’s aggressiveness2. Patients’ overall prognosis3. 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
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Features of basal-like breast CAHistology:• 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
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1. Histologic type
2. Histologic grade (Bloom-Richardson)
3. TNM (size, node, distant metastasis)
4. Ki-67 index
5. Lympho-vascular invasion
8. Status of resection margins
9. ER, PR, HER2/neu status
10. In situ components, if present
6. Necrosis
7. Tumour border
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Modifed Bloom-Richardson gradeTubule 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 fieldFrom 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.
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1. Histologic type
2. Histologic grade (Bloom-Richardson)
3. TNM (size, node, distant metastasis)
4. Ki-67 index
5. Lympho-vascular invasion
8. Status of resection margins
9. ER, PR, HER2/neu status
10. In situ components, if present
6. Necrosis
7. Tumour border
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1. Histologic type
2. Histologic grade (Bloom-Richardson)
3. TNM (size, node, distant metastasis)
4. Ki-67 index
5. Lympho-vascular invasion
8. Status of resection margins
9. ER, PR, HER2/neu status
10. In situ components, if present
6. Necrosis
7. Tumour border
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Ki-67 index
- Ki-67 recurrence rate ; overall survival (1)
- 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)
(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
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1. Histologic type
2. Histologic grade (Bloom-Richardson)
3. TNM (size, node, distant metastasis)
4. Ki-67 index
5. Lympho-vascular invasion
8. Status of resection margins
9. ER, PR, HER2/neu status
10. In situ components, if present
6. Necrosis
7. Tumour border
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How about peri-neural invasion?
No study has yet proven its independent
prognostic significance
Present in ~10% of high-grade tumours
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1. Histologic type
2. Histologic grade (Bloom-Richardson)
3. TNM (size, node, distant metastasis)
4. Ki-67 index
5. Lympho-vascular invasion
8. Status of resection margins
9. ER, PR, HER2/neu status
10. In situ components, if present
6. Necrosis
7. Tumour border
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Carter D et al. Am J Surg Pathol 1978;2:39–46
Prognostic value of Tumor necrosis & Tumor border
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1. Histologic type
2. Histologic grade (Bloom-Richardson)
3. TNM (size, node, distant metastasis)
4. Ki-67 index
5. Lympho-vascular invasion
8. Status of resection margins
9. ER, PR, HER2/neu status
10. In situ components, if present
6. Necrosis
7. Tumour border
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1. Histologic type
2. Histologic grade (Bloom-Richardson)
3. TNM (size, node, distant metastasis)
4. Ki-67 index
5. Lympho-vascular invasion
8. Status of resection margins
9. ER, PR, HER2/neu status
10. In situ components, if present
6. Necrosis
7. Tumour border
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Survival analysis: DCIS in invasive breast CA
Rosemary R. Millis et al. Breast Cancer Research and Treatment 84: 197–198, 2004.
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1. Histologic type
2. Histologic grade (Bloom-Richardson)
3. TNM (size, node, distant metastasis)
4. Ki-67 index
5. Lympho-vascular invasion
8. Status of resection margins
9. ER, PR, HER2/neu status
10. In situ components, if present
6. Necrosis
7. Tumour border
HER2/neu
Estogen receptor
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Overview on ER, PR, HER2 status in breast cancer
HER2/neu overexpressed in 25 – 30%
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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
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Hiroo Nakajima et al. World J Surg (2008) 32:2477–2482
Prognosis of each sub-type of breast CA
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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
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“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
Proportion of positive cells (nuclei) - 0% = 0 - <1% = 1 - 1–10% = 2 - 11–33% = 3 - 34–66% = 4 - 67–100% = 5
Quickscore:0 8
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Quickscore : What should be the cut off?
Harvey JM et al. J Clin Oncol. 1999 May;17(5):1474-81.
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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
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But many labs use the 10% cut off rule!
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HER2/neu Immunohistochemistry
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What is known about HER2 and response to Trastuzumab?
Guido Sauter et al
J Clin Oncol 29. 2009 by American Society of Clinical Oncology
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Mass R et al. Clinical Breast Cancer 6:240-246, 2005
HER2 gene amplication detected by In Situ Hybridization is superior to HER2 protein overexpression detected by IHC in predicting
Response to Trastuzumab.
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Does HER2 over- expression defined by IHC predict response to Trastuzumab?
YES! If not false-positive
Poor fixation
Artifact Antigen retrievaltechniques
Inexperienceinterpreter
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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
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How about HER2 statusand response to Tamoxifen?
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De Laurentiis M et al. Clin Cancer Res. 2005 Jul 1;11(13):4741-8
HER2 overexpression is correlated with resistance to Tamoxifen in metastastic breast cancers
ER, PR IHC tests are no longer important in metastatic setting
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Does HER2 overexpression predict resistanceto Tamoxifen in early breast cancers?
Controversial studies: no conclusion yet
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Should we trust all these
studies?
Should we trust all these
studies?
Why don’t we conduct studies
on our own population?
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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)
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Sample of a standard report
Conclusion:
1. Lumpectomy: Atypical Ductal Hyperplasia (Proliferative lesion with atypia)
2. Nuclear grade: 33. Growth pattern: solid type4. Areas of involvement: multifocal (3 foci)5. Overall size: 0.8 cm6. Microinvasion: absent7. Resection margins: not involved / negative (6 mm)
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Standard pathology report for invasive breast carcinoma
1. Histologic type2. Histologic grade (Bloom-Richardson)3. TNM (size, extension, node, distant meta.)4. Ki-67 index5. Lympho-vascular/perineural invasion6. Status of resection margin (> 1 mm safe)7. ER, PR, HER2/neu status8. In situ component, if present
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Sample of a standard reportConclusion:Tumorectomy – left breast : Invasive component: 1. Type: Invasive ductal adenocarcinoma 2. Poorly differentiated, Bloom score 83. Maximal diameter : 1.8 cm4. Lymphovascular invasion: present5. 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 tumor8. 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
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References and suggested readings1. Richard J et al. Benign Breast Disorders. The New England Journal of Medicine. Volume 353:275-285
(July 2005)2. Turner NC & Reis-Filho JS (2006). Basal-like breast cancer and the BRCA1 phenotype. Oncogene
25:5846–5853 3. Rouzier R et al. (2005). Breast cancer molecular subtypes respond differently to preoperative
chemotherapy. Clin Cancer Res 11:5678–5854. 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 5. 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, 1504-15136. Frédérique Spyratos et al. Correlation between MIB-1 and Other Proliferation Markers: Clinical
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