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Other Guidelines
The management of lobular carcinoma in situ (LCIS). Is LCIS
the same as ductal carcinoma in situ (DCIS)?
Molecular genetics
There has been an explosion of new and innovative techniques for
molecular genetic analysis. This is resulting in the generation of new data on
the molecular alterations present in both preinvasive and invasive lesions. In
breast cancer, it is hoped that this new information will help elucidate
pathogenesis in terms of precise chromosomal events. In addition, in cases such
as ALH and LCIS wheremorphologic and immunohistochemical classification remains
controversial, molecular analysis may clarify the uncertainties.
Comparative genomic hybridisation (CGH) analysis is a technique
where ''test'' DNA is compared with normal DNA on metaphase chromosome spreads
to assess DNA copy number changes. Computer-aided analysis can identify
chromosome loci that differ from normal. These loci are potential sites of, for
example, amplifications of oncogenes or losses of tumour suppressor genes. This
method can be applied to paraffin-embedded tissue, and with the use of laser
capture microdissection, allows for precise analysis of even small lesions such
as ALH/LCIS. Loss of heterozygosity (LOH) studies refer to identification of
loci in test DNA that have ''lost'' one copy of a gene, presumably through DNA
deletion. This event is often associated with loss of a tumour suppressor gene.
CGH analysis of LCIS and ALH
[45] has demonstrated loss of material from chromosomes 16p, 16q,
17p, and 22q and gain of material from 6q at a similar high frequency in both
lesions. Losses at 1q, 16q, and 17p are also seen in ILCs
[46]
[47]. LOH data in LCIS are limited but do demonstrate a similarity
between LCIS and ILC
[48]
[49]. E-cadherin is a candidate tumour suppressor gene on 16q22.1 that
is involved in cell-cell adhesion and in cell cycle regulation through the
catenin/Wnt pathway
[50]. Most IDCs of no special type (NST) have been shown to exhibit
positive staining by immunohistochemistry, whereas most ILCs are negative
[19]
[20]. Berx et al
[51]
[52]. consistently identified protein-truncating mutations in ILCs but
failed to demonstrate mutations in other subtypes. Roylance et al.[53]
also failed to find any pathogenic mutation in lowgrade IDCs. The LOH at 16q
(the locus of the E-cadherin gene) found in lobular carcinomas is usually
accompanied by truncating mutations or gene promoter methylation, and absent
staining by immunohistochemistry
[41] [53].
E-cadherin staining has also been identified in DCIS, and although
the molecule is expressed in normal epithelium, staining is rarely seen in
LCIS. Recently, some authors have advocated the use of E-cadherin as an adjunct
antibody in the differentiation of LCIS from DCIS
[22]
[23] [39] [54].
In addition, Vos et al.41 have demonstrated the same truncating mutation in the
E-cadherin gene in LCIS and the adjacent ILC. The data provide strong evidence
for the role of E-cadherin gene in the pathogenesis of lobular lesions and
support the hypothesis for a precursor role for LCIS.
In addition to lobular breast carcinoma, E-cadherin mutation has
been linked to the pathogenesis of diffuse gastric carcinoma. In cases of
familial predisposition to diffuse gastric cancer, a germline mutation of
E-cadherin has also been demonstrated in up to one third of the cases. In
contrast, apart from anecdotal cases
[55], no such germline mutations have been identified in cases of
familial LCIS and ILC, despite the clear pathogenetic role of E-cadherin
mutation in these lesions.
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