Breast malignant, males, children
In situ carcinoma
Lobular carcinoma in situ (LCIS)

Author: Sucheta Srivastava, M.D. (see Authors page)
Editorial Board Member Review: Emily S Reisenbichler, M.D.

Revised: 12 October 2017, last major update September 2017

Copyright: (c) 2002-2017, PathologyOutlines.com, Inc.

PubMed Search: Lobular carcinoma in situ [title]

Cite this page: Srivastava, S. Lobular carcinoma in situ (LCIS). PathologyOutlines.com website. http://pathologyoutlines.com/topic/breastmalignantlcis.html. Accessed December 13th, 2017.
Definition / general
  • Lobulocentric proliferation of small uniform cells which fill and distend most of the acini in the involved lobule
Essential features
  • Lobulocentric proliferation of monomorphic cells which fill and distend lobular units, in contrast to atypical lobular hyperplasia (ALH, only partially involves the lobule by filling up the acini without significant distention)
  • Cells are small (slightly larger than lymphocytes), uniform, round and loosely cohesive, may have intracytoplasmic mucin vacuoles, dense cytoplasm and distinct cell membranes
  • Nuclei are small, monotonous, eccentric, without significant atypia or mitoses, nucleoli can be seen
  • Can extend into the ducts when extensive
  • LCIS is no longer classified as Tis because it is considered a risk factor, not a malignancy (Amin: AJCC Cancer Staging Manual, 8th Edition, 2016)
Terminology
  • "Lobular neoplasia" terminology is used by some authors to denote the histologic overlap / frequent coexistence of ALH and LCIS (Cancer 1978;42:737)
ICD-10 coding
  • D05 carcinoma in situ of breast
    • D05.0 lobular carcinoma in situ of breast
    • D05.00 lobular carcinoma in situ of unspecified breast
    • D05.01 lobular carcinoma in situ of right breast
    • D05.02 lobular carcinoma in situ of left breast
Epidemiology
  • Estimated incidence of 2.7 per 100K
  • Present in 0.5 to 3.8% of benign breast specimens (Cancer 1978;42:737, Hum Pathol 1991;22:1232)
  • Mean age 44 - 46 years
  • Often an incidental microscopic finding
  • No clinical features (palpable mass) or radiological features and usually not associated with microcalcifications
  • Often multicentric (50%), frequently bilateral (30%)
  • Confers a relative risk (in either breast) of subsequent invasive carcinoma of 8 - 10 times
Etiology
  • Most often diagnosed in premenopausal women
  • Only 10 - 12% occur in postmenopausal women
  • Not related to use of exogenous estrogens
Clinical features
  • No specific clinical features
  • Most times incidental finding in biopsy for some other mass producing lesion such as a fibroadonoma
  • 50 - 60% are multicentric, 30 - 40% are bilateral
  • Presence of LCIS in the background of invasive ductal carcinoma also implies high risk of bilaterality (Surgery 1982;91:234)
  • LCIS is considered a precursor lesion to invasive lobular carcinoma, based on the information below and simultaneous genetic testing (Mod Pathol 2010;23 Suppl 2:S14)
    • There is significant risk of invasive carcinoma in another quadrant or opposite breast, which may be coexisting
    • Time to invasive carcinoma after initial diagnosis of LCIS on biopsy is 15 - 30 years
    • Invasive carcinoma can be ductal or lobular but lobular type is much more common
    • Ipsilateral invasive lobular carcinoma is three times more common than contralateral invasive lobular carcinoma
  • LCIS is no longer classified as Tis because it is considered a risk factor, not a malignancy (Amin: AJCC Cancer Staging Manual, 8th Edition, 2016)
Diagnosis
Radiology description
  • There are no radiologic features specific to LCIS
  • Microcalcifications are not commonly seen in LCIS
    • Only 4 of 50 patients LCIS had microcalcifications in the LCIS (which were confirmed on pathology) (J Natl Cancer Inst 1979;62:639)
    • Microcalcifications are usually present in commonly coexisting lesions such as sclerosing adenosis, columnar cell hyperplasia, atrophic lobules and ducts, collagenous spherulosis
  • LCIS can have associated imaging abnormalities, most commonly grouped amorphous calcifications on mammography, a shadowing, avascular, irregular, hypoechoic mass on US or heterogeneous nonmass-like enhancement with persistent enhancement kinetics on MRI (Acad Radiol 2013;20:463)
  • Florid LCIS can cause marked expansion of ducts and lobules which may be extensive
    • It can frequently have necrosis and calcifications similar to DCIS
    • Appearance on mammography can resemble / suggest DCIS
Prognosis and treatment
  • Clinical follow up and biopsy of contralateral breast if indicated is recommended for LCIS
  • Surgical biopsy is recommended when core needle biopsy contains LCIS accompanied by "high risk" proliferative lesions (radial scar / ADH), when florid LCIS present or discordance between histology and imaging (AJR Am J Roentgenol 1999;173:291)
  • Clinical trials with antiestrogens in patients with LCIS only and increased risk of subsequent breast carcinoma (positive family history) have shown 56% reduction in risk of developing subsequent carcinoma (Recent Results Cancer Res 2009;181:113)
  • Multiple studies have demonstrated that presence of LCIS at or close to the margin of resection does not influence the local recurrence of invasive carcinoma
  • However coexistence of LCIS with DCIS significantly increases the frequency of ipsilateral recurrence of DCIS when patients have conservative surgical management (Cancer 2009;115:1203)
  • Obtaining negative surgical margins in excision specimens for classic LCIS is not necessary or recommended
  • However, there is no clear consensus among surgeons regarding the management of florid LCIS at the margins, due to insufficient outcome data (Arch Pathol Lab Med 2017 Jun 2 [Epub ahead of print])
Case reports
Clinical images

Images hosted on PathOut server:

MRI, contributed by Mark R. Wick, M.D.

