38
Lobular Carcinoma in Situ of the Breast
KRISTINE E. CALHOUN AND BENJAMIN O. ANDERSON
obular neoplasia is the overarching nomenclature used to
L describe the spectrum of proliferative but noninfiltrative
changes seen within the lobular units of the breast. Lobular
neoplastic lesions include atypical lobular hyperplasia (ALH) and
lobular carcinoma in situ (LCIS), each of which is associated with
an increased risk of developing a subsequent invasive breast cancer
(IBC).1,2 Pathologically, lobular neoplasia is diagnosed when the
acini of the terminal duct lobular units are filled and distended
by small, uniform, loosely cohesive cells.3 fte distinction between
ALH and LCIS has historically been based on the degree of his-
tologic change observed by the pathologist. At the cellular and
proteinomic levels, ALH and LCIS have striking similarities to
invasive lobular cancers (ILC) with most staining positive for
estrogen receptors (ERs), having low proliferative index rates, and
being ErbB2 (HER2/neu) negative.3
Although recognized since the 1940s as a unique histopath-
ologic finding, controversy remains regarding both the clinical
significance and overall invasive malignant potential of LCIS.
LCIS is a marker for the development of invasive carcinoma,
but the location for that subsequent cancer is not confined to
the site at which LCIS was found. Actually, LCIS is a significant
breast cancer risk factor for subsequent cancer in both breasts
and with either ductal or lobular histology. Analogous to ductal
carcinoma in situ (DCIS) and invasive ductal carcinoma, genetic
evidence suggests that LCIS can be a nonobligatory precursor of
ILC. However, the frequency with which malignant progression
from LCIS to ILC actually occurs remains an area of vigorous
debate. From a diagnostic perspective, management dilemmas
continue as to whether LCIS requires surgical excision when it
is seen on percutaneous needle sampling or if there are cases in
which no further workup beyond needle biopsy is required. At
the opposite extreme, there is debate if some LCIS cases should
be removed with negative surgical margins after open surgical
biopsy for therapeutic purposes, which then begs the question of
whether radiation therapy should be offered to these potentially
more aggressive cases. Although treatment strategies have evolved
from routine mastectomy to surveillance since LCIS was first
described,4 some in the medical community continue to question
whether more aggressive intervention should occur in selected
LCIS cases.
fte purposes of this chapter are to define the historical back-
ground that led to our current understanding of LCIS biology,
delineate histopathologic features of classic and “pleomorphic”
LCIS, discuss the clinical presentation and natural history of
LCIS, examine the evidence for and against routine surgical exci-
sion after the diagnosis of LCIS on image-guided sampling, review
the role for chemoprevention in LCIS management, and discuss
the role of surgical prophylaxis for LCIS in the small subgroup of
patients for whom it may be appropriate.
Historical Background
LCIS as a Premalignant Lesion
Lobular neoplasia was initially described in 1941 when Foote and
Stewart published their classic report of LCIS.4 At that time, LCIS
was generally seen in conjunction with ILC, as illustrated in
Godwin’s 1952 case report in which he describes it as a premalig-
nant lesion.5 Because LCIS was believed to be an obligate precur-
sor to invasive cancer, mastectomy was initially recommended as
an appropriate therapeutic procedure after its histologic diagnosis
on breast biopsy, and this remained the standard of care for the
next 40 years. Today we recognize the selection bias from that
period before mammographic screening when all breast cancers
were diagnosed as clinically detected findings such as palpable
masses. In today’s era of mammographic imaging and needle
biopsy, we are now able to examine lobular neoplasia in isolation
and recognize that early reports greatly exaggerated its malignant
potential (Table 38.1).4–11
LCIS as a Risk Factor for Invasive Breast Cancer
and Lobular Neoplasia
In the late 1970s the dominant belief that LCIS required thera-
peutic mastectomy was questioned when Haagensen at Columbia
and Rosen at Memorial Sloan-Kettering both independently
began to advocate for less drastic management.9,12 In Haagensen’s
series, 211 women with pure LCIS underwent excision alone and
were followed for evidence of development of subsequent IBC.
Of the women, 10% developed an ipsilateral breast cancer, and
9% were subsequently diagnosed with a contralateral invasive
tumor.9 When occurring in the same breast, the invasive cancers
were not always found at the original LCIS biopsy site. Haagensen
argued that LCIS is better described as a risk factor than a prein-
vasive cancer because longitudinal series show IBC of either ductal
or lobular histology developing in either breast with similar fre-
quency. As a risk marker for cancer, bilateral mastectomy was felt
to be overly aggressive and largely unnecessary in the setting of
LCIS.
To dissuade surgeons from managing LCIS as a malignant
lesion warranting mastectomy, Haagensen and colleagues recom-
mended reclassifying LCIS as lobular neoplasia, thus eliminating
the word carcinoma from the name and removing any distinc-
tion between ALH and LCIS.9 ftey reasoned that avoiding
553
554 SECTIONI IXI Current Concepts and Management of Early Breast Carcinoma (Tis, Tmic, T1)

TABLE
38.1 Evolution of Lobular Carcinoma in Situ (LCIS)

1865 Cornil6 Described intraepithelial breast

carcinoma in lobules
1919 Ewing7 Published photomicrographs of
LCIS
1931 Cheatle and Cutler8 Challenged whether malignant-
appearing cells confined to
lobules/ducts were
“precancerous”
1941 Foote and Stewart4 Coined term lobular carcinoma in
situ
1950s LCIS generally seen together with
invasive cancer, assumed to be
premalignant hazard • Fig. 38.1 Histologic spectrum of classic lobular carcinoma in situ. Low-
1952 Godwin5 Suggested that LCIS evolves into grade monotonous appearing nuclei with scant cytoplasm—so-called
ILC; recommended type A cells.
mastectomy for treatment
1978 Haagensen et al.9 Defined lobular neoplasia (ALH LCIS similarly continues to be included in the National Compre-
and LCIS) as fundamentally hensive Cancer Network (NCCN) Breast Cancer Guidelines,
benign
although specific cancer management is not recommended if the
1980s LCIS shifts to being identified as classic form of LCIS alone is identified at biopsy.14 Inclusion in
a risk factor for invasive cancer guideline documents is unfortunate because it can perpetu-
cancer ate concern among women diagnosed with LCIS and stimulate
1996 Frost et al.10 Describes pleomorphic LCIS fear that they too have breast cancer, when they fundamentally
11
do not.
2000 Middleton et al. Proposes relationship between
pleomorphic LCIS and
pleomorphic ILC LCIS Histopathology
Morphologic Features of LCIS
fte histologic distinction between lobular and ductal neoplastic
mastectomy was appropriate because of both the low incidence of processes was initially based on location in the ductal-lobular
subsequent breast cancer observed and the nearly equal hazard of system and differences in cytologic characteristics. In their original
contralateral breast cancer, which would be left unaddressed by a 1941 description, Foote and Stewart described LCIS as a prolif-
unilateral mastectomy. In a 21-year follow-up study of Haagensen eration of small, uniform, discohesive cells filling and often dis-
and colleagues’ original patients, among the 99 patients available tending the acinar units within a lobule.4 In this classic form of
for follow-up, 24% developed either DCIS or IBC, far lower LCIS, the nuclei are round, have indistinct nucleoli, uniform
than the rates that would be expected with an obligate precur- chromatin and a distinctly monotonous, low-grade appearance
sor malignant lesion.13 Observation in place of mastectomy was with minimal mitotic activity (Fig. 38.1). fte lobular-based pro-
gradually accepted as adequate management for lobular neoplasia, liferation of LCIS is typically solid, without the architectural
leading ultimately in the 1990s to the abandonment of routine lumen formation typical of cribriform pattern DCIS. Lobular
mastectomy after an LCIS diagnosis. proliferations that fill and distend at least 50% of the acini in a
lobule are classified as LCIS, whereas involvement of less than
Continued Definition of LCIS as a Unique 50% of the acini is considered ALH (Fig. 38.2). Because this
definition of lobular distention can be subjective and the 50%
Stage 0 Preinvasive “Cancer” threshold is somewhat arbitrary, some pathologists prefer the all-
Despite a growing body of supportive evidence, there still exists encompassing term lobular neoplasia, whereas others favor the
some resistance to the hypothesis that lobular neoplasia represents separate terminology, arguing that it remains clinically useful
a single pathologic entity of limited malignant potential. Several because LCIS conveys a higher IBC risk than does ALH. Page
large professional entities, including the Surveillance, Epidemiol- and colleagues estimated that ALH conveys a four- to fivefold
ogy, and End Results (SEER) Program, the National Surgical increased invasive cancer risk, whereas LCIS conveys a full nine-
Adjuvant Breast and Bowel Program (NSABP) and the American fold increased risk in the absence of endocrine suppression.15
Joint Commission on Cancer, have continued to classify LCIS as LCIS frequently extends beyond the lobules to involve the
a Stage 0 lesion at this time, although significant discussion ductal system. ftis pattern of spread has a Pagetoid appearance,
regarding whether this should be the case is underway and this meaning that the neoplastic cells infiltrate from the lobule down
designation may change. Despite this classification, there is agree- into the adjacent duct, separating the basement membrane from
ment that observation rather than mastectomy is now the pre- the overlying epithelium, displacing and often attenuating the
ferred course of treatment when lobular neoplasia is diagnosed. normal ductal epithelial layer (Fig. 38.3). As with other etiologies,

