Section 4 -

Lobular Neoplasia (ALH and LCIS) Sunil R Lakhani Molecular and Cellular Pathology School of Medicine, The University of Queensland Mayne Medical School Australia

Lobular Neoplasia (ALH and LCIS) Lobular carcinoma in situ (LCIS) has traditionally been regarded as 'just a risk indicator', implying that it is not a precursor of invasive cancer in the way that DCIS is. The molecular and epidemiological data gathered over the last decade has challenged and overturned that view. The neoplastic cells of LCIS typically show a discohesive pattern; however they can vary in terms of nuclear morphology and cytoplasmic appearance. Three types of cells are on record: type A, the bona fide lobular carcinoma cells, are small, have round-to-ovoid nuclei, uniform chromatin, inconspicuous nucleoli and scant cytoplasm; type B cells, are bigger, have a more abundant and clearer cytoplasm, slightly more pleomorphic nuclei, with clumped chromatin and conspicuous nucleoli. The recently described pleomorphic variant is composed of cells that are similar to those seen in apocrine carcinomas, but more discohesive; they have abundant finely granular pinkish cytoplasm, pleomorphic nuclei, with prominent macro-nucleoli. The similarities between atypical lobular hyperplasia (ALH), LCIS and their invasive counterparts are overwhelming and are not restricted to the morphological and immunohistochemical levels. CGH analysis on ALH and LCIS has shown losses of 16p, 16q, 17p and 22q and gain of material from 1q and 6q, highlighting the overlapping molecular cytogenetic features of these lesions. Although limited, LOH data in ALH, LCIS and associated invasive lobular carcinomas also confirm the similarities between these lesions. The target gene of 16q loss in ALH and LCIS is CDH1, which maps to 16q22.1 and encodes E-cadherin, a protein involved in cell-cell adhesion and in cell cycle regulation through b –catenin/Wnt pathway. Although this gene was first reported as an invasion/metastasis associated gene, evidence suggest that it may also have tumour suppressor properties. E-cadherin is reduced or absent in the vast majority of LCIS, whereas it is reported to be expressed in normal or only slightly reduced levels in DCIS and other types of invasive breast carcinomas. Based upon these findings, immunohistochemistry with antibodies for E-Cadherin has been advocated as an invaluable ancillary method for differentiating solid low grade DCIS from LCIS. Epidemiological studies show that the behaviour of LCIS and ALH is quite different from that of DCIS. LCIS is multifocal and bilateral in a high proportion of cases and approximately one fifth of the cases will progress to invasive cancer over a 20-25 year follow up period. When an invasive carcinoma is found associated with or following a diagnosis of LCIS, it usually shows lobular morphology. Invasive ductal carcinomas, especially of low-grade/tubular type, can also be found but at a lower frequency. It has been reported that the risk is similar in both breasts; however, there are good data to suggest that the risk is skewed in favour of the ipsilateral breast. This together with the molecular data strongly supports the concept that ALH and LCIS should not only be considered risk indicators, but also non-obligate precursors of invasive carcinoma. The understanding of lobular neoplasia has swung back to recognition of its neoplastic and precursor nature, however, management remains difficult, principally due to lack of data. Whether the finding of ALH/LCIS on a core biopsy should lead to further excision is a controversial issue. A number of studies have tried to address this question but all suffer from a variety of limitations including small numbers, retrospective nature of the studies and inability to dissect out the importance of lobular lesions from the associated ductal proliferations. Overall, the studies suggest that approx 15% of ALH and 20% of LCIS are associated malignancy on further excision. However, my personal opinion is that this information has to be used in context of 'why the core biopsy was done'. Without taking this into account, it is difficult to make definitive statements about management. Pathological reporting and management based on excisional specimens is also