Updates on Breast Diseases: What clinicians need to know from pathologists

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

http://www.univ-sante.edu.kh/

Benign breast lesions

Richard J et al. The New England Journal of Medicine. Volume 353:275-285 (July 2005)



http://content.nejm.org/content/vol353/issue3/images/large/09t1.jpeg

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

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


Malignant lesions


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%)


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

8. Status of resection margins

9. ER, PR, HER2/neu status

10. In situ components, if present

6. Necrosis

7. Tumour border


Histologic type: different prognosis

Darius Dian et al . Arch Gynecol Obstet (2009) 279:23–28


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


Basal-like?


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


1. Histologic type



4. Ki-67 index





6. Necrosis

7. Tumour border


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.


1. Histologic type



4. Ki-67 index





6. Necrosis

7. Tumour border


1. Histologic type



4. Ki-67 index





6. Necrosis

7. Tumour border


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


1. Histologic type



4. Ki-67 index





6. Necrosis

7. Tumour border


Sebastian F et al. Ann Surg. 2004 August; 240(2): 306–312.


How about peri-neural invasion?

No study has yet proven its independent

prognostic significance

Present in ~10% of high-grade tumours


1. Histologic type



4. Ki-67 index





6. Necrosis

7. Tumour border


Carter D et al. Am J Surg Pathol 1978;2:39–46

Prognostic value of Tumor necrosis & Tumor border


1. Histologic type



4. Ki-67 index





6. Necrosis

7. Tumour border



1. Histologic type



4. Ki-67 index





6. Necrosis

7. Tumour border


Survival analysis: DCIS in invasive breast CA

Rosemary R. Millis et al. Breast Cancer Research and Treatment 84: 197–198, 2004.


1. Histologic type



4. Ki-67 index





6. Necrosis

7. Tumour border

HER2/neu

Estogen receptor


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


Hiroo Nakajima et al. World J Surg (2008) 32:2477–2482

Prognosis of each sub-type of breast CA


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

Proportion of positive cells (nuclei) - 0% = 0 - <1% = 1 - 1–10% = 2 - 11–33% = 3 - 34–66% = 4 - 67–100% = 5

Quickscore:0 8

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



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

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.

Does HER2 overexpression defined by IHC predict response to Trastuzumab?

YES! If not false-positive

Poor fixation

Artifact Antigen retrievaltechniques

Inexperienceinterpreter

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 statusand response to Tamoxifen?

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

Does HER2 overexpression predict resistanceto Tamoxifen in early breast cancers?

Controversial studies: no conclusion yet

Should we trust all these

studies?

Should we trust all these

studies?

Why don’t we conduct studies

on our own 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. 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)

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

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

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

Implications of the MIB-1 Cutoff Value. Cancer 2002 Apr 15;94(8):2151-9 7. Perou CM, Sorlie T, Eisen MB et al (2000). Molecular portraits of human breast tumors. Nature 406:747–

7528. Hiroo Nakajima et al. Prognosis of Japanese Breast Cancer Based on Hormone Receptor and HER2

Expression Determined by Immunohistochemical Staining. World J Surg (2008) 32:2477–24829. Sebastian F et al. Prognostic Value of Lymphangiogenesis and Lymphovascular Invasion in Invasive

Breast Cancer. Ann Surg. 2004 August; 240(2): 306–312. 10. Rosemary R. Millis et al. Ductal in situ component and prognosis in invasive mammary carcinoma.

Breast Cancer Research and Treatment 84: 197–198, 2004.

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Updates on Breast Diseases: What clinicians need to know from pathologists