• Fig. 38.2 cLionboumlaar car in situ. This acinus is completely filled with
loosely cohesive, small round cells with hyperchromatic nuclei. The cells
are evenly spaced and markedly distend the acinar space. (400×.)
• Fig. 38.3 Pagetoid extension of lobular carcinoma in situ up a duct.
there can be significant variation in the degree and extent to which
LCIS involves the breast. Uncommonly, classic LCIS will appear
especially florid, with markedly distended lobules and foci of
necrosis. ftese cases can be difficult to distinguish from DCIS,
which more classically contains this type of central necrosis. 16
Expression of the cell adhesion molecule E-cadherin (E-cadherin)
is typically lost in LCIS and retained in DCIS, making the use of
immunohistochemistry staining for this marker useful in this dif-
ferential (Fig. 38.4).17–19
Pleomorphic LCIS
ftere have been multiple descriptions of LCIS showing an in situ
lobular pattern of growth similar to the classic LCIS form (see
Fig. 38.1) but a high-grade, pleomorphic cytology that more
resembles the aggressive phenotype of high-grade DCIS.9,11,20-23
Such lesions have been variably called pleomorphic LCIS (Fig.
38.5). In contrast to the monomorphic cells of classic LCIS,
pleomorphic LCIS cells have marked nuclear atypia, demonstrate
variation in size and have frequent to abundant mitotic activity.
fte pleomorphic form of LCIS more frequently contains central
comedo necrosis, making its appearance strikingly similar to
CHAPTER 38 Lobular Carcinoma in Situ of the Breast 555
• Fig. 38.4 Loss of epithelial cadherin (E-cadherin) expression supports
the lobular phenotype of the process. Thin, attenuated E-cadherin positive
normal ductal cells are still present.
• Fig. 38.5 Pleomorphic lobular carcinoma in situ has high-grade nuclei
and is often associated with comedo-type necrosis, closely mimicking
high-grade comedo ductal carcinoma in situ.
comedo-type high-grade DCIS. In the past, pleomorphic LCIS
was commonly diagnosed as high-grade DCIS by pathologists
who were concerned that the high-grade cytology represented an
aggressive in situ process that should be managed as such. A
molecular factor that distinguishes lobular from ductal pathology
is the expression of E-cadherin, a cellular adherence protein that
is present in ductal pathology but is absent in lobular disease. fte
development of an immunohistochemical test for E-cadherin
helped standardize pathology interpretation and is now a standard
discriminating test when the in situ morphology is unclear or
ambiguous. Histologic clues to this diagnosis include finding a
discohesive appearance within a solid, high-grade in situ lesion,
the presence of intracytoplasmic lumens or the coexistence of
classic LCIS. E-cadherin staining is often required for confirma-
tion that the cells are lobular in origin. It has been speculated that
pleomorphic LCIS may have an increased likelihood of being
associated with ILC and, in particular, its pleomorphic subtype
that is among invasive cancers known to be more biologically
aggressive.11,17,19-20,23
556 SECTIONI IXI Current Concepts and Management of Early Breast Carcinoma (Tis, Tmic, T1)

Immunohistologic Features and Molecular TABLE Selected Long-Term Follow-up Studies of

38.2 Patients With Lobular Carcinoma in Situ
Genetics of LCIS
Most often, classic LCIS is strongly positive for ER expression Haagensen, 198635
and, in keeping with its low-grade biology, rarely demonstrates Mean follow-up, years 14.7
HER2 overexpression or p53 alterations.24,25 ftis behavior con-
trasts with pleomorphic LCIS, which typically has lower levels of Ipsilateral cancer 11%
ER expression and can be positive for HER2 overexpression or Contralateral cancer 27/258 (10%)
contain p53 alterations, factors that all suggest a more aggressive 36
behavior at the cellular level.11,23 Molecular analysis of pleomor- Anderson, 1974
phic LCIS suggests that although it is highly likely to contain Mean follow-up, years 15
some of the same molecular alterations seen in classic LCIS (such
as 1q gains and 16q losses), it frequently has accumulated addi- Ipsilateral cancer 20%
tional alterations that are more typical of high-grade ductal Contralateral cancer 17%
carcinomas.26,27 37
Wheeler et al., 1974
Mean follow-up, years 15.7
Clinical Presentation, Natural History, and Ipsilateral cancer 4%
Biologic Significance of LCIS Contralateral cancer 15%
Clinical Features of LCIS P1a9g9e1etal., 15

LCIS typically presents as an asymptomatic, occult lesion inciden- Mean follow-up, years 19
tally discovered during histologic workup for another clinical or Ipsilateral cancer 15%
radiographic indication. Only rarely will LCIS present as a dis-
crete lesion seen either by mammogram or ultrasound.28 It is even Contralateral cancer 10%
less common for lobular neoplasia to present as a clinically pal- R1o9s7e8net al., 12

pable mass. Most instances of LCIS are incidentally discovered on

breast biopsy conducted for another reason. Although fewer than Mean follow-up, years 24
5% of breast biopsies performed for benign conditions ultimately Ipsilateral cancer 22%
yield a diagnosis of LCIS, it is hypothesized that the true inci-
dence may be much higher in the general female population Contralateral cancer 20%
because a large number of women with lobular neoplasia remain K2i0n1g5et al., 34

undiagnosed as they have no other indication for breast biopsy.3,29

LCIS is commonly widespread in the breast, with patterns that
are multifocal, multicentric, and/or bilateral. Early publications
detailed its multifocal nature,4,30 noting that when patients under-
went mastectomy after surgical biopsy showing LCIS, the breast
specimen commonly had residual disease in areas outside the
biopsy cavity, with a diffuse speckled, microscopic distribution
through multiple lobules of a given region. Rosen and colleagues
observed that LCIS was commonly multicentric, being present in
multiple quadrants of the breast in 24 of 50 (48%) mastectomy
specimens.31 Beute and colleagues found that among 119 patients
diagnosed with LCIS between 1974 and 1987 in their institution,
82 had both breasts sampled either by mirror-image biopsy or
contralateral mastectomy. Of these, LCIS was found to be bilat-
eral in half (41/82) of the patients.32
Risk of Subsequent Invasive Carcinoma After
LCIS Diagnosis
Women diagnosed with LCIS are typically quoted to have an 8- to
10-fold increased lifetime risk for developing breast cancer in both
the ipsilateral and the contralateral breast.14 fte absolute risk of
breast cancer after LCIS is 20% to 25% after 20 years.33 Mathe-
matical modeling suggests that during the first 15 years after
biopsy, women with LCIS have 10.8 times the risk of breast cancer
development compared with women of comparable age who lack
proliferative disease findings on breast biopsy.15 A more recent
publication from Memorial Sloan Kettering Cancer Center exam-
ining 29 years of clinical surveillance reported a 15.8% rate of
Mean follow-up, years 29
Ipsilateral cancer 10%
Contralateral cancer 5%
subsequent breast cancer development among 1060 women diag-
nosed previously with LCIS.34 fte majority of the cancers were
ipsilateral (63%), with 25% contralateral and 12% bilateral with
both ductal and lobular invasive histology. Chemoprevention was
the only factor found on multivariate analysis to influence breast
cancer risk, substantially decreasing it.34 On average, they found
a 2% annual incidence of breast cancer development in the setting
of a prior diagnosis of LCIS.
In general, the risks of cancer in the ipsilateral and the contra-
lateral breast are approximately equal, as shown in multiple lon-
gitudinal studies of patients diagnosed with LCIS by surgical
biopsy (Table 38.2).12,15,34–37 ftese studies illustrate the primary
reason that LCIS is not typically treated surgically with lumpec-
tomy: the only logical operation would be a bilateral mastectomy,
which would be unnecessary approximately 80% of the time.
It is possible that some subgroups of LCIS may exhibit a more
aggressive unilateral biology and preinvasive behavior. fte extent
of LCIS (few lobules vs. extensive disease) and subtyping based
on classic versus pleomorphic histopathology has not always been
a standard part of pathology reports. As a result, retrospective
analysis of population-based data is challenging, and additional