controversial. Most people report LCIS at margins; however, the further management will depend on the associated pathology. If LCIS only is seen in an excision biopsy – no further excision is required. If LCIS is seen in association with an invasive cancer and is at margins no further excision is required if the invasive cancer is excised. It is of course important that the multidisciplinary team and clinicians involved in the case understand the implications of such findings and do not over interpret this information in terms of requirement for further excision, which is not indicated in the majority of cases. There is little doubt that at present, clinico-pathologic correlation remains the most critical issue. Patient with mass lesions, parenchymal distortions, discordance in the triple examination, and presence of pleomorphic variants of LCIS should go on to further excision. Selected further reading Foote FW, Stewart FW. Lobular carcinoma in situ. Am J Pathol 1941:491-495. Haagensen CD, Lane N, Lattes R, Bodian C. Lobular neoplasia (so-called lobular carcinoma in situ) of the breast. Cancer 1978;42(2):737-69. Page DL, Dupont WD, Rogers LW, Rados MS. Atypical hyperplastic lesions of the female breast. A long-term follow- up study. Cancer 1985;55(11):2698-708. Eusebi V, Betts C, Haagensen DE, Jr., Gugliotta P, Bussolati G, Azzopardi JG. Apocrine differentiation in lobular carcinoma of the breast: a morphologic, immunologic, and ultrastructural study. Hum Pathol 1984;15(2):134-40. Rasbridge SA, Gillett CE, Sampson SA, Walsh FS, Millis RR. Epithelial (E-) and placental (P-) cadherin cell adhesion molecule expression in breast carcinoma. J Pathol 1993;169(2):245-50. Sneige N, Wang J, Baker BA, Krishnamurthy S, Middleton LP. Clinical, histopathologic, and biologic features of pleomorphic lobular (ductal-lobular) carcinoma in situ of the breast: a report of 24 cases. Mod Pathol 2002;15(10):1044-50. Page DL, Kidd TE, Jr., Dupont WD, Simpson JF, Rogers LW. Lobular neoplasia of the breast: higher risk for subsequent invasive cancer predicted by more extensive disease. Hum Pathol 1991;22(12):1232-9. Urban J. Bilaterality of cancer of the breast: Biopsy of the opposite breast. Cancer 1967;20:1867-1870. Rosen PP, Kosloff C, Lieberman PH, Adair F, Braun DW, Jr. Lobular carcinoma in situ of the breast. Detailed analysis of 99 patients with average follow-up of 24 years. Am J Surg Pathol 1978;2(3):225-51. 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(9352):125-9. Vos CB, Cleton-Jansen AM, Berx G, de Leeuw WJ, ter Haar NT, van Roy F, et al. E-cadherin inactivation in lobular carcinoma in situ of the breast: an early event in tumorigenesis. Br J Cancer 1997;76(9):1131-3. Lu YJ, Osin P, Lakhani SR, Di Palma S, Gusterson BA, Shipley JM. Comparative genomic hybridization analysis of lobular carcinoma in situ and atypical lobular hyperplasia and potential roles for gains and losses of genetic material in breast neoplasia. Cancer Res 1998;58(20):4721-7. Lakhani S, Collins N, Sloane J, Stratton M. Loss of Heterozygosity in lobular carcinoma in situ of the breast. J Clin Pathol: Mol Pathol 1995;48:M74-M78. Berx G, Cleton-Jansen AM, Strumane K, de Leeuw WJ, Nollet F, van Roy F, et al. E-cadherin is inactivated in a majority of invasive human lobular breast cancers by truncation mutations throughout its extracellular domain. Oncogene 1996;13(9):1919-25. Elsheikh TM, Silverman JF. Follow-up surgical excision is indicated when breast core needle biopsies 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(4):534-43. Foster MC, Helvie MA, Gregory NE, Rebner M, Nees AV, Paramagul C. Lobular carcinoma in situ or atypical lobular hyperplasia at core-needle biopsy: is excisional biopsy necessary? Radiology 2004;231(3):813-9. Dershaw DD. Does LCIS or ALH without other high-risk lesions diagnosed on core biopsy require surgical excision? Breast J 2003;9(1):1-3. Harvey JM, Sterrett GF, Frost FA. Atypical ductal hyperplasia and atypia of uncertain significance in core biopsies from mammographically detected lesions: correlation with excision diagnosis. Pathology 2002;34(5):410-6. Shin SJ, Rosen PP. Excisional biopsy should be performed if lobular carcinoma in situ is seen on needle core biopsy. Arch Pathol Lab Med 2002;126(6):697-701.