1

Factors Predictive of Malignant Upstaging of

Atypical Ductal Hyperplasia of the Breast

- Can Surgical Excision Biopsy be avoided?

Tiffany Sin Hui Bong, Thaddaeus Jun Kiat Tan, Juliana Teng Swan Ho, Wai Yee Ng, Jill Su Lin

Wong, Sue Zann Lim, Veronique Kiak Mien Tan, Benita Kiat Tee Tan, Preetha Madhukumar, Wei

Sean Yong, Kong Wee Ong, Yirong Sim*

Dr Tiffany Bong

SingHealth Duke-NUS Breast Centre

National Cancer Centre Singapore

Singapore General Hospital

• Atypical Ductal Hyperplasia (ADH) of the Breast

• Proliferation of dysplastic monotonous epithelial cell populationsin involved ducts

• High risk lesion classified between usual ductal hyperplasia (UDH)and ductal carcinoma in-situ (DCIS)

• Relative risk of future breast cancer: 4 1-6

• Incidence of breast cancer at 25 years follow-up: 30% 3,7

Introduction

1. Dupont WD, Page DL. Risk factors for breast cancer in women with proliferative breast disease. N Engl J Med 1985;312:146-151

2. Hartmann LC, Sellers TA, Frost MH, et al. Benign breast disease and the risk of breast cancer. N Engl J Med 2005;353:229-237

3. Hartmann LC, Radisky DC, Frost MH, et al. Understanding the premalignant potential of atypical hyperplasia through its natural history: a longitudinal cohort study. Cancer Prev Res (Phila) 2014;7:211-217

4. London SJ, Connolly JL, Schnitt SJ, Colditz GA. A prospective study of benign breast disease and the risk of breast cancer. JAMA 1992;267:941-944[Erratum, JAMA 1992;267:1780.]

5. Page DL, Dupont WD, Rogers LW, Rados MS. Atypical hyperplastic lesions of the female breast: a long-term follow-up study. Cancer 1985;55:2698-2708

6. Degnim AC, Visscher DW, Berman HK, et al. Stratification of breast cancer risk in women with atypia: a Mayo cohort study. J Clin Oncol 2007;25:2671-2677

7. Page DL, Schuyler PA, Dupont WD, Jensen RA, Plummer WD Jr, Simpson JF. Atypical lobular hyperplasia as a unilateral predictor of breast cancer risk: a retrospective cohort study. Lancet 2003;361:125-129

Introduction

Figure 1: Panel A - Atypical ductal hyperplasia with a proliferation of monotonous cells inarchitecturally complex patterns, including secondary lumens and micropapillary formations.(Reproduced from Hartmann et al)

• Distinguishing ADH from DCIS

• Cellular changes of DCIS that occupy less than 2 separate duct spaces

• <2mm in maximum dimension

Introduction

Distinction between ADH and ductal

carcinoma in situ (DCIS) equivocal

Sampling error inherent with core

needle biopsy (CNB)

+

Excision biopsy after diagnosis of ADH on CNB is still

recommended

To identify clinico-radiologic factors which predictmalignant upstaging of ADH on core needle biopsy(CNB) in an Asian population

Aim of Study

• Target population: Consecutive patientswho were recalled for imagingabnormalities and had ADH diagnosed onCNB in the National Cancer CentreSingapore between 2010 and 2015.

• Histologic upstaging: Lesions diagnosedas ADH on CNB that were subsequentlyrevealed to harbour malignancy (DCIS orinvasive carcinoma) on surgical excisionbiopsy.

Methods

47,934 women underwent mammographic screening under BreastScreen Singapore between

2010 and 2015

5,742 breast CNB performed

2,686 breast CNB performed at National Cancer Centre

89 patients with 91 ADH lesions diagnosed on CNB

Clinico-radiologic features were examined

• All mammograms are read by at least 3 specialistbreast radiologists.

• All core biopsies performed with either 11- or 14-gauge Trucut biopsy or vacuum-assisted breast biopsyneedle.

• Associations between clinico-radiological factors wereassessed with Fisher’s exact test.

• Independent clinico-radiological factors wereidentified with multivariate analysis with Coxregression model.

Methods

Results (I) - Demographics

Table 1. The demographic characteristics of the study patients.

Results (II) - Radiological Characteristics(a) Breast Densities

Figure 2: Distribution of mammographic parenchymal density among patients with CNB-diagnosed ADH (n=89)

Mammographic Parenchymal

Density

Almost entirely fat Scattered fibroglandulartissue

Heterogeneously dense

Extremely dense

Proportion amongst n=89

patients

0% (n=0)

10%(n=9)

65% (n=58)

25%(n=22)

Results (II)- Radiological Characteristics(b) Radiological Abnormalities

Figure 3: Abnormalities noted on screening mammogram in n=89 patients.