prospective data are necessary to answer this question. Rendi
and colleagues attempted to provide more clarity on whether
the amount of LCIS seen at core needle sampling had any cor-
relation with the risk of identifying subsequent invasive disease.
In their study of 106 patients with pure lobular neoplasia diag-
nosed on core sampling, they found that among the 33 patients
with pure LCIS, the upgrade rate at excision for malignancy was
4.4% and only occurred when extensive (more than four foci)
of LCIS was present initially.38 Such findings have allowed the
NCCN screening and diagnosis panel to suggest that for indi-
viduals with classic LCIS on core sampling where the finding is
concordant with breast imaging findings, surveillance alone is
sufficient and surgical excision may not be necessary for definitive
diagnosis.39
Female Steroid Hormones and LCIS
Changing Incidence Rates of LCIS and the
Influence or Exogenous Hormones on
Lobular Carcinogenesis
fte incidence rates of ILC increased steadily from 1977 to 1999,
whereas the incidence rates of IDC increased at a similar rate until
1987 and then leveled off until 1999.40,41 Since 1999, however,
rates of both ILC and IDC have declined by approximately 4%
per year.42 LCIS incidence rates increased in parallel with ILC
rates from 1977 to 1999, although rates of LCIS held steady from
1999 to 2006, despite a decline in ILC during that same time
period. On the basis of available SEER data from the United
States, LCIS rates are highest among women aged 50 to 69 years,
but although diagnosis of LCIS increased up until 2006 for
women aged 30 to 49 and aged 70 years or older, rates fell after
2002 among women 50 to 69 years of age. In contrast, ILC rates
remain highest among women 70 years of age or older, with
declines in ILC cases since 2002 among both 50- to 69-year-old
women and those aged 70 years and older. ILC rates among
women 30 to 49 years of age have increased slowly over the past
30 years but remain much lower than the rates seen among
women 50 years of age and older.
Rising rates of all lobular pathology through 2002, as well
as their subsequent fall, may be related to changing patterns of
combined estrogen and progestin menopausal hormone therapy
(CHT) use. Although it is established that CHT use increases
breast cancer risk,4,5 almost all studies that have reported on
associations between CHT and risk of ILC versus IDC indi-
cate that this association varies by histologic type.9,12,13 In these
studies, CHT use is associated with 2.0- to 3.9-fold increases
in ILC risk, but has much less of an impact on IDC risk. fte
publication of the Women’s Health Initiative randomized trial
results of CHT use in 2002, which demonstrated that the risks
of long-term CHT use (for >5 years) outweighed its benefits,
resulted in a dramatic decline in the use of CHT among women
worldwide. It has been hypothesized that abrupt cessation in
CHT use is at least partially responsible for the decline in total
breast cancer rates after 2002 observed in the United States and
may account for the drop in ILC and LCIS incidence rates since
2002 primarily among women most likely to be CHT users, those
50 to 69 years of age. Despite this reasonable hypothesis, others
have argued that saturation of screening, and not a decrease in
CHT use, may be a greater contributor to the decline in overall
breast malignancy rates demonstrated since 2002.42 Interestingly,
CHAPTER 38 Lobular Carcinoma in Situ of the Breast 557
a more recent SEER database study suggests that the rate of
LCIS increased from 2.00 in 100,000 patients in 2000 to 2.75
in 100,000 patients in 2009.43
In general, lobules become atrophic and tend to disappear after
menopause unless the patient is taking hormone therapy. Despite
this finding, Wellings and colleagues reported that some human
mammary lobules persist after menopause and certain atypical
lobules are morphologically similar to preneoplastic alveolar
nodules that occur in strains of mice with a propensity for devel-
oping mammary carcinoma.44 ftey suggest that these persistent
atypical mammary lobules could be precancerous in human
beings. ftese findings might help explain why ILC rates are
highest among women 70 years of age and older.
Not all cases of LCIS are diagnosed in the postmenopausal
setting. A recent publication by McEvoy and colleagues identified
58 women with atypical breast lesions, including eight with pure
LCIS, diagnosed under age 35 years. At median follow-up of 86
months, seven of the cohort had developed breast cancer, with
four among those initially found to have LCIS, two whose initial
lesion was ALH and one whose initial lesion was atypical ductal
hyperplasia (ADH). ftere were four ipsilateral cancers, including
three initially diagnosed with LCIS and three contralateral cancers
ultimately identified at a mean age of 41 years. ftese authors
concluded that young women with atypical lesions were at a strik-
ingly high risk of developing breast cancer and advocated for close
clinical surveillance and follow-up.45
Endocrine Chemoprevention for LCIS
Chemoprevention of Invasive Breast Cancer
On the basis of the finding that LCIS signifies an increased risk of
ipsilateral and contralateral breast cancer development, devising a
systemic chemoprevention strategy makes biological sense in this
patient population. Unfortunately, the literature from random-
ized trials directly addressing breast cancer risk reduction among
patients with LCIS is limited. Tamoxifen is a selective ER modu-
lator (SERM) with both agonist and antagonist properties com-
monly used in the treatment of both early-stage and metastatic
breast cancer. Tamoxifen has also been shown to decrease the risk
of contralateral breast cancer46 in women receiving treatment in
the adjuvant setting, and thus was chosen for evaluation in the
prevention setting. Historically, four large randomized clinical
trials evaluated the use of tamoxifen for breast cancer risk reduc-
tion. Two of these trials showed a statistically significant reduction
in the incidence of IBC among women treated with 5 years of
tamoxifen compared with those that received placebo.47,48 In the
NSABP P-01 prevention trial, there was a 49% reduction in the
incidence of IBC (p < .00001), whereas the International Breast
Cancer Intervention Study (IBIS-I) showed a 27% reduction in
risk among individuals taking the drug (p = .004). Two additional
trials reported smaller, nonsignificant decreases in breast cancer
risk among tamoxifen-treated women,49,50 whereas a meta-analysis
that combined results from all four trials showed a 34% to 38%
reduction in breast cancer risk.51
Only the NSABP P-01 trial specifically evaluated a subset of
participants with LCIS. ftis trial enrolled 13,388 women at
increased risk of breast cancer by virtue of an elevated Gail model
score (5-year risk ≥1.66% of developing breast cancer), age greater
than 60 years, or a past history of biopsy-proven LCIS or ADH.
Participants in this trial were randomized to tamoxifen (20 mg
daily) versus placebo, for a planned duration of 5 years. Six
558 SECTIONI IXI Current Concepts and Management of Early Breast Carcinoma (Tis, Tmic, T1)
percent of study participants had a history of LCIS, and an addi-
tional 9.1% of enrollees had a history of atypia. As noted earlier,
a 49% reduction in breast cancer incidence was seen overall in
this study. fte relative risk of breast cancer was 0.44 (95% con-
fidence interval [CI] 0.16–1.06) among women with a history of
LCIS and 0.14 (95% CI 0.03–0.47) among women with a history
of atypia. Importantly, no reduction was seen in the risk of
ER-negative breast cancer, nor was a difference in overall survival
noted between the two study arms. On the basis of the NSABP
P-01 trial results, the US Food and Drug Administration (FDA)
approved tamoxifen for breast cancer prevention.
Raloxifene is another SERM that has a slightly different side
effect profile than its cousin, tamoxifen. In initial studies testing
its efficacy for treating and preventing postmenopausal osteopo-
rosis, patients taking raloxifene were also noted to have a reduced
incidence of breast cancer.52,53 ftis led to the Study of Tamoxifen
and Raloxifene (STAR) trial, a head-to-head comparison of ral-
oxifene to tamoxifen for breast cancer chemoprevention, in which
the two agents were shown to be equivalent in terms of reducing
the risk of IBC in postmenopausal women.54 Slightly more than
9% of study participants had a history of LCIS. Overall, breast
cancer events were similar in women with LCIS compared with
that of the entire study population and did not differ by treatment
arm. Interestingly, the number of noninvasive breast cancers was
lower among tamoxifen-treated women (30 vs. 44 women cases
of DCIS; 21 vs. 29 cases of LCIS). It is important to note that
although the NSABP P-01 trial included both pre- and postmeno-
pausal women, only postmenopausal women were eligible for the
STAR trial. ftus although the STAR trial resulted in FDA
approval for raloxifene for the indication of breast cancer risk
reduction in postmenopausal women, tamoxifen remains the only
FDA-approved agent for breast cancer chemoprevention in pre-
menopausal women.55
Aromatase Inhibitors for Chemoprevention
In clinical trials in the adjuvant treatment setting, aromatase
inhibitors have been shown to be superior to tamoxifen in terms
of their effect on contralateral breast cancer,56 leading to interest
in investigating these agents in the prevention setting. Two
placebo-controlled clinical trials examining the efficacy of aroma-
tase inhibitors for prevention of breast cancer in postmenopausal
women have now been published. fte IBIS-II study enrolled
postmenopausal women aged 40 to 70 at increased risk of breast
cancer, including women with a history of LCIS, atypical hyper-
plasia (AH), or surgically treated DCIS, and randomized partici-
pants to anastrozole versus placebo for a period of 5 years. 57
ftere were a total of 154 (8%) patients with LCIS/AH in the
treatment arm, plus 190 (10%) with LCIS/AH in the placebo
arm. Overall, there was a significant decrease in the number of
breast cancers identified in the anastrozole group, and although it
did not reach statistical significance, women with LCIS/AH and
without prior hormone replacement therapy (HRT) exposure in
the anastrozole had an increased benefit and greater risk reduc-
tion than others in the study.57 ftese results were similar to the
MAP.3 study, which enrolled postmenopausal women at least 35
years of age and at increased risk of breast cancer based on either
the Gail Model or a previous history of LCIS, AH, or DCIS. 58
Women with atypia/LCIS accounted for 11% of the overall
study participants. Study participants were randomized to either
5 years of exemestane (Aromasin) or placebo and stratified based
on Gail score and current aspirin use. At 3 years follow-up, of
4560 patients enrolled, 11 cancers had developed in the treat-
ment group and 32 in the placebo arm, and the superiority of
exemestane to placebo was seen in all subgroups, including those
with LCIS.58 fte American Society of Clinical Oncology in
2013 updated their guidelines on chemoprevention for breast
cancer, recommending tamoxifen for premenopausal women, as
well as raloxifene or exemestane for use in postmenopausal
females.59 (fte IBIS-II trial results were published after this
guideline update.)
Finally, the safety of using combined HRT (CHRT) in women
with a history of LCIS is currently unknown. Indirect evidence
of a potential relationship between CHRT and lobular carcinoma,
as well as the potential for increased breast density and reduced
mammographic sensitivity, argue against using CHRT in this
population.
Surgical Intervention for LCIS
Surgical Excisional Biopsy Showing LCIS
Historical data indicate that lobular neoplasia is found in 0.5% to
4% of excisional biopsies and 1.5% of core needle breast biopsies.
Typically, additional invasive intervention is not indicated when
LCIS is diagnosed by surgical excision, even when the lesion is
seen at the surgical margin. Because LCIS generally does not
itself require surgical treatment, surgical biopsy showing LCIS
should not itself demand further intervention because surgical
margins are not clinically relevant. Unlike surgical treatment for
DCIS or invasive cancer, it is not necessary to surgically remove
more breast tissue simply because the tissue that was excised had
LCIS at the edge of the excision specimen. ftis conclusion is
supported by a 2004 study of 40 patients with invasive cancer
and associated lobular neoplasia. Although 14 of the patients
had either close (<2ormfrm
an)kly positive margins for lobular
neoplasia, none suffered local recurrence in the breast after a
median of 67 months’ follow-up.60 Such results suggest that
observation can safely replace excision when margins show LCIS
involvement.
Core Needle Samples Showing LCIS
Percutaneous core needle biopsy is the sampling method now
typically used for the primary evaluation of suspicious breast find-
ings. Although the benefits of tissue sampling with this technique
are established, needle biopsy has an inherent potential risk of
sampling error or underestimation of malignancy due to collect-
ing smaller specimens than are obtained at surgery. fte likelihood
of such underestimation has been extensively studied for ADH at
core needle biopsy. Surgical excision is recommended in this
setting because approximately 20% of ADH cases have been
shown to have coexistent in situ or invasive malignancy identified
at subsequent excisional biopsy.
It remains more controversial whether surgical excision is also
required when LCIS is the most severe histopathology result iden-
tified by core needle biopsy sampling. Evidence-based manage-
ment recommendations have been challenging due to the relatively
infrequent occurrence of pure LCIS at percutaneous biopsy. LCIS
has been reported to comprise from 0.2% to 1.2% of core biopsy
results,61–63 and thus most studies have included only small
numbers of patients. Generalization of study results has been
problematic because a variety of biopsy devices and needle gauges
have been used. ftere is little question that excision is indicated

