Lobular Carcinoma in Situ (LCIS) (E-cadherin Negative) with Comedonecrosis, Present at the Inked Margin
Memorial Sloan-Kettering Cancer Center
New York, NY
A 44 year old woman underwent excision of new mammographic calcifications in the left breast. The
diagnosis was "intraductal carcinoma, solid type with comedonecrosis and calcifications, close to the
margin". Re-excision yielded the findings shown in Figures 1-5; the findings in figure 6 were not noted.
More surgery followed, showing "multifocal LCIS, extending into ducts, with foci of comedonecrosis,
present at two distinct foci of the inked resection margin." The patient received no radiotherapy.
Ten years later, new pleomorphic calcifications were detected in the same breast, as well as
ipsilateral axillary lymphadenopathy. Biopsy showed invasive lobular carcinoma with lymph node
metastases. The patient received neo-adjuvant chemotherapy, and later underwent left modified radical
mastectomy. A year later she developed cerebellar metastases with leptomeningeal involvement and died of
Extensive solid carcinoma in situ is present, centered in the TDLU. Some of the acini show massive distention and central necrosis.
Extensive solid carcinoma in situ is present, centered in the TDLU. Some of the acini show massive distention and central necrosis.
Massively expanded acini with central necrosis abut the inked margin.
The carcinoma consists of a monotonous proliferation of small cells, with central nucleus. Few large histiocytes are admixed with the carcinoma in situ.
The carcinoma in situ consists of small cells, with scant cytoplasm and inconspicuous nucleoli. Rare binucleate cells are present. Intracytoplasmic vacuoles indent some of the nuclei, with resulting signet ring morphology.
Scattered tumor cells admixed with few lymphocytes are present in the stroma adjacent to in situ carcinoma. This focus, not present in the original slides, was unveiled only in a deeper section.
The in situ carcinoma in this case consists of a solid and monotonous proliferation of small and
slightly dishesive cells expanding lobules and small ducts. Few acini show massive distension (more than
100 cells across), with focal central necrosis and associated calcifications. No gland formation and no
polarized cells are present. The nuclei are small to slightly enlarged (1.5-2X RBC), have central or
slightly eccentric position within the cell and show low grade atypia. The neoplastic cells are
morphologically consistent with type A (small) and type B (large) classic LCIS cells, however, the
presence of focal necrosis with associated calcifications is unusual in a lobular lesion, and suggests
DCIS. A focus of microinvasive lobular carcinoma (not present in the original slides) is identified in a
deeper section obtained from one of the tissue blocks. Few ducts involved by CIS with central necrosis
are close to or transected at the margin. Classic LCIS is also present, merging with the solid
The neoplastic cells showed no membranous immunoreactivity for E-cadherin (not shown).
The differential diagnosis in this case is between low grade DCIS versus an
unusual variant of LCIS. The diagnostic dilemma is also reflected in the
original diagnoses rendered for this neoplasm, which ranged from "intraductal carcinoma, solid type, with
comedonecrosis" to "LCIS with comedonecrosis".
This case prompts a discussion about:
- use of E-cadherin immunostain as an aid in the
differential diagnosis of solid mammary carcinoma in situ (CIS);
- biology and management of E-cadherin negative CIS
with morphologic features intermediate between DCIS and LCIS.
E-cadherin and classification of mammary solid carcinoma in situ
E-cadherin is a transmembrane glycoprotein involved in cell-to-cell adhesion through Ca2+-dependent
homotypic binding. The encoding gene (CDH1) maps to chromosome 16q22.1. The normal mammary epithelium
expresses E-cadherin and displays strong, linear and continuous membranous immunoreactivity for this
antigen. The same staining pattern is observed in ductal carcinomas. The myoepithelium also expresses
E-cadherin, but shows granular and discontinuous ("dot-like") membranous reactivity. In contrast, the
E-cadherin gene is consistently lost and/or functionally inactivated in lobular neoplasia, resulting in
loss of membranous positivity in all lobular lesions. Therefore, immunoperoxidase staining for
E-cadherin is widely used at most centers to confirm lobular differentiation. The widespread application
of this staining has revealed that some solid CIS with ambiguous morphology are E-cadherin negative,
consistent with lobular differentiation.
In the discussion of this case, we will focus our attention on E-cadherin negative carcinomas in situ
with morphology different from that of classic LCIS, with some comments regarding biology and management
of these tumors, and then briefly review some aberrant patterns of E-cadherin immunostain.