(n=83)

(n=5)

(n=3)

• Microcalcification was the most common finding for ADH

• Microcalcificationdistribution

• Diffuse distribution more likely to be upstaged 91%

5% 3%

Calcification

Mass

Distortion

Results (II) - Radiological Characteristics(c) Univariate Analysis

Variable Upgrade to DCIS or IBC (total n=91 lesions)

Odds Ratio (95% CI)

p-value

No (n=64) Yes (n=27)

Mass present on US, N (%) 3 (4.7) 6 (22.2) 5.81 (1.33 - 25.32) 0.019*

Mass lesion on MMG, N (%) 1 (1.6) 4 (14.8) 10.96 (2.63 - 45.6) 0.001*

Microcalcification distribution, N(%)None Diffuse Regional Grouped Segmental

3(4.7)2 (3.1)

9 (14.1)34 (53.1)16 (25.0)

6 (22.2)3 (11.1)1 (3.7)

11 (40.7)6 (22.2)

0.17 (0.04 - 0.75) 0.019*

Mammographic parenchymal density N (%)Scattered areas of fibroglandular density

Heterogenously dense

Extremely dense

4 (6.3)

40 (62.5)

20 (31.3)

6 (22.2)

19 (70.4)

2 (7.4)

0.32 (0.08 - 1.26)

0.07 (0.01 - 0.46)

0.102

0.006*

Table 2: Univariate analysis of factors predicting for upgrade to DCIS or invasive carcinoma on excision biopsy.

Variable Multivariate analysis

p-value Hazard ratio 95% CI

Mammographic parenchymal density (compared to scattered areas of fibroglandular density)- Heterogeneously dense- Extremely dense

0.014

0.0950.004

0.30 0.04

0.07 - 1.240.005 - 0.35

Presence of mass on ultrasound 0.010 10.51 1.74 - 63.36

Results (II) - Radiological Characteristics(d) Multivariate Analysis

Table 3: Multivariate analysis of factors predicting for upgrade to DCIS or invasive carcinoma on excision biopsy.

• Presence of mass on imaging

• More aggressive lesion with higher potential of localinvasiveness

• Consistent with previous studies 1,2

• Breast parenchymal density

• Scattered areas of fibroglandular density more likely tobe upstaged

• 20% upstaging rate in the absence of residual calcification after biopsy

Discussion (I) - Radiological Features

1. Khoury, T., Chen, X., Wang, D., Kumar, P., Qin, M., Liu, S., & Turner, B. (2015). Nomogram to predict the likelihood of upgrade of atypical ductal hyperplasia diagnosed on a core needle biopsy in mammographically detected lesions. Histopathology, 67(1), 106-120. doi: 10.1111/his.12635

2. McGhan, L., Pockaj, B., Wasif, N., Giurescu, M., McCullough, A., & Gray, R. (2012). Atypical Ductal Hyperplasia on Core Biopsy: An Automatic Trigger for Excisional Biopsy?. Annals Of Surgical Oncology, 19(10), 3264-3269. doi: 10.1245/s10434-012-2575-0

Results (III) – Biopsy Needle Size

Variable Odds Ratio p-value

Needle gauge size (compared to size 11)Size 14

3.53 (1.23 - 10.11) 0.019

No. of tissue cores obtained 0.89 ( 0.80 - 0.99) 0.026

Core biopsy method (compared to Trucut biopsy)Vacuum assisted biopsy

0.21 ( 0.05 - 0.83) 0.031

Univariate analysis

No significant variables were identified on multivariate analysis. Factors investigated include:- Core biopsy method - Needle gauge size- Number of tissue cores obtained- ADH foci to core ratio- Residual calcifications post biopsy

• First known study in Southeast Asia in this decade reviewing upstaging rate of CNB-diagnosed ADH and the predictive factors

• Upstaging rate: 29.7%

• 27.5% DCIS, 2.2% invasive ductal carcinoma

• Lower end of spectrum of upstaging of 18-69% 1-4

Conclusion

1. DAHLSTROM, J., SUTTON, S. and JAIN, S. (1996). Histological precision of stereotactic core biopsy in diagnosis of malignant and premalignant breast lesions. Histopathology, 28(6), pp.537-541.2. Harvey, J., Sterrett, G. and Frost, F. (2002). Atypical ductal hyperplasia and atypia of uncertain significance in core biopsies from mammographically detected lesions: correlation with excision diagnosis.

Pathology, 34(5), pp.410-416.3. Jackman, R., Birdwell, R. and Ikeda, D. (2002). Atypical Ductal Hyperplasia: Can Some Lesions Be Defined as Probably Benign after Stereotactic 11-gauge Vacuum-assisted Biopsy, Eliminating the

Recommendation for Surgical Excision?. Radiology, 224(2), pp.548-554.4. Liberman, L., Cohen, M., Dershaw, D., Abramson, A., Hann, L. and Rosen, P. (1995). Atypical ductal hyperplasia diagnosed at stereotaxic core biopsy of breast lesions: an indication for surgical biopsy.

American Journal of Roentgenology, 164(5), pp.1111-1113.

• Upstaging of CNB-diagnosed ADH independently associated with presence of mass on ultrasound and breast parenchymal density of scattered fibroglandular density

• Increased needle gauge size, increased number of cores obtained and use of vacuum assisted device associated with lower risk of upstaging

• In the absence of residual calcification after biopsy, significant upstaging rate of 20%

• Future work

• Include histologic factors

• Nomogram to risk-stratify CNB-diagnosed lesions to reduce unnecessary surgical intervention in low-risk patients

Conclusion

19

Thank You