Pertinent Issues Related to In Situ and Invasive Lobular Carcinoma
in Contemporary Breast Carcinoma Patients
William Beaumont Hospital
Royal Oak, MI
Large bore needle core biopsies have become the standard method of initial diagnosis for
most patients. These specimens engender a novel set of issues that were not operative in open biopsy and
mastectomy specimens. This presentation will address the issues that pertain to lobular neoplasia.
For many years lobular carcinoma in situ (LCIS) has been considered and treated as a prognostic
marker of increased risk of bilateral carcinoma rather than a direct precursor lesion
Recent studies have that treatment other than tamoxifen for usual-type low-grade LCIS is probably not
indicated since the long-term risk of subsequent invasive carcinoma or DCIS is sufficiently low
. These observations and outcomes were based on open biopsy specimens/ partial mastectomy
specimens in which ALH or LCIS was the only lesion present in the specimen.
| Question 1: Is a subsequent excisional biopsy warranted if (only) atypical lobular hyperplasia (ALH) or LCIS is found in a needle core biopsy?|
The long-term outcome risks of isolated ALH/ LCIS found in an open (excisional) biopsy
specimen is unrelated to the issue of using ALH/ LCIS as a tissue marker of neoplastic processes in the
adjacent, unsampled, breast parenchyma.
Retrospective needle core-excisional biopsy correlation studies have produced generally
affirmative results. A few authors concluded that subsequent excisional biopsy is not warranted when
ALH/LCIS is the only finding
, whereas most have concluded that follow-up excisional biopsy
around the needle core biopsy tract or marker clips is appropriate
. Some authors
included additional decision factors such as whether the needle core biopsy was performed for a mass
lesion or whether there were residual microcalcifications in the adjacent parenchyma. Given the
limitations of small numbers of studied cases and variations in institutional practice parameters,
widespread implementation of these factors is dubious. The association of a significant lesion in the
adjacent parenchyma when only ALH or LCIS is found in a needle core biopsy appears to be similar to the
rate when only ADH is present in the needle core biopsy. Approximately 10% - 20% of subsequent
excisional biopsy specimens will have DCIS or invasive carcinoma when only ALH or LCIS is present in the
needle core biopsy. The rate of coexistent, adjacent tissue malignancy is increased when additional
lesions, such as ADH are present with the ALH/ LCIS in the same needle core biopsy specimen.
In the context of a marker for adjacent tissue malignancy, a new question is raised,
whether ALH/ LCIS can be a direct precursor lesion? Almost all evidence supports an affirmative
response. Morphologically, microinvasive lobular carcinoma in association with LCIS has been reported
. Genetic studies have found similar or identical mutations in LCIS and the
corresponding invasive lobular carcinoma supporting that LCIS can be a direct precursor lesion to
. On a side note: that LCIS is a precursor lesion yet is treated as
a prognostic risk marker is best explained by the comments of Dr Fisher based on NSABP data; that LCIS
was a direct precursor lesion, similar to, but more indolent than grade 1 DCIS .
| Conclusion: ALH/ LCIS alone on a needle core biopsy should be followed by an excisional biopsy of the target area.|
| Question 2: How does E-cadherin immunohistochemistry help establish distinguish between LCIS and DCIS and what does focal or inconclusive staining mean?|
E-cadherin is a calcium-dependent, transmembrane protein responsible for the majority of
intercellular adhesion and cell-polarity by binding to E-cadherin molecules of adjacent epithelial cells.
The cytoplasmic region of E-cadherin is bound to the actin cytoskeleton by binding to β- or
γ-catenin, which are bound α-catenin that is attached to actin filaments.
The E-cadherin gene, named CDH1 consists of 16 exons (a
large gene) on 16q22.1. Lobular neoplasia (LCIS and invasive lobular carcinoma) are genetically
characterized by a unique set of CDH1 biallelic mutations which distinguish it from ductal and other
types of carcinoma. Most commonly in LCIS, one CDH1 gene is inactivated by a frameshift insertion,
deletion or nonsense mutation that produces a truncation mutation of the E-cadherin protein and the
second allele is inactivated by either a large pan-gene deletion [termed loss of heterozygosity (LOH)] or
CDH1 promoter gene inactivation due to hypermethylation. Approximately 80% of the second CDH1 gene
inactivations are due to LOH and 20% are caused by promoter gene hypermethylation.
The truncated, mutant E-cadherin protein is no longer able function appropriately and bind to the
E-cadherin molecules of other cells, resulting in the complete absence of functional E-cadherin and
complete cellular dyshesion. Depending where the mutation occurs in the CDH1 gene alters the
immunohistochemical staining pattern in lobular carcinoma. Truncation mutations of the transmembrane or
extracellular segments of E-cadherin leads to the inability of E-cadherin to localize to the membrane and
the truncated protein becomes soluble. This results absent membrane immunohistochemical staining and
sometimes diffuse faint cytoplasmic reactivity, depending where the truncation mutation occurred.
Truncation mutations within the proximal cytoplasmic segment of E-cadherin results is a nonfunctional
protein due to interruption of the binding of β- or γ-catenin. In some of these cases, a
shortened, but intact transmembrane E-cadherin protein is produced which results in focal, punctate
membrane staining. Truncation mutations that occur in the C-terminal 72 AA conserved region of
E-cadherin directly impact the binding site of β- or γ-catenin. Since E-cadherin is bound to
β- or γ-catenin within endoplasmic reticulum before it migrates to the membrane, there is strong
staining of the perinuclear region of cells and absent membrane immunoreactivity
Importantly, ductal carcinomas can also show no or decreased E-cadherin immunoreactivity.