E-Cadherin negative CIS = Special variants of LCIS
E-cadherin negative CIS with ambiguous morphology are usually characterized by massive expansion of
ducts and lobules by dishesive neoplastic cells showing central necrosis and associated calcifications.
They can roughly be divided into two subgroups depending on cell morphology:
A) E-cadherin negative solid mammary CIS composed of type A (small) and/or type
B (large) LCIS cells with comedo-type necrosis (like the current case). Jacobs described 6 tumors
with this morphology 
and Maluf reported 3 . Fadare and colleagues reported 18
cases, the largest series to date, which they called "LCIS with comedonecrosis" . Rosen
refers to these lesions as "florid LCIS with necrosis" . Despite the typical type A and/or
type B LCIS cytomorphology, these tumors differ from classic LCIS because of central necrosis and massive
acinar expansion (more than 100 cells across) (Table I).
B) E-cadherin negative solid mammary CIS composed of large and dishesive
pleomorphic cells. The neoplastic cells show abundant cytoplasm and plasmacytoid morphology.
Marked nuclear enlargement (>3X size of a lymphocyte) and nuclear membrane irregularities are
present, with prominent nucleoli. The nuclear atypia is similar to that of intermediate nuclear grade
ductal carcinoma. Central necrosis and associated calcifications are usually present. Jacobs described
5 tumors with this morphology , but the term "pleomorphic" LCIS was first introduced by
Sneige . The cells of pleomorphic LCIS do not resemble those of classic LCIS, but the finding
of marked dishesion, a morphologic correlate of E-cadherin negativity, is a useful clue to the diagnosis
(Table I) . In situ (and invasive) pleomorphic lobular carcinoma has a pattern of E-cadherin
and bears genetic alterations
consistent with lobular
At present, it is generally accepted that E-cadherin negative CIS represent special variants of LCIS
 , but no real uniform consensus exists on these lesions.
Special LCIS are usually ER and PR positive, Her-2 negative
although positivity for
Her-2 has been reported .
Lobular neoplasia also shows cytoplasmic positivity for p120
, the cytoplasmic ligand
of E-cadherin, and for keratin 34 b E12
, but no specific information is available
about the expression of these markers in special LCIS.
b) Biology and treatment
Information on the biology of special LCIS is extremely limited, as in the past they were diagnosed
and treated as DCIS.
Whereas classic LCIS is an incidental histologic finding, Sapino and colleagues have reported 10 cases
of special LCIS which were detected mammographically because of associated calcifications. The
calcifications were limited to one quadrant in 7 cases, and present throughout the entire breast in 3.
Invasive carcinoma was identified in four of the ten cases. Seven patients underwent mastectomy, and the
remaining 3 were treated with breast conservation, and showed no evidence of disease at the time of the
study, but follow-up was short (range 2-11 months) .
Of note, there is uniform consensus that any lesion yielding special LCIS in a core biopsy needs to be
All patients with "LCIS with comedonecrosis" reported by Fadare and colleagues were women, ranging in
age from 41 to 85 years (mean 61.3). Twelve lesions were identified in breast excisions or mastectomy
specimens and 6 in incisional biopsies. Six patients had only in situ carcinoma (33%). The invasive
carcinoma in the remaining 12 cases (67%) was predominantly lobular (7 classic lobular, 1 pleomorphic
lobular, 1 ductal, 1 mixed ductal and lobular, 1 tubular and one case with separate ductal and lobular
carcinomas). Calcifications were associated with the tumor in 10/18 cases (55%). On core biopsy
material, two cases were initially diagnosed as DCIS and the patients received radiation; one of the two
recurred seven years later with LCIS with comedonecrosis without invasion. No additional follow-up was
available for any of the other cases .
Sneige and colleagues studied 24 cases of pleomorphic LCIS, including 10 in situ (42%), and 14 with
associated invasive pleomorphic lobular carcinoma. Classic LCIS with type A and type B morphology
coexisted with pleomorphic LCIS in 40% of these cases and transition into pleomorphic LCIS was observed
in four. Of the 10 patients with only pleomorphic LCIS, 5 were managed conservatively, and two underwent
mastectomy. Six of these patients had no evidence of disease in follow-up periods ranging from 4 to 32
months, whereas the seventh recurred after 12 months with carcinoma in situ morphologically similar to
the prior .