when LCIS is present and this result is discordant relative to the
clinical or imaging finding, or when it is found along with other
high-risk lesions, such as a radial scar or ADH, which are them-
selves indications for surgical biopsy.62 Although the number of
cases in each study is small, historical results suggested rates of
underestimation of malignancy for LCIS were comparable to
those seen with ADH. In a multisite investigation of cases with
LCIS as the most severe core needle sampling histopathology,
Lechner and associates found 34% (20/58) were associated with
malignancy at surgical excision,61 whereas Shin and Rosen reported
upgrade rates of 21% (3/14) in this setting. 64 Mahoney and col-
leagues hypothesized that excision might not be necessary when
LCIS was found using larger caliber 11-gauge vacuum-assisted
breast biopsy, but their study still demonstrated malignancy in
33% (4/12) cases.63
More recently, a multicenter investigation from Italy found
that the rate of upstage to malignancy after excision when LCIS
was found during image guided sampling was 18%.65 fteir entire
cohort included women with pure LCIS, as well as LCIS associ-
ated with other high-risk lesions, but among the small subset of
individuals with pure LCIS, a 20.3% upstage rate was identified.
Rendi and colleagues also found a high risk of upstage to cancer
when extensive (more than four) foci of LCIS were seen on core
sampling.38 In contrast, another study of 87 cases of lobular neo-
plasia found an upgrade rate of only 3.4% and only when the
imaging Breast Imaging Reporting and Data System (BI-RADS)
score was 4 or higher, when there was concurrent ADH, or in the
setting of a breast cancer history in either breast. 66 ftese authors
challenged the need for routine surgical excision and instead pro-
posed that clinical and radiographic surveillance is appropriate
when the core needle sampling finding of lobular neoplasia,
including classic LCIS, is concordant with imaging and the
patient has no prior or current cancer history. A similarly low 3%
rate of upgrade to malignancy was also recently reported for a
multicenter, prospective trial of 77 patients with pure lobular
neoplasia on core biopsy.67 ftese authors also endorsed observa-
tion, not excision, for patients with pure LN on core biopsy and
concordant imaging findings.
On the basis of the results of these and other small studies
and on the clinical experience of their expert panel, the NCCN
breast cancer diagnosis and screening guidelines have progressively
softened their recommendation that surgical excision for all cases
of LCIS found at core needle biopsy is required. Guidelines as
of 2016 state that excision for classic LCIS should be performed
if pathology and imaging findings are discordant or when LCIS
is found in conjunction with ADH, whereas observation alone
is now allowed for classic LCIS that is concordant with imaging
findings.39 fte NCCN guidelines do acknowledge in a footnote
that multifocal/extensive LCIS associated with more than four
terminal ductal lobular units (TDLU) may be associated with
an increased risk of invasive disease being found at excision for
classic LCIS, in keeping with the Rendi and colleagues article,
but do not specifically state that these cases require excision. It
seems reasonable, and is within the NCCN guidelines, to recom-
mend excision for classic LCIS seen on core biopsy when there
are discordant pathology and imaging findings, when the lesion
is associated with additional atypical findings (ALH, ADH, FEA,
etc.), when the lesion is extensive and/or involves more than four
TDLUs, and when the classic LCIS is associated with a mass
on imaging. In the setting of pleomorphic LCIS, the NCCN
recommends management along the breast cancer treatment
pathway.39
CHAPTER 38 Lobular Carcinoma in Situ of the Breast 559
The Use of Breast Magnetic Resonance Imaging
for Lobular Neoplasia
Although the use of bilateral breast magnetic resonance imaging
(MRI) among women at high risk for the development of breast
cancer has been investigated, no current recommendations address
the use of screening MRI among those with lobular neoplasia.
American Cancer Society guidelines updated in 2015 support
annual MRI screening for limited groups of individuals, such as
women with known BRCA mutation carriers, those with high-risk
conditions such as Li-Fraumeni syndrome and Cowden disease,
individuals exposed to chest radiation between the ages of 10 and
30, and those with a calculated lifetime breast cancer risk greater
than 20% to 25% based on family history.68 fte American Cancer
Society found insufficient evidence to recommend routine annual
MRI for women diagnosed with LCIS, ALH, or ADH in the
absence of other high-risk conditions, citing a lack of data due to
a paucity of studies specifically addressing women with these risk
factors, whereas the most recent NCCN cancer screening guide-
lines state that MRI for patients with a history of LCIS or ADH/
ALH can be considered.39
Some studies have specifically looked at the role of MRI in the
setting of lobular neoplasia. One from Memorial Sloan-Kettering
Cancer Center reported results when MRI was used as a screening
tool for women with biopsy-proven ADH and/or LCIS, but not
ALH. MRI led to an increased number of biopsies among the 182
individuals (135 with LCIS) who submitted to the screening
versus the 196 who declined. fte addition of surveillance breast
MRI led to detection of otherwise occult malignancy in 4% (5 of
135) of women with LCIS undergoing this test. Of note, when a
new cancer was subsequently diagnosed, individuals in the MRI
cohort were found to have earlier stage lesions than those followed
with conventional imaging.69 In addition, Sung and associates
investigated the use of MRI in 220 women with a history of LCIS.
During their study period, 17 cancers were detected, 12 with MRI
alone and 5 with mammography alone. ftey concluded that MRI
is a useful adjunct to traditional mammogram in patients with
prior findings of LCIS and resulted in a 4.5% incremental breast
cancer detection rate.70 A more recent study from Ehasani and
colleagues evaluated 282 high-risk women with MRI, including
40 with a history of LCIS and/or AH. ftey reported a breast
cancer detection rate of 4.6% during the study period, with 10
of 13 found by MRI, and 2 of those among women with LCIS,
suggesting again that MRI may be a useful adjunct to traditional
clinical examination and mammography in these high-risk
patients.71
Breast Conservation in Patients Who Have LCIS
Coincident With Invasive Cancer
In general, the presence of LCIS in conjunction with an invasive
malignancy is not a contraindication for breast conserving surgery.
Although studies have some mixed results, the majority of reports
have failed to demonstrate an increased risk of ipsilateral breast
cancer recurrence after breast conservation for invasive cancer
coincident with LCIS.72,73 Abner and colleagues from Harvard’s
Joint Center for Radiation fterapy found that the 8-year local
recurrence rate was 13% among the 119 patients with associated
LCIS adjacent to the tumor compared with 12% for the 1062
patients without associated LCIS (p = not significant).73 fte
extent of LCIS did not appear to affect the risk of recurrence. Two
additional publications continue to support these findings. Pierce
560 SECTIO NI IXI Current Concepts and Management of Early Breast Carcinoma (Tis, Tmic, T1)
and colleagues identified 64 individuals treated with lumpectomy