I have encountered rare grade 1 ductal carcinomas (almost all have been tubular) with intact, well-formed
ducts with no E-cadherin. This phenomenon has been noted by several authors and is used as evidence that
loss or decreased E-cadherin expression is an epiphenomenon in ductal carcinomas whereas it is an early
and necessary molecular event in most, if not all lobular carcinomas. Decreased and absent E-cadherin
immunoreactivity results from a different series of molecular events in ductal carcinomas than in lobular
carcinomas. The CDH1 gene is prone to large deletions which can be identified by the LOH assay. As
mentioned previously, large LOH-level deletions of one CDH1 gene occurs in most lobular carcinomas
(>90%). Similar, large deletions of the CDH1 gene also occur in ductal carcinomas. In the William
Beaumont Hospital molecular laboratory, approximately 50% of grade 2 ductal carcinomas and 80% of grade 3
carcinomas have a LOH deletion mutation of one CDH1 gene (making it a useful marker to include in
molecular clonality assays). Unlike lobular carcinomas, ductal carcinomas do not incur point mutations
of the second CDH1 gene that produce truncated E-cadherin proteins. Higher grade ductal carcinomas also
have numerous somatic mutations that occur throughout the genome, of which deletion mutations in
β-catenin are especially common. Mutations in any of the catenin genes alters or prevents normal
E-cadherin function, leading to decreased immunoreactivity and usually a focal dyshesive infiltrative
growth pattern. Usually, the altered E-cadherin staining in ductal carcinomas is decreased intensity or
retained partial membrane reactivity. It is rare to see a complete absence of E-cadherin staining in
ductal carcinoma. Lastly, E-cadherin antibody is prone to produce focal membranous staining in poorly
fixed tissues, possibly due to retained, agglutinated antibody within the clefts of cell stromal
| Conclusion: Only the complete absence of E-cadherin membrane staining is supportive of lobular carcinoma. Because punctate membrane immunoreactivity can occur in a small minority of lobular and many ductal carcinomas, this pattern should be interpreted as noncontributory. Focal membrane reactivity is characteristic of many ductal carcinomas and is not a pattern seen in lobular carcinoma. |
| Question 3: What is the morphologic definition of lobular carcinoma and why is this important?|
It may seem strange to include this question at the end of a discussion pertaining to the
lesion. However, as molecular events become better characterized, immunohistochemical staining patterns
become dogma, it is worthwhile in my opinion to ask this question in order to improve the accuracy and
consistency of contemporary surgical pathology. A poll of practicing surgical pathologists would
probably find that most are of the opinion that they can clearly define the entity and that their
criteria are within the range of standard practice parameters. In this context, a recent SEER analysis
reported the incidence of lobular carcinoma increased 1.65x from 1987 to 1999
carcinomas constituted 9.5% of all carcinomas in 1987 compared to a 15.6% proportion in 1999. It is
doubtful that this increase can be attributed to simply to biology. I propose that the major factor
behind this increase is the imprecise application of lobular carcinoma by pathologists. It is my
anecdotal experience that lobular carcinoma is used by some for carcinomas with even a focal area of
dyshesive growth pattern. In support if this opinion is data showing that the reproducibility of the
diagnosis of invasive lobular carcinoma is poor with kappa values between general surgical pathologists
for pure invasive lobular carcinoma and for the presence of an invasive lobular carcinoma component of
0.31 and 0.32, respectively which was only marginally better among pathologists experienced in breast
pathology (0.43 and 0.46) . The importance of lobular carcinoma as a morphologic subtype of
carcinoma is increasing, not decreasing. It is one of the principle indications for a preoperative
breast MRI. Many surgeons consider it a more difficult lesion to adequately treat with breast conserving
therapy. A recent study concluded that lobular carcinoma responds less favorably to neoadjuvant
chemotherapy than ductal carcinoma . There is increasing pressure for pathologists not to
miss lobular carcinoma and it is therefore used more indiscriminately for all tumors with a dyshesive
growth pattern. An extreme example of this is the entity of pleomorphic lobular carcinoma. Initially
coined to distinguish it from classical-type lobular carcinoma , numerous studies have
seemingly merged it back with classical lobular carcinoma, despite sharing no histological, clinical,
mammographic, prognostic, or genetic similarities with classical lobular carcinoma
Higher grade ductal carcinoma often have a dyshesive, single cell infiltrative pattern of
growth around its periphery. As mentioned previously, a dyshesive growth pattern in ductal carcinoma is
usually due to somatic mutations in one of the catenin genes. The catenins, especially β-catenin
act as 'nuts' and cement to anchor the transmembranous E-cadherin molecule in place. Somatic mutations
typically accrue during mitoses, so it is not surprising to see dyshesive infiltrative pattern at the
peripheral, infiltrating edge of higher grade ductal carcinomas. Since needle core biopsies most
commonly sample the periphery of carcinomas (especially large neoplasms), the dyshesive growth pattern is
disproportionately represented, possibly facilitating the opportunity for pathologists to diagnose these
areas as invasive lobular carcinoma. Being cognizant of this phenomenon and the morphologic
identification of higher grade nuclei and or abortive ducts should allow pathologists to classify these
lesions as ductal carcinoma in my opinion.
| Conclusions: Lobular carcinoma, as a diagnostic entity should be restricted to a completely dyshesive, grade 1 nuclear invasive carcinoma. Although mixed lobular-ductal carcinoma occur, they are extremely rare. Higher grade carcinomas or those with focal abortive duct formation that is admixed with dyshesive, similar nuclear grade carcinoma should be classified as ductal carcinoma in my opinion.|
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