Abstract
One of the most controversial issues in breast pathology is whether lobular neoplasia (LN) is a risk factor or a precursor lesion of invasive lobular carcinoma (ILC). This is consequent to the fact that no conclusive data on the biology of LN exist. Molecular studies of LN and ILC are scanty, variable, and not consistent. Clonality of 12 cases of LN and ILC present simultaneously in the same block has been studied. Cells from both lesions were obtained by microdissection and were studied for mitochondrial DNA (mtDNA), D-loop sequencing, and neighbor-joining trees. Eight of the same cases were studied with comparative genomic hybridization (CGH) array to have additional data consistent with mtDNA. In all cases, loss of heterozygosity was studied for D16S496,locus 16q22.1 related to e-cadherin. It appears that no fewer than eight cases were genetically very similar (clonal) with mtDNA. Seven of these cases appeared also clonal with CGH array. It is concluded that in the present series, LN and ILC are genetically related lesions in the majority of cases and that LN might be the precursor of ILC.
Similar content being viewed by others
References
Andersen JA (1974) Multicentric and bilateral appearance of lobular carcinoma in situ of the breast. Acta Pathol Microbiol Scand 82:730–734
Andersen JA (1977) Lobular carcinoma in situ of the breast. Cancer 39:2597–2602
Anderson S, Bankier AT, Barrel BG, de Bruijn MH, Coulson AR, Drouin J, Eperon IC, Nierlich DP, Roe BA, Sanger F, Schreier PH, Smith AJ, Staden R, Young IG (1981) Sequence and organization of the human mitochondrial genome. Nature 290:457–465
Barrett MT, Scheffer A, Ben-Dor A, Sampas N, Lipson D, Kincaid R, Tsang P, Curry B, Baird K, Meltzer PS, Yakhini Z, Bruhn L, Landerman S (2004) Comparative genomic hybridization using oligonucleotide microarrays and total genomic DNA. Proc Natl Acad Sci U S A 101:1765–1777
Bratthauer GL, Tavassoli FA (2002) Lobular intraepithelial neoplasia: previously unexplored aspects assessed in 775 cases and their clinical implications. Virchows Arch 440:134–138
Elsheikh TM, Silverman JF (2005) 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 29:534–543
Etzell JE, DeVries S, Chew K, Florendo C, Molinaro A, Ljung BM (2001) Loss of chromosome 16q in lobular carcinoma in situ. Hum Pathol 32:292–296
Eusebi V, Azzopardi JG (1980) Lobular endocrine neoplasia in fibroadenoma of the breast. Histopathology 4:413–428
Eusebi V, Betts CM, Haagensen DE, Gugliotta P, Bussolati G, Azzopardi JG (1984) Apocrine differentiation in lobular carcinoma of the breast. Hum Pathol 15:134–140
Eusebi V, Feudale E, Foschini MP, Micheli A, Conti A, Riva C, Di Palma S, Rilke F (1994) Long term follow up of in situ carcinoma of the breast. Semin Diagn Phathol 11(n 3):223–235
Eusebi V, Magalhaes F, Azzopardi JG (1992) Pleomorphic lobular carcinoma of the breast: an aggressive tumor showing apocrine differentiation. Hum Pathol 23:655–662
Foote FW, Stewart FW (1941) Lobular carcinoma in situ. Am J Pathol 17:491–500
Foschini MP, Righi A, Cucchi MC, Ragazzini T, Merelli S, Santeramo B, Eusebi V (2006) The impact of large sections and 3D technique on the study of lobular in situ and invasive carcinoma of the breast. Virchows Arch 448:256–261
Frost AR, Tsangaris TN, Silverberg SG (1996) Pleomorphic lobular carcinoma in situ. Pathol Case Rev 1:27–31
Gad A, Azzopardi JG (1975) Lobular carcinoma of the breast: a special variant of mucin-secreting carcinoma. J Clin Pathol 28:711–716
Hwang ES, Nyante SJ, Chen Y-Y, Moore D, DeVries S, Korkola JE, Esserman LJ, Waldman FM (2004) Clonality of lobular carcinoma in situ and synchronous invasive lobular carcinoma. Cancer 100:2562–2572
Kang D, Hamasaki N (2005) Mitochondrial DNA in somatic cells: a promising target of routine clinical tests. Clin Biochem 38:687–695
Kapushesky M, Kemmeren P, Culhane AC, Durinck S, Ihmels J, Korner C, Kull M, Torrente A, Sarkans U, Vilo J, Brazma A (2004) Expression profiler: next generation—an online platform for analysis of microarray data. Nucleic Acids Res 1:465–470
Kimura M (1980) A simple method for estimating evolutionary rate of base substitution through comparative studies of nucleotide sequences. J Mol Evol 16:111–116
