Lesions of Uncertain Malignant Potential (B3) ADH, LIN, FEA, Papilloma

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Jasmin Richards
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1 Diagnosis and Treatment of Patients with Primary and Metastatic Breast Cancer Lesions of Uncertain Malignant Potential (B3) ADH, LIN, FEA, Papilloma

2 Lesions of Uncertain Malignant Potential (B3) (including Precursor Lesions ) Version 2005: Audretsch / Thomssen Versions : Albert / Brunnert / Fersis / Friedrich / Gerber / Kreipe / Nitz / Schreer / Sinn Version 2013: Kreipe / Rody

3 Pathology Reporting for Minimal Invasive Biopsies B Classification* B1 = unsatisfactory / normal tissue only B2 = benign lesion B3 = lesion of uncertain malignant potential B4 = suspicion of malignancy B5 = malignant B5a = non-invasive B5b = invasive B5c = in-situ/invasion not assessable B5d = non epithelial, metastatic * National Coordinating Group for Breast Screening Pathology (NHSBSP), E.C. Working Group on Breast Screening Pathology, S3-Leitlinien

4 Major Type of B3 Lesions and their Prospective Predictive Value (PPV) for Malignancy in Resection Specimen Type of B3-lesions: ~PPV** (n=732) (n = 149) Atypical ductal hyperplasia (ADH) 50% 41% Lobular intraepithelial neoplasia (LN/LIN) 21% 0% Flat epithelial atypia (FEA) 21% 14% Radial scar 12% 3% Complex sclerosing lesion 9% 3% Papillary lesions 13% 7% Cellular fibroepithelial lesions / phylloides tu. 0% Adenomyoepithelioma B3 risk of upgrade after minimally invasive biopsy: PPV = 25%* 10% * Houssami N et al ** Rakha EA et al a u.b

5 Management after Minimal Invasive Biopsy Imaging guided minimal invasive biopsy Imaging of specimen Pathology of specimen B 3 lesion Multidisciplinary conference: pathology and imaging results concordant? no Diagnostic approach: tissue aquisition yes Management according to type of lesion Definition of standard elements: Clinical status decision action Logical consequence

6 Atypical Ductal Hyperplasia (ADH) Synonyms: Atypical intraductal epithelial proliferation (AIDEP), ductal intraepithelial neoplasia grade 1B (DIN1B) Definition: Any architectural atypia with micropapillary or cribriform proliferations and non-high grade nuclear atypia not exceeding 2 mm in diameter or two completely filled ducts is ADH. Proliferation exceeding 2 mm or two completely filled ducts has to be considered as low-grade intraductal carcinoma (lowgrade DCIS) Due to poor reproducibility 2nd opinion may be considered Indicator-/Precursor-lesion: Ipsi- and contralateral enhanced breast cancer risk: unifocal 4 x at 10 years, multifocal (more than 3 foci) 10 x at 10 years. Enhanced breast cancer risks at diagnosis before age 45 yrs.: 6 x at 10 years.

7 Risk of Breast Cancer after ADH Stratification of breast cancer risk* 1 lesion: RR 3.88 (95%CI ) 3 lesions: RR (95% CI ) Less than 45 years at diagnosis: RR 6.78 (95%CI ) *Degnim AC et al. J Clin Oncol 2007;28:

8 Strategy after Diagnosis of ADH ADH in core- / vacuum-assisted biopsy: Oxford / AGO LoE / GR Open excisional biopsy 3a C ++ Open excisional biopsy may be omitted, with: a) A small lesion ( 2 TDLU* in vacuum biopsy) and b) Complete removal of imaging abnormality 5a C + ADH at margins in resection specimen: No further surgery, if incidental finding accompanying invasive or intraductal carcinoma 3a C ++ * Terminal ductal-lobular unit

9 Lobular Intraepithelial Neoplasia (LIN) Includes: Atypical lobular hyperplasia, lobular carcinoma in situ, LCIS/CLIS LIN1 3 classification is not sufficiently validated Pleomorphic LIN and LIN with necrosis or with distension and confluence of lobules are classified as B5a Indicator-/Precursor-lesion: Ipsi- and contralateral enhanced breast cancer risk: 7 x at 10 years

10 Strategy after Diagnosis of LIN Oxford / AGO LoE / GR LIN in core- / vacuum-assisted biopsy: Open excisional biopsy, if careful correlation with imaging is discordant and not conclusive 2b C ++ LIN is frequently associated with invasive cancer which may be not represented in core- or vacuum-assisted biopsy LIN at margins of resection specimen: No further surgery / re-excision unless imaging abnormality is not removed 3a C ++ LIN accompanying intraductal or invasive carcinoma in patients with BCT No further resection 2a C ++ Exception: Pleomorphic LIN and LIN with necrosis Complete resection 5 D ++