who had LCIS and an invasive lesion present. Local control rates
when LCIS was present were excellent and equal to those seen in
women without evidence of LCIS, even if the lobular neoplasia
was multifocal and/or involved the surgical margin.74 In addition,
Morrow and colleagues failed to find a correlation between LCIS
either in the surgical specimen or the resection margin and local
failure in an analysis of 2894 women treated with breast conserv-
ing therapy over a 27-year period.75
In contrast to these favorable reports, some authors have
instead suggested that patients with IBC and coincident LCIS
(IBC + LCIS) may be at increased risk for ipsilateral breast tumor
recurrence, with some citing the presence of LCIS as an indepen-
dent risk factor for local failure after breast conserving therapy.76–78
Despite these conflicting data, our institution does not routinely
offer reexcision to individuals solely based on the presence of LCIS
at a surgical margin, even if the specimen is a lumpectomy for
invasive cancer.
Controversy remains about what to do when the involved
margin reveals the pleomorphic LCIS. Limited data suggest that
individuals with pleomorphic LCIS may have poorer outcomes
than those with the classic subtype. It is possible that pleomorphic
LCIS, like DCIS, should be excised with negative surgical margins.
fte historic data regarding outcomes of patients with pleomor-
phic LCIS were worrisome. In 1991 Page and colleagues described
cancer risk implications among different patterns of the LCIS
spectrum.15 ftirty-nine patients with a diagnosis of isolated LCIS
underwent surgical biopsy, not mastectomy, and were followed
for an average of 19 years. fte absolute risk of invasive cancer was
17% at 15 years. fte histologic pattern of 10 invasive carcinomas
developing in 9 patients was predominantly of the lobular type,
with 3 pure and 4 variant types representing 70% of the developed
carcinomas. ftree of those women with IBC died at an average
interval of 5.3 years. All 3 women had a histologic pattern of
pleomorphic ILC.15 In general, pleomorphic ILC with associated
LCIS appears to portend a poorer outcome when the sparse data
in the literature are examined. In a 1992 report from Italy, the
authors described 10 cases of pleomorphic ILC, 6 of which
included LCIS.79 Six of 10 patients died within 42 months of
diagnosis. ftree other patients developed recurrence or distant
metastases at short intervals. fte authors concluded that pleomor-
phic ILC is a highly lethal variant of invasive carcinoma.
In 1992, Weidner and Semple compared the clinical course of
25 cases of classic ILC with 16 cases of pleomorphic ILC.80 Sur-
vival until recurrence was significantly worse in the patients with
pleomorphic ILC. Patients with positive nodes and pleomorphic
histology were 30 times more likely to experience breast cancer
recurrence than patients with the classic ILC histology. A more
recent article by Bentz and colleagues evaluated 12 patients with
pleomorphic ILC, 11 of whom had long-term clinical follow-up.20
Of the 12 cases, 7 had coexisting pleomorphic LCIS. Nine patients
developed fatal metastatic disease, with a median survival of 2.1
years. Middleton and colleagues from the National Cancer Insti-
tute identified 38 cases of pleomorphic ILC.11 Pleomorphic LCIS
was associated with pleomorphic ILC in 45% of cases. Of the 19
patients available for follow-up, 7 had no evidence of disease at
last examination (range 1–15 years), 3 were alive with disease
(range 2–14 years), and 9 were dead of disease (range 2 months
to 9 years). Six patients had subsequent diagnoses of tumor in the
contralateral breast. fteir analysis showed that pleomorphic ILC
tends to appear in older postmenopausal women who present with
locally advanced disease.
ftese findings suggest that pleomorphic ILC may be as aggres-
sive as most forms of IDC and that pleomorphic LCIS could be
a harbinger for that aggressive underlying biology. ftis part of the
spectrum of LCIS may warrant different management than classic
LCIS. Although large case series are lacking due to the rarity of
pure pleomorphic LCIS, two recent studies have shed additional
light on pleomorphic LCIS as an entity. Flanagan and colleagues
looked at 23 cases of pure pleomorphic LCIS diagnosed over a
15-year period.81 ftese authors found that of 21 patients under-
going surgery for a core biopsy finding of pleomorphic LCIS,
33% had a subsequent diagnosis of invasive cancer and 19% had
DCIS identified. In addition, 48% of the cases revealed extensive,
multifocal pleomorphic LCIS and 71% were found to have a close
or positive surgical margin. When negative margin resection was
attempted, mastectomy was the usual outcome. Interestingly, they
identified no ipsilateral breast cancer recurrences, even when close
or positive margins persisted and suggested that negative margin
resection for pleomorphic LCIS may not always be necessary.81
Another publication, however, found a 19.4% (n = 6) local
recurrence rate among 47 women diagnosed with pleomorphic
LCIS. In this study, two of the local recurrences occurred in
women with positive pleomorphic LCIS margins, with the other
four recurrences happening despite negative surgical margins.
More surprising was the finding that 7 women with positive
pleomorphic LCIS margins had not suffered from a recurrence at
the time of publication.82 A clear consensus regarding pleomor-
phic LCIS margin management fails to exist and each patient
should be discussed individually.
Is There a Defined Role for Surgical Prophylaxis
With LCIS?
In general, LCIS is no longer believed to be a pathologic entity
that mandates surgery. Although the risk of developing invasive
cancer with LCIS is elevated above the general population, most
women with this diagnosis will not develop IBC within their
natural lifetimes. Of those women who do get breast cancer, the
relative risk appears to be similar for both breasts. ftus, if one
were to perform surgery for LCIS, the only logical operation
would be bilateral total mastectomy. One of the most important
changes in the surgical management of lobular neoplasia, there-
fore, has been the abandonment of routine mastectomy after a
diagnosis of LCIS, a change supported by data from the NSABP,
which suggested that LCIS could be safely treated conservatively
and that mastectomy was not required for oncologic control.83
Although such surgery is felt to be excessive for the majority
of individuals with LCIS, there may be circumstances in which
bilateral mastectomy is a reasonable consideration. Bilateral pro-
phylactic mastectomy (with or without reconstruction), regardless
of the reason why it is performed, confers greater than a 90% risk
reduction against the development of subsequent breast cancer.84
If a patient is otherwise a reasonable candidate for prophylactic
surgery, such as an individual from a high-risk family in which
genetic testing is noninformative or those with a known genetic
mutation, and if that woman is then found to have LCIS, she
might have heightened consideration for such a procedure. Any
use of prophylactic surgery for breast cancer risk reduction must
be highly individualized and warrants considerable introspec-
tion before a definitive decision is made. Counseling for both
medical and psychological issues is mandatory, as is ample time
to make an appropriate personal decision. We generally recom-
mend referral to our high-risk clinic for a thorough discussion