This data document that special variants of LCIS are very rare and seldom occur in isolation (only
about 40% of reported cases). The frequent association with invasive carcinoma, which is usually of
lobular type, suggests a more aggressive behavior than classic LCIS. In the current case microinvasive
lobular carcinoma was present, admixed with focal chronic inflammation.
The case discussed here was initially diagnosed as DCIS with necrosis, but the patient did not receive
radiation therapy. "LCIS with comedonecrosis" was present at the margin of her final re-excision
specimen, but no additional surgery was performed, as for classic LCIS. Regarding margin status, the
latest WHO book recommendations state that "re-excision should be considered in cases with massive acinar
distention, and when pleomorphic, signet ring or necrotic variants are identified at or close to the
margin" . Classic LCIS is usually found near special LCIS variants, as it was in this case.
This patient recurred with invasive lobular carcinoma about 10 years after the initial diagnosis and
died of disease shortly after. This case highlights the aggressive biology of LCIS with comedonecrosis,
a special type of LCIS.
Lobular carcinoma in situ (LCIS) (E-cadherin negative) with comedonecrosis, present at the
inked margin. Focal microinvasive lobular carcinoma.
Unusual or aberrant E-cadherin staining patterns
Although E-cadherin is a reliable tool in the differential between ductal and lobular carcinoma,
aberrant and/or mixed patterns of immunoreactivity have been reported.
Jacobs described 6 cases of CIS with indeterminate features which showed a mixed pattern of E-cadherin
positivity, suggesting a mixed DCIS/LCIS phenotype .
Maluf had 2 of such cases 
and Goldstein reported 17 more . From a practical standpoint, finding of any E-cadherin
positivity is usually regarded as supportive evidence of ductal differentiation. Recently, however, Da
Silva and colleagues have reported aberrant positivity for E-cadherin in LCIS  . This unusual
finding can possibly lead to overdiagnose of DCIS, especially in the assessment of margin
status . Aberrant expression of E-cadherin, including positive staining in areas with
lobular morphology and negative staining in areas with obvious gland formation, has also been described
in 5 cases of invasive carcinoma .
Mahler-Araujo and colleagues have observed reduction or complete loss of E-cadherin immunoreactivity
in some non-lobular breast carcinomas. E-cadherin staining was negative in 34.6% of triple negative
carcinomas, and in 40.7% of basal carcinomas (defined as triple negative and either EGFR and/or CK5/6
positive). Interestingly, the group of E-cadherin negative carcinomas also included 11.3% of ER positive
tumors, and 21.1% of grade 1 tumors (4 cases only), in addition to grade 3 carcinomas (17.4%)
We have also observed sporadic cases of aberrant reactivity for E-cadherin, most often characterized
by loss of membranous reactivity in lesions with obvious ductal morphology.
Therefore, caution should always be used in the analysis of E-cadherin immunoreactivity (just as for
any other immunostaining pattern), and the results should always be interpreted in combination with
Take home points
- E-cadherin immunoreactivity is useful in the diagnostic
evaluation of carcinomas in situ with indeterminate features.
- Lack of membranous immunoreactivity for E-cadherin
supports lobular differentiation in most cases, but few exceptions exist.
- The differential diagnosis of solid carcinoma in situ
with necrosis and calcifications includes special variants of LCIS.
- Special LCIS variants are more aggressive than classic
- Additional surgery is recommended when special LCIS with
central necrosis and massive acinar distention is present at or near a margin.
Table I - Morphologic Features Helpful in the Differential Diagnosis of Classic LCIS Versus Special LCIS Versus DCIS
| || C-LCIS || S-LCIS || DCIS|
|Dishesive Growth || Present || Present || Absent|
|Cell Polarity || Absent || Absent || Usually Present|
|Tdlu Involvement || Typical, Distended Acini || Typical, Massive Acinar Expansion || Possible "Lobular Cancerization"|
|Interdigitating Myoepithelium || Common || May be Focally Present || Absent|
|Necrosis || Absent || Often Present || Often Present|
|Mitoses || Absent || Present || Present|
|Calcifications ||Rare || Frequent || Frequent|
|Cell Shape || Round "Fried Egg" || Round to Plasmacytoid || Columnar|
|Cytoplasm || Scant || Scant to Abundant || Variable|
|Nuclear Pleomorphism || Absent || Present in Pleomorphic Variant || Absent to Present|
|Nucleoli || Rare || Common || Common|
|Associated Invasive Carcinoma || Possible || Frequent || Possible to Frequent|
C-LCIS= classical LCIS; S-LCIS= special variants of LCIS
- Jacobs TW, Pliss N, Kouria G, Schnitt SJ. Carcinomas in situ of the breast with indeterminate features: role of E-cadherin staining in categorization. Am J Surg Pathol. Feb 2001;25(2):229-236.
