1. Lobular Neoplasia of Breast Susanna Tam Wai Yin Kwong Wah Hospital Joint Hospital Surgical Grand Round21st April, 2012

2. Lobular Neoplasia ♣Comprises LCIS & ALH ♣Rare breast lesion –3.19 per 100000 women; 0.5-4% in all biopsy »Ellis OI et al. Invasive breast carinoma. In: Tavassoli FA et al. Tumours of the Breast and Female Genital Organs. Lyon: IARC Press;; 2003:60-62. –More than doubled in the past 25 yrs »Elsheikh TM et al. Follow-up surgical excision is indicated when breast core needle biopsyies show atypical lobular hyperplasia or lobular carcinoma in situ: a correlative study of 33 patients with review of the literature. Am J Surg Pathol. 2005;29:534-543. ♣Clinically important: –risk marker, possible precursor of CA breast ♣Challenges & controversies in: –Diagnosis & classification –Understanding of its biological behaviour –Appropriate management

3. Outline 1.Pathology & cytogenetics 2.Clinical Features –Upstaging –Marker of increased risk 3.Management

4. PATHOLOGY

5. Lobular Carcinoma in-situ (LCIS) ♣A monomorphic population of dyshesive cells expanding the terminal duct lobular unit –Acini are completely filled with cells and causing distension of at least 50% of the acini »Foote FW Jr, Stewart FW (1941) Lobular carcinoma in situ. A rare form of mammary cancer. Am J Pathol 17:491–496 Frances P O’Malley. Lobular neoplasia: morphology, biological potential and management in core biopsies. Modern Pathology (2010) 23, S14–S25

6. Atypical Lobular Neoplasia (ALH) ♣A less well developed form of LCIS –Acini only partially filled by loosely cohesive cells; <50% of acini involved if distension present »Page DL, Dupont WD, Rogers LW, et al. Atypical hyperplastic lesions of the female breast. A long-term follow-up study. Cancer 1985;55:2698–2708. »Dupont WD, Page DL. Risk factors for breast cancer in women with proliferative breast disease. N Engl J Med 1985;312:146–151 ALH LCIS Frances P O’Malley. Lobular neoplasia: morphology, biological potential and management in core biopsies. Modern Pathology (2010) 23, S14–S25

7. MOLECULAR PATHOLOGY & CYTOGENETICS Hanby AM et al. In situ and invasive lobular neoplasia of the breast. Histopathology 2008; 52: 58-66 O’Malley FP. Lobular neoplasia: morphology, biological potentil and management in core biopsies. Modern Pathology 2010. 23:S14-25.

8. E-Cadherin –An adhesion molecule localized at zonula adherens which enchances cellular cohesion ♣Biallelic loss or down-regulation of E-cadherin gene (CDH1;16q21.1) in LN & ILC –differentiates vs. ductal neoplasms –a/w inherited ILC and diffuse gastric CA

9. Am J Surg Pathol 2007;31:417–426

10. CLINICAL FEATURES

11. Presentation ♣Clinically occult ♣Often not detectable by MMG ♣Multicentric & bilateral ♣Incidentally found on core bx

12. Upstaging on Excision Patients & Methods ALHLCIS Hussain M et al. Management of lobular carcionma in-stu and atypical hyperplasia of the breast – a review. Eur J Surg Oncol. 2011; 37:279-89 1229 LN, 789 (64%) excision Outcomes of patients without excision rarely reported 19%32% Luedtke C et al. Outcomes of prospective excision for classic LCIS and ALH on percutaneous breast core biopsy. Abstract no. 209. US and Canadian Acad of Pathology Annual Meeting; 2011. Retrospective review at Memorial Sloan-Kettering Cancer Center (MSKCC) 82 LN, routine excision 11 were excluded for synchronous lesions requiring excision or radiologic-pathologic discordance 3% one low grade DCIS & one tubular cancer 0% Translational Breast Cancer Research Consortium. TBCRC 020 Prospective study started Nov 2004 Expected to complete by 2014 In progress http://pub.emmes.com/stud y/bcrc/

13. Marker of Increased CA Risk ♣Subsequent CA develops away from original core bx site ♣Ipsilateral breast slightly > contralateral »Renshaw AA et al. Lobular neoplasia in breast core needle biopsy specimens is associated with a low risk of ductal carcionma in sit u or invasive carcinoma on subsequent excision. Am J Clin Pathol 2006; 126:310-313.

14. Relative Risk ♣ALH: 4-5x; LCIS: 8-10x »Page DL etal. Lobular neoplasia of the breast: higher risk for subsequent invasiver cancer predicted by more extensive disease. Hum Pathol. 1991;22:1232-9. ♣Lifetime risk ~1% per year after dx of LCIS –13% in first 10yrs, 26% after 20yrs, 35% by 35yrs »Bodian CA et al. Lobular neoplasia. Long term risk of breast cancer and relation to other factors. Cancer. 1996;78:1024-34.

15. MANAGEMENT

16. LN Diagnosed by Core Bx ♣Routine local excision ♣Or only if: 1.Presence of another lesion indicating excision 2.Radio-pathological discordance 3.Associated mass/distortion 4.Indeterminate between ductal and lobular lesion 5.Pleomorphic LCIS or other variants –1-3% missing rate »Renshaw AA et al. Lobular neoplasia in breast core needle biopsy specimens is associated with a low risk of ductal carcionma in sit u or invasive carcinoma on subsequent excision. Am J Clin Pathol 2006; 126:310-313.

17. Surveillence ♣Yearly MMG, P/E Q6-12mth »NCCN Breat Cancer Screening and Diagnois Clinical Practice Guidelines ♣Routine MRI screening not supported –No difference in cancer detection rate or trend towards earlier stage at dx »American Cancer Society guidelines »O ppong BA et al. Recommendations for women with lobular carcinoma in situ (LCIS). Oncology. Oct 2011: 1051-1058

18. Chemoprevention ♣Premenopausal: 5yrs of tamoxifen »NSABP Breast Cancer Prevention Trial (BCPT, P-1) 1998 ♣Postmenopausal: raloxifene »Multiple Outcomes of Raloxifene Evaluation (MORE) study 1999 »NSABP Study of Tamoxifen and Raloxifene (STAR, P-2) 2006 ♣Aromatase inhibitors - not recommended »American Society of Clinical Oncology (ASCO) ♣Highly effective with significant risk –LCIS: 56% ↓; atypical hyperplasia 86% ↓ –3x PE, 2.5x endometrial CA, 1.8x stroke »Fisher B et al. Tamoxifen for prevention of beast cancer: report of the National Sugical Adjunct Breast and Bowel Project P-1 study. J Natl Cancer Inst. 1998;90:1371-1388. ♣Not widely embraced `.` risk »Port et al. Patient reluctance toward tamoxifen use for breast cancer primary prevention. Ann Surg Oncol. 2001;8:580-5.

19. Bilateral Prophylactic Mastectomy ♣For a subset of high risk patients (e.g. Strong FHx) ♣Careful counselling & ample time for consideration needed – risk, benefit, QoL, cosmetic outcome ♣+/- nipple preservation and/or reconstruction »Oppong BA et al. Recommendations for women with lobular carcinoma in situ (LCIS). Oncology. Oct 2011: 1051-1058

20. Conclusion ♣Understanding of LN is evolving –“carcinoma in-situ”  marker of increased CA risk  + non-obligate precursor ♣Avoid over-treatment –Surveillence is mandatory –If dx by core bx  excision only in selected cases –If dx by mammotome / surgical excision  re- excision not needed ♣Further prospective follow-up & cytogenetic study is warranted

21. End