of nonsurgical options, including more rigorous surveillance and
chemoprevention.
Conclusions
LCIS, which is defined as involvement of more than 50% of the
affected acini of the lobule, exists as two main subtypes, classic
and pleomorphic. Since the initial description of LCIS in the
1940s, our understanding of the lesion has changed dramati-
cally and continues to evolve. Historically, LCIS was felt to be a
direct precursor to invasive malignancy. With time, LCIS instead
came to be thought of instead as a marker for the develop-
ment of malignancy in either breast. Aggressive surgical resection
mandating bilateral mastectomy was replaced with programs of
surveillance involving clinical and radiographic examinations. By
combining epidemiologic evidence arguing that LCIS confers
increased bilateral risk of developing invasive cancer with current
molecular evidence that supports lobular neoplasia as a precur-
sor lesion, a model encompassing both concepts has emerged.
Although lobular neoplasia may be a precursor to some invasive
carcinomas with its frequent multifocal and bilateral distribu-
tion and relatively low lifetime risk of evolving into an invasive
carcinoma, this biologic entity can be treated as a “risk indica-
tor” lesion without complete surgical resection. Future challenges
will determine whether there are high-risk subtypes of LCIS,
such as the pleomorphic form, that may behave as high-risk pre-
cursor lesions requiring surgical or hormonal-based therapeutic
interventions.
LCIS is usually discovered incidentally during biopsy for
another clinical or radiographic indication. LCIS incidence
appears to be influenced by the use of exogenous hormones, with
diagnoses decreasing concurrent with decreasing CHT use since
2002, with a slight increase between 2002 and 2009. When LCIS
is identified, the lifetime risk of an invasive cancer is thought to
be 8 to 10 times that seen among women who lack such a diag-
nosis. fte risk of invasive cancer development can be decreased
by the use of a chemopreventive antihormonal endocrine agent,
such as tamoxifen, raloxifene, or an aromatase inhibitor. Tamoxi-
fen is approved for both pre- and postmenopausal women with
lobular neoplasia, whereas raloxifene is approved only for those
who are postmenopausal.
CHAPTER 38 Lobular Carcinoma in Situ of the Breast 56
1
When LCIS is diagnosed on a core needle biopsy, current
guidelines recommend consideration of diagnostic surgical exci-
sional sampling for discordant pathology/imaging findings, with
extensive LCIS, and when the lesion is associated with other atypi-
cal findings, core biopsy is used to eliminate the possibility of a
missed malignancy. Observation alone without excision is being
offered to an increasing number of individuals with classic LCIS
on core sampling that is deemed concordant with imaging find-
ings. Aggressive surgical resection of all LCIS disease to achieve a
negative surgical margin, even at the time of lumpectomy for a
concurrent invasive tumor, is not advocated because LCIS is often
multicentric, multifocal, and bilateral. Such clinical presentations
make bilateral mastectomy the only way to ensure removal of all
of the LCIS present, an approach that is therapeutically aggressive
(and unnecessary) for this high-risk factor, unless there are other
compelling and confounding breast cancer risk factors present.
Finally, the biological behavior of pleomorphic LCIS remains
controversial in terms of long-term outcomes and risk of invasive
cancer development.
Selected References
3T4A., PKilienwgskie M, Muhsen S, et al. Lobular carcinoma in situ: a
29-year longitudinal experience evaluating clinicopathologic features
and breast cancer risk. J Clin Oncol. 2015;33:3945-3952.
3en8d.i R MH, Dintzis SM, Lehman CD, et al. Lobular in-situ neopla-
sia on breast core needle biopsy: imaging indication and pathologic
extent can identify which patients require excisional biopsy. Ann
Surg Oncol. 2012;19:914-921.
5is5v.anV athan K, et al. American Society of Clinical Oncology clinical
practice guideline update on the use of pharmacologic interventions
including tamoxifen, raloxifene, and aromatase inhibition for breast
cancer risk reduction. J Clin Oncol. 2009;27:3235-3258.
a6k7h.liNs F, Gilmore L, Gelman R, et al. Incidence of adjacent syn-
chronous invasive carcinoma and/or ductal carcinoma in situ in
patients with lobular neoplasia on core biopsy: results from a pro-
spective multi-institutional registry (TBCRC 020). Ann Surg Oncol.
2016;23:722-728.
8la1n.agFan MR, Rendi MH, Calhoun KE, et al. Pleomorphic lobular
carcinoma in situ: radiologic-pathologic features and clinical man-
agement. Ann Surg Oncol. 2015;22:4263-4269.
A full reference list is available online at ExpertConsult.com.