- Maluf HM, Swanson PE, Koerner FC. Solid low-grade in situ carcinoma of the breast: role of associated lesions and E-cadherin in differential diagnosis. Am J Surg Pathol. Feb 2001;25(2):237-244.
- Fadare O, Dadmanesh F, Alvarado-Cabrero I, et al. Lobular intraepithelial neoplasia [lobular carcinoma in situ] with comedo-type necrosis: A clinicopathologic study of 18 cases. Am J Surg Pathol. Nov 2006;30(11):1445-1453.
- Rosen PP. Lobular carcinoma in situ and atypical lobular hyperplasia. In: Pine Jr JW, ed. Rosen's Breast Pathology. Philadelphia, PA: Lippincott Williams & Wilkins, a Wolters Kluwer business; 2009:637-689.
- Sneige N, Wang J, Baker BA, Krishnamurthy S, Middleton LP. Clinical, histopathologic, and biologic features of pleomorphic lobular (ductal-lobular) carcinoma in situ of the breast: a report of 24 cases. Mod Pathol. Oct 2002;15(10):1044-1050.
- Palacios J, Sarrio D, Garcia-Macias MC, Bryant B, Sobel ME, Merino MJ. Frequent E-cadherin gene inactivation by loss of heterozygosity in pleomorphic lobular carcinoma of the breast. Mod Pathol. Jul 2003;16(7):674-678.
- Simpson PT, Reis-Filho JS, Lambros MB, et al. Molecular profiling pleomorphic lobular carcinomas of the breast: evidence for a common molecular genetic pathway with classic lobular carcinomas. J Pathol. Jul 2008;215(3):231-244.
- 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. Sep 2005;207(1):1-13.
- World Health Organization Classification of Tumors. Pathology and Genetics of Tumours of Breast and Female Genital Organs. In: Tavassoli F, Devilee P, eds. Lyon, France: IARC Press; 2003:37-38.
- Sapino A, Frigerio A, Peterse JL, Arisio R, Coluccia C, Bussolati G. Mammographically detected in situ lobular carcinomas of the breast. Virchows Arch. May 2000;436(5):421-430.
- Dabbs DJ, Carter G, Fudge M, Peng Y, Swalsky P, Finkelstein S. Molecular alterations in columnar cell lesions of the breast. Mod Pathol. Mar 2006;19(3):344-349.
- Sarrio D, Perez-Mies B, Hardisson D, et al. Cytoplasmic localization of p120ctn and E-cadherin loss characterize lobular breast carcinoma from preinvasive to metastatic lesions. Oncogene. Apr 22 2004;23(19):3272-3283.
- Bratthauer GL, Moinfar F, Stamatakos MD, et al. Combined E-cadherin and high molecular weight cytokeratin immunoprofile differentiates lobular, ductal, and hybrid mammary intraepithelial neoplasias. Hum Pathol. Jun 2002;33(6):620-627.
- Moinfar F, Man YG, Lininger RA, Bodian C, Tavassoli FA. Use of keratin 35betaE12 as an adjunct in the diagnosis of mammary intraepithelial neoplasia-ductal type--benign and malignant intraductal proliferations. Am J Surg Pathol. Sep 1999;23(9):1048-1058.
- Goldstein NS, Bassi D, Watts JC, Layfield LJ, Yaziji H, Gown AM. E-cadherin reactivity of 95 noninvasive ductal and lobular lesions of the breast. Implications for the interpretation of problematic lesions. Am J Clin Pathol. Apr 2001;115(4):534-542.
- Da Silva L, Parry S, Reid L, et al. Aberrant expression of E-cadherin in lobular carcinomas of the breast. Am J Surg Pathol. May 2008;32(5):773-783.
- Harigopal M, Shin SJ, Murray MP, Tickoo SK, Brogi E, Rosen PP. Aberrant E-cadherin staining patterns in invasive mammary carcinoma. World J Surg Oncol. Nov 14 2005;3:73.
- Mahler-Araujo B, Savage K, Parry S, Reis-Filho JS. Reduction of E-cadherin expression is associated with non-lobular breast carcinomas of basal-like and triple negative phenotype. J Clin Pathol. May 2008;61(5):615-620.