Kumar S, Gadagkar SR (2000) Efficiency of the neighbor-joining method in reconstructing deep and shallow evolutionary relationships in large phylogenies. J Mol Evol 51:544–553
Kumar S, Tamura K, Jakobsen IB, Nei M (2001) MEGA2: molecular evolutionary genetics analysis software. Bioinformatics 17:1244–1245
Lakhani SR, Collins N, Sloane JP (1995) Loss of heterozygosity in lobular carcinoma in situ of the breast. J Clin Pathol 48:74–78
Lingjaerde OC, Baumbusch LO, Liestol K, Glad IK, Borresen-Dale AL (2005) CGH-Explorer: a program for analysis of array-CGH. Bioinformatics 21:821–822
Martinez V, Azzopardi JG (1979) Invasive lobular carcinoma of the breast: incidence and variants. Histopathology 3:467–488
Morandi L, Pession A, Marucci G, Foschini MP, Pruneri G, Viale G, Eusebi V (2003) Intraepidermal cells of Paget’s carcinoma of the breast can be genetically different from those of the underlying carcinoma. Hum Pathol 34(12):1321–1330
Nayar R, Zhuang Z, Merino MJ, Silverberg SG (1997) Loss of heterozygosity on chromosome 11q13 in lobular lesions of the breast using tissue microdissection and polymerase chain reaction. Hum Pathol 28:277–282
Nei M, Kumar S (1994) MEGA: Molecular Evolutionary Genetics Analysis software for microcomputers. Comput Appl Biosci 10:189–191
O’Hagan RC, Brennan CW, Strahs A, Zhang X, Kannan K, Donovan M, Cauwels C, Sharpless NE, Wong WH, Chin L (2003) Array comparative genome hybridization for tumor classification and gene discovery in mouse models of malignant melanoma. Cancer Res 63:5352–5356
Ottesen GL, Graversen HP, Blichert-Toft M, Zedeler K, Andersen JA (1993) Lobular carcinoma in situ of the female breast short-term results of a perspective nationwide study. Am J Surg Pathol 17(1):14–21
Page DL, Schuyler PA, Dupont WD, Jensen RA, Plummer WD, Simpson JF (2003) Atypical lobular hyperplasia as a unilateral predictor of breast cancer risk: a retrospective cohort study. Lancet 361:125–129
Reis-Filho JS, Simpson PT, Jones C, Steele D, Mackay A, Iravani M, Fenwick K, Valgeirsson H, Lambros M, Ashworth A, Palacious J, Schmitt F, Lakhani SR (2005) Pleomorphic lobular carcinoma of the breast: role of comprehensive molecular pathology in characterization of an entity. J Pathol 207:1–13
Saitou N, Nei M (1987) The neighbor joining method: a new method to reconstructing phylogenetic trees. Mol Biol Evol 4:406–425
Sanchez-Estevez C, Guo M, Herman JG, Gamallo C, Esteller M, Palacios J (2003) Epigenetic and genetic alterations of APC and CDH1 genes in lobular breast cancer: relationships with abnormal E-cadherin and catenin expression and microsatellite instability. Int J Cancer 106:208–215
Sieben NLG, Haar NT, Cornelisse CJ, Fleuren GJ, Cleton-Jansen AM (2000) PCR artifacts in LOH and MSI analysis of microdissected tumor cells. Hum Pathol 31:1415–1419
Soares J, Tomasic G, Bucciarelli E, Eusebi V (1994) Intralobular growth of myoepithelial cell carcinoma of the breast. Virchows Arch 425:205–210
Tavassoli FA (1999) Pathology of the breast. Appleton—Lange, Stamford, CT
Tot T (2003) The diffuse type of invasive lobular carcinoma of the breast: morphology and prognosis. Virchows Arch 443:718–724
Vos CB, Cleton-Jansen AM, Berx G (1997) E-cadherin inactivation in lobular carcinoma in situ of the breast: an early event in tumori-genesis. Br J Cancer 76:1131–1133
WHO (2003) Tumours of the breast and female genital organs. IARC Press, Lyon
Woischnik M, Moraes CT (2002) Pattern of organization of human mitochondrial pseudogenes in the nuclear genome. Genome Res 12:885–893
Acknowledgements
This work was supported by grants number 2002064975 and 2005063089 (COFIN) from the Ministry of University and Research (MIUR).
The authors thank Dr. Alberto Goldoni (from Medical Genetics Unit, S. Orsola-Malpighi Hospital, University of Bologna) for the bioinformatics support.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Morandi, L., Marucci, G., Foschini, M.P. et al. Genetic similarities and differences between lobular in situ neoplasia (LN) and invasive lobular carcinoma of the breast. Virchows Arch 449, 14–23 (2006). https://doi.org/10.1007/s00428-006-0192-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00428-006-0192-7