References
1. Li CI, Malone KE, Saltzman BS, et al. Risk of invasive breast carci-
noma among women diagnosed with ductal carcinoma in situ and
lobular carcinoma in situ, 1988–2001. Cancer. 2006;106:2104-2112.
2. Menon S, Porter GJ, Evans AJ, et al. fte significance of lobular
neoplasia on needle core biopsy of the breast. Virchows Arch.
2008;452:473-479.
3. Arpino G, Laucirica R, Elledge RM. Premalignant and in situ
breast disease: biology and clinical implications. Ann Intern Med.
2005;143:446-457.
4. Foote FJ, Stewart F. Lobular carcinoma in situ: a rare form of
mammary carcinoma. Am J Pathol. 1941;17:491-496.
5. Godwin JT. Chronology of lobular carcinoma of the breast: report
of a case. Cancer. 1952;5:259-266.
6. Cornil A-V. Contributions a l’histoire du developpement his-
tologique des tumeurs epitheliales (sqirrhe, encephaloide, etc.). J
Anat Physiol. 1865;2:266-276.
7. Ewing J. Neoplastic Diseases. Philadelphia: WB Saunders; 1919.
8. Cheatle GL, Cutler M. Tumours of the Breast. London: Edward
Arnold & Co.; 1931.
9. Haagensen CD, Lane N, Lattes R, Bodian C. Lobular neopla-
sia (so-called lobular carcinoma in situ) of the breast. Cancer.
1978;42:737-769.
10. Frost AR, Tsangaris TN, Silverberg SG. Pleomorphic lobular carci-
noma in situ. Case Rev. 1996;1:27-31.
11. Middleton L, Palacios D, Bryant B, et al. Pleomorphic lobular carci-
noma: morphology, immunohistochemistry, and molecular analysis.
Am J Surg Pathol. 2000;24:1650-1656.
12. Rosen PP, Lieberman PH, Braun DWJ, et al. Lobular carcinoma
in situ of the breast. Detailed analysis of 99 patients with average
follow-up of 24 years. Am J Surg Pathol. 1978;2:225-251.
13. Bodian CA, Perzin KH, Lattes R, et al. Prognostic significance of
benign proliferative breast disease. Cancer. 1993;71:3896-3907.
14. NCCN Clinical Practice Guidelines in Oncology (NCCN Guide-
lines) Breast Cancer Version 2.2016. “Lobular Carcinoma in situ.”
15. Page DL, Kidd TE Jr, Dupont WD, et al. Lobular neoplasia of the
breast: higher risk for subsequent invasive cancer predicted by more
extensive disease. Hum Pathol. 1991;22:1232-1239.
16. Fadhare O, Dadmanesh F, Alvarado-Cabrero I, et al. Lobular
intraepithelial neoplasia [lobular carcinoma in situ] with comedo-
type necrosis: a clinicopathologic study. Hum Pathol. 1984;15:
134-140.
17. Acs G, Lawton T, Rebbeck T, et al. Differential expression of E-
cadherin in lobular and ductal neoplasms of the breast and its
biologic and diagnostic implications. Am J Clin Pathol. 2001;115:
85-98.
18. Jacobs T, Pliss N, Kouria G, Schnitt S. Carcinomas in situ of the
breast with indeterminate features: role of E-cadherin staining in
categorization. Am J Surg Pathol. 2001;25:229-236.
19. Maluf H, Swanson P, Koerner F. Solid low-grade in situ carcinoma
of the breast: role of associated lesions and E-cadherin in differential
diagnosis. Am J Surg Pathol. 2001;25:237-244.
20. Bentz J, Yassa N, Clayton F. Pleomorphic lobular carcinoma of
the breast: clinicopathologic features of 12 cases. Mod Pathol.
1998;11:814-822.
21. Bodis S, Siziopikou KP, Schnitt SJ, et al. Extensive apoptosis in
ductal carcinoma in situ of the breast. Cancer. 1996;77:1831-1935.
22. Frost A, Tsangaris T, Silverberg S. Pleomorphic lobular carcinoma
in situ. Pathol Case Rev. 1996;1:27.
23. Sneig N, Wang J, Baker BA, et al. Clinical, histopathologic, and
biologic features of pleomorphic lobular (ductal-lobular) car-
cinoma in situ of the breast: a report of 24 cases. Mod Pathol.
2002;15:1044-1050.
24. Fulford LG, Reis-Fihlo JS, Lakhani SR. Lobular in situ neoplasia.
Current Diag Pathol. 2004;10:183-192.
25. Lerwill MP. fte evolution of lobular neoplasia. Adv Anat Pathol.
2006;13:157-165.
CHAPTER 38 Lobular Carcinoma in Situ of the Breast 561.e1
26. Simpson PT, Reis-Filho JS, Lambros MB, et al. Molecular profil-
ing of lobular carcinomas of the breast: evidence for a common
molecular genetic pathway with classic lobular carcinomas. J Pathol.
2008;215:231-244.
27. Reis-Filho JS, Simpson PT, Jones C, et al. Pleomorphic lobular
carcinoma of the breast: role of comprehensive molecular pathology
in characterization of an entity. J Pathol. 2005;207:1-13.
28. Bauer VP, Ditkoff BA, Schnabel F, et al. fte management of lobular
neoplasia identified on percutaneous core breast biopsy. Breast J.
2003;9:4-9.
29. Anderson BO, Li CI, Lawton TJ, Rinn K, Moe RE. Clinical man-
agement of lobular carcinoma in situ. In: Singletary SE, Robb GL,
Hortobagyi GN, eds. Advanced Therapy of Breast Disease. 2nd ed.
Hamilton, Canada: B.C. Decker; 2004:269-280.
30. Muir J. fte evolution of carcinoma of the mamma. J Pathol Bacte-
riol. 1941;52:155-172.
31. Rosen PP, Senie R, Schottenfeld D, Ashikari R. Noninvasive breast
carcinoma: frequency of unsuspected invasion and implications for
treatment. Ann Surg. 1979;189:377-382.
32. Beute BJ, Kalisher L, Hutter RVP. Lobular carcinoma in situ of the
breast: clinical, pathologic and mammographic features. AJR Am J
Roentgenol. 1991;157:257-265.
33. Degnim AC, King TA. Surgical management of high risk breast
lesions. Surg Clin North Am. 2013;93:329-340.
34. King TA, Pilewskie M, Muhsen S, et al. Lobular carcinoma in situ: a
29-year longitudinal experience evaluating clinicopathologic features
and breast cancer risk. J Clin Oncol. 2015;33:3945-3952.
35. Haagensen CD. Lobular neoplasia (lobular carcinoma in situ). In:
Haagensen CD, ed. Diseases of the breast. Philadelphia: WB Saun-
ders; 1986:192-241.
36. Anderson JA. Multicentric and bilateral appearance of lobular
carcinoma in situ of the breast. Acta Pathol Microbiol Scand.
1974;82:730-734.
37. Wheeler JE, Enterline HT, Roseman JM, et al. Lobular carci-
noma in situ of the breast: long-term followup. Cancer. 1974;34:
554-563.
38. Rendi MH, Dintzis SM, Lehman CD, et al. Lobular in-situ neopla-
sia on breast core needle biopsy: imaging indication and pathologic
extent can identify which patients require excisional biopsy. Ann
Surg Oncol. 2012;19:914-921.
39. NCCN Clinical Practice Guidelines in Oncology (NCCN Guide-
lines), Breast Cancer Screening and Diagnosis, version 1.2016-July
27, 2016.
40. Li CI, Anderson BO, Porter P, et al. Changing incidence rate of
invasive lobular breast carcinoma among older women. Cancer.
2000;88:2561-2569.
41. Li CI, Anderson BO, Daling JR, Moe RE. Trends in incidence
rates of invasive lobular and ductal breast carcinoma. JAMA.
2003;289:1421-1424.
42. Carson W, Sanchez-Forgach E, Stomper P, et al. Lobular carcinoma
in situ: observation without surgery as an appropriate therapy. Ann
Surg Oncol. 1994;1:141-146.
43. Portschy PR, Marmor S, Nzara R, et al. Trends in incidence and
management of lobular carcinoma in situ: a population-based analy-
sis. Ann Surg Oncol. 2013;20:3240-3246.
44. Wellings SR, Jensen HM, DeVault MR. Persistent and atypical
lobules in the human breast may be precancerous. Experientia.
1976;32:1463-1465.
45. McEvoy MP, Coopey SB, Mazzola E, et al. Breast cancer risk and
follow-up recommendations for young women diagnosed with atyp-
ical hyperplasia and lobular carcinoma in situ (LCIS). Ann Surg
Oncol. 2015;22:3346-3349.
46. Tamoxifen for early breast cancer: an overview of the randomised
trials. Early Breast Cancer Trialists’ Collaborative Group. Lancet.
1998;351:1451-1467.
47. Cuzick J, et al. Long-term results of tamoxifen prophylaxis for breast
cancer—96-month follow-up of the randomized IBIS-I trial. J Natl
Cancer Inst. 2007;99:272-282.