11 Flat Epithelial Atypia (FEA) Synonyms: Columnar cell hyperplasia with atypia, columnar cell metaplasia with atypia, ductal intraepithelial neoplasia grade 1A (DIN 1A) Differential diagnosis: ADH is discriminated by architectural features (micropapillary, cribriform) B3 Clinging carcinoma is discriminated by high grade nuclear atypia (G2/G3) and classified as B5a Marker lesion: FEA is frequently associated with calcifications and may be associated with intraductal carcinoma. Therefore, correlation with imaging is mandatory.

12 Strategy after Diagnosis of FEA Oxford / AGO LoE / GR FEA in core biopsy/vacuum-assisted biopsy: Open excisional biopsy 3b C + Open excisional biopsy may be omitted, with: a small lesion ( 2 TDLU* in vacuum biopsy) and complete removal of imaging abnormality 5a C + FEA at margins in resection specimen: 3b C ++ No further surgery, unless calcifications have not been completely removed * Terminal ductal-lobular unit

13 Papilloma Includes: central papilloma, large duct papilloma, major duct papilloma, intraductal papilloma, atypical intraductal papilloma (B3) To be discriminated from peripheral papillomas arising in the TDLU, size 2 mm, may be multiple To be discriminated from intraductal papillary carcinoma and encapsulated papillary carcinoma Indicator lesion: May be associated with in-situ or invasive cancer (10%, in case of atypical papilloma up to 20% ), increased ipsilateral risk for cancer (4.6% to 13% in case of atypical papilloma)

14 Strategy after Diagnosis of Central Papilloma Papilloma in core- / vacuum-assisted biopsy: Open excisional biopsy Oxford / AGO LoE / GR 3a C ++ Papilloma at margins of resection specimen: No study data available

15 Follow-up Imaging for Women Age Years with B3-Lesions Oxford / AGO LoE / GR FEA, non-atypical Papilloma Screening mammography 5 C ++ LIN Mammography (12 months) 3a C ++ ADH Mammography (12 months) 3a C ++ Women with LIN and ADH should be informed about their elevated risk of breast cancer 3a C ++

16 Medical Prevention for Women at Increased Risk (including Women with LIN and ADH) Oxford / AGO LoE / GR Tamoxifen for women >35 years Risk reduction of invasive BrCa and DCIS 1a A +* Raloxifen for postmenopausal women - Risk reduction of invasive BrCa only 1b A +* Aromatase inhibitors for postmenopausal women 5 D +/-** Medical prevention should only be offered after individual and comprehensive counseling; the net benefit strongly depends on risk status, age and preexisting risk factors for side effects. *Risk situation as defined in NSABP P1-trial (1,66% in 5 years) ** Study participation recommended

17 5 5 Outcome of Medical Prevention (1) NSABP-P1 Study, update 2005 Placebo Rate / 1000 WE Tamoxifen Rate / 1000 WE RR 95% CI All women w/o LCIS W LCIS w/o AH w AH y risk <2% y risk > 5% One 1 st relatives >= three1 st relatives Fractures Endometrial Ca Tamoxifen Rate / 1000 WE Raloxifen Rate / 1000 WE RR 95% CI All women W/O LCIS W LCIS W/O AH W AH y risk <3% y risk > 5% One 1 st relatives >=two 1 st relatives Endometrial CA Thromboembolisms Develeoping Cataracts NSABP-P2 Study, STAR trial Should only be offered to women at high risk, e.g. with LIN with ADH with a strong family history Should not be offered to women with a moderate risk over the age of 50 with an increased risk for thromboembolic events

18 5 Outcome of Medical Prevention (2) Risks and benefits with long-term Tamoxifen use compared with placebo: results from the IBIS-I Trial, 96 months median follow-up (Cuzick J et al J Natl Cancer Inst 2007: ) RR 95% CI AR per 1000* NNT / NNH** BC Incidence Invasive BC Thromboembolism Deep vein thrombosis Headache Gynecological / vasomotoric symptoms Breast complains Risk communication: AR*: absolute risk difference per 1000 women NNT/NNH** number needed to treat or number needed to harm only shown for statistically significant events over the entire follow-up period Data computed by guideline authors Visvanathan K et al. JCO 2009;27:

Nicole Kounalakis, MD

Breast Disease: Diagnosis and Management Nicole Kounalakis, MD Assistant Professor of Surgery Goal of Breast Evaluation The goal of breast evaluation is to classify findings as: normal physiologic variations