561.e2 SECTION XIII Current Concepts and Management of Early Breast Carcinoma (Tis, Tmic, T1)
48. Fisher B, et al. Tamoxifen for prevention of breast cancer: report of
the National Surgical Adjuvant Breast and Bowel Project P-1 Study.
J Natl Cancer Inst. 1998;90:1371-1388.
49. Powles T, et al. Interim analysis of the incidence of breast cancer in
the Royal Marsden Hospital tamoxifen randomised chemopreven-
tion trial. Lancet. 1998;352:98-101.
50. Veronesi U, et al. Prevention of breast cancer with tamoxifen: pre-
liminary findings from the Italian randomised trial among hys-
terectomised women. Italian Tamoxifen Prevention Study. Lancet.
1998;352:93-97.
51. Cuzick J, et al. Overview of the main outcomes in breast-cancer
prevention trials. Lancet. 2003;361:296-300.
52. Ettinger B, et al. Reduction of vertebral fracture risk in postmeno-
pausal women with osteoporosis treated with raloxifene: results from
a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene
Evaluation (MORE) Investigators. JAMA. 1999;282:637-645.
53. Martino S, et al. Continuing outcomes relevant to Evista: breast
cancer incidence in postmenopausal osteoporotic women in a ran-
domized trial of raloxifene. J Natl Cancer Inst. 2004;96:1751-1761.
54. Vogel VG, et al. Effects of tamoxifen vs raloxifene on the risk of
developing invasive breast cancer and other disease outcomes: the
NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial.
JAMA. 2006;295:2727-2741.
55. Visvanathan K, et al. American Society of Clinical Oncology clinical
practice guideline update on the use of pharmacologic interventions
including tamoxifen, raloxifene, and aromatase inhibition for breast
cancer risk reduction. J Clin Oncol. 2009;27:3235-3258.
56. Forbes JF, et al. Effect of anastrozole and tamoxifen as adjuvant
treatment for early-stage breast cancer: 100-month analysis of the
ATAC trial. Lancet Oncol. 2008;9:45-53.
57. Cuzick J, Sestak I, Forbes JF, et al. Anastrazole for prevention of
breast cancer in high-risk postmenopausal women (IBIS-II): and
international, double-blinded, randomized placebo-controlled trial.
Lancet. 2014;383:1041-1048.
58. Goss PE, Ingle JN, Ales-Martinez JE, et al. Exemestane for breast-
cancer prevention in postmenopausal women. N Engl J Med.
2011;364:2381-2391.
59. Visvanathan K, Hurley P, Bantug E, et al. Use of pharmacologic
interventions for breast cancer risk reduction: American Society
of Clinical Oncology clinical practice guideline. J Clin Oncol.
2013;31:2942-2962.
60. Stoiler AJ, Barre JS, Bolton GM, et al. Breast conservation therapy
for invasive lobular carcinoma: the impact of lobular carcinoma in
situ in the surgical specimen and local recurrence and axillary node
status. Am Surg. 2004;70:818-821.
61. Lechner MC, Jackman RJ, Brem RF, et al. Lobular carcinoma in
situ and atypical lobular hyperplasia at percutaneous biopsy with
surgical correlation: a multi-institutional study (abstr). Radiology.
1999;213:106.
62. Liberman L, Sama M, Susnik B, et al. Lobular carcinoma in situ
at percutaneous breast biopsy: surgical biopsy findings. AJR Am J
Roentgenol. 1999;173:291-299.
63. Mahoney MC, Robinson-Smith TM, Shaughnessy EA. Lobular
neoplasia at 11-gauge vacuum-assisted stereotactic biopsy: correla-
tion with surgical excisional biopsy and mammographic follow-up.
AJR Am J Roentgenol. 2006;187:949-954.
64. 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;126:697-701.
65. Bianchi S, Bendinelli B, Castellano I, et al. Morphological
parameters of lobular in situ neoplasia in stereotactic 11-gauge
vacuum-assisted needle core biopsy do not predict the presence of
malignancy on subsequent surgical excision. Histopathology. 2013;63:
83-95.
66. Chaudhary S, Lawrence L, McGinty G, et al. Classic lobular neopla-
sia on core biopsy: a clinical and radio-pathologic correlation study
with follow-up excision biopsy. Mod Pathol. 2013;26:762-771.
67. Nakhlis F, Gilmore L, Gelman R, et al. Incidence of adjacent syn-
chronous invasive carcinoma and/or ductal carcinoma in situ in
patients with lobular neoplasia on core biopsy: results from a pro-
spective multi-institutional registry (TBCRC 020). Ann Surg Oncol.
2016;23:722-728.
68. American Cancer Society Guidelines: MRI as an Adjunct to Mam-
mography. Revised online 20 October 2015.
69. Port EA, Park A, Borgen PI, et al. Results of MRI screening for
breast cancer in high-risk patients with LCIS and atypical hyper-
plasia. Ann Surg Oncol. 2007;14:1051-1057.
70. Sung JS, Malak SF, Bajaj P, et al. Screening breast MR imaging
in women with a history of lobular carcinoma in situ. Radiology.
2011;261:414-420.
71. Ehsani S, Strigel RM, Pettke E, et al. Screening Magnetic Resonance
Imaging recommendations and outcomes in patients at high risk for
breast cancer. Breast J. 2015;21:246-253.
72. Moran M, Haffty BG. Lobular carcinoma in situ as a component of
breast cancer: the long-term outcome in patients treated with breast-
conservation therapy. Int J Radiat Oncol Biol Phys. 1998;40:353-358.
73. Abner AL, Connolly JL, Recht A, et al. fte relation between the
presence and extent of lobular carcinoma in situ and the risk of
local recurrence for patients with infiltrating carcinoma of the breast
treated with conservative surgery and radiation therapy. Cancer.
2000;88:1072-1077.
74. Ben-David MA, Kleer CG, Paramagul C, et al. Is lobular carcinoma
in situ as a component of breast carcinoma a risk factor for local
failure after breast-conserving therapy? Results of a matched pair
analysis. Cancer. 2006;106:28-34.
75. Ciocca RM, Li T,Freedman GM, et al. Presence of lobular carcinoma
in situ does not increase local recurrence in patients treated with
breast-conserving therapy. Ann Surg Oncol. 2008;15:2263-2271.
76. Sasson AR, Fowble B, Hanlon AL, et al. Lobular carcinoma in situ
increases the risk of local recurrence in selected patients with stages
I and II breast carcinoma treated with conservative surgery and
radiation. Cancer. 2001;91:1862-1869.
77. Mechera R, Viehl CT, Oertli D. Factors predicting in-breast tumor
recurrence after breast-conserving surgery. Breast Cancer Res Treat.
2009;116:171-177.
78. Jolly S, Kestin LL, Goldstein NS, et al. fte impact of lobular car-
cinoma in association with invasive breast cancer on the rate of
local recurrence in patients with early-stage breast cancer treated
with breast-conserving therapy. Int J Radiat Oncol Biol Phys.
2006;66:365-371.
79. Eusebi V, Magalhaes F, Azzopardi JG. Pleomorphic lobular carci-
noma of the breast: an aggressive tumor showing apocrine differen-
tiation. Hum Pathol. 1992;23:655-662.
80. Weidner N, Semple JP. Pleomorphic variant of invasive lobular
carcinoma of the breast. Hum Pathol. 1992;23:1167-1171.
81. Flanagan MR, Rendi MH, Calhoun KE, et al. Pleomorphic lobular
carcinoma in situ: radiologic-pathologic features and clinical man-
agement. Ann Surg Oncol. 2015;22:4263-4269.
82. Khoury T, Karabakhtsian RG, Mattson D, et al. Pleomorphic
lobular carcinoma in situ of the breast: clinicopathological review
of 47 cases. Histopathology. 2014;64:981-993.
83. Fisher ER, Land SR, Fisher B, et al. Pathologic findings of the
National Surgical Adjuvant Breast and Bowel Project. Twelve-
year observations concerning lobular carcinoma in situ. Cancer.
2003;100:238-244.
84. Hartmann LC, Schaid DJ, Woods JE, et al. Efficacy of bilateral
prophylactic mastectomy in women with a family history of breast
cancer. N Engl J Med. 1999;340:77-84.