Gross description
  • LCIS by itself does not cause any grossly visible / palpable alteration in breast tissue
  • There may be abnormal findings secondary to the coexisting lesions / proliferative changes such as cysts, firm / hard tissue or nodularity, which are not attributable to LCIS
Microscopic (histologic) description
  • LCIS involves terminal duct lobular unit (TDLU) filling and expanding acini
  • Proliferation of monomorphic, loosely cohesive cells that are evenly spaced ("marbles in a bag"), slightly larger than normal, with indistinct cell borders and pale cytoplasm, have uniform small nuclei, evenly distributed chromatin and inconspicuous nucleoli
  • Two types of cells are described:
    • Type A: loosely cohesive cells with uniform, small nuclei and homogenous chromatin, inconspicuous nucleoli
    • Type B: poorly cohesive cells with mild to moderate nuclear variability and prominent nucleoli
  • Intracytoplasmic vacuoles / lumina, mucin with eccentric nuclei pushed against membrane (signet ring cells) can be seen but this feature is not specific for LCIS
  • Classic LCIS does not show nuclear pleomorphism, mitosis, comedo necrosis
  • LCIS most often involves lobules but may also grow along the basement of extralobular ducts in "pagetoid fashion"
  • "Pagetoid spread" is characteristic spread of malignant cells underneath normal terminal duct epithelium in a cloverleaf pattern, without destroying the ductal epithelium and filling up the ductal lumina
  • LCIS may secondarily involve or arise in sclerosing adenosis, radial scar, fibroadenoma, collagenous spherulosis and papilloma
  • Atypical lobular hyperplasia (ALH) and LCIS have been considered distinct entities; the difference between the two forms relates to the extent and degree of distension of acini
    • Classify as LCIS if lobular proliferation involves, expands or distorts at least 50%+ acini in lobule; otherwise call atypical lobular hyperplasia
  • "Rosen triad" - tubular carcinoma, columnar cell lesions, LCIS / ALH
  • Columnar cell lesions commonly have microcalcifications which frequently are the targets on mammography leading to discovery of LCIS
  • 
"Florid LCIS" refers to a growth pattern of LCIS in which neoplastic cells fill and expand ducts in a solid architectural pattern, similar to the solid growth seen in DCIS
  • Comedo type necrosis can be present in LCIS that has the typical cytological and architectural features, and although atypical, this (by itself) should not be diagnosed as pleomorphic LCIS (Am J Surg Pathol 2006;30:1445)
Microscopic (histologic) images

Scroll to see all images:


Images hosted on PathOut server:


Images contributed by Sucheta Srivastava, M.D.

LCIS, classic type 4x - H&E

LCIS, classic type 10x - H&E

LCIS, classic type 20x - H&E

LCIS, classic type 4x -
E-cadherin (IHC)

LCIS, classic type 4x - ER (IHC)

LCIS, classic type 4x - HER2 (IHC)

LCIS, classic type 4x -
E-cadherin / p120 (IHC)

LCIS, classic type 10x -
E-cadherin / p120 (IHC)



AFIP fascicle images (3rd series):

Normal epithelium is replaced
by uniform cells that fill
acini, individual glands
are round and discrete

Discrete acini have
haphazardly arranged
monomorphic cells with scant
cytoplasm and dark nuclei

Monomorphic cells
have no specific
orientation to
basement membrane

Pagetoid spread of LCIS cells into normal acini (arrow)

Type A (central) and type B (peripheral) cells

Involvement of duct
and lobule, with pagetoid
extension beneath duct
epithelium in lower left

Layer of LCIS
cells beneath
attenuated
ductal epithelium

Signet ring cells

Cytoplasmic vacuoles (arrows)

Serrated (sawtooth)
pattern with LCIS
involvement of ducts
and ductules only


Cloverleaf pattern
in atrophic TDLU in
postmenopausal
woman

Resembles
invasive carcinoma
but has alveolar
pattern of LCIS

Merging with DCIS

With microinvasion (linear strands or single cells)

Contributed by Mark R. Wick, M.D.

Fibroadenoma with LCIS and invasive lobular carcinoma; contributed by Semir Vranić, M.D.



Images hosted on other servers:

Various images

Lobules are distended by monomorphic cells

Intracytoplasmic lumina


Involving sclerosing adenosis
(Fig. 4a / b)

Comparison with low grade DCIS

Various images

Lobules are distended by monomorphic cells

Prominent intracytoplasmic vacuoles


With comedonecrosis

Various images

With adjacent infiltrating lobular carcinoma

Core biopsy

Involving adenosis



Stains:

Mucicarmine+

Fig. 3a:
factor VIII
Fig. 3b: low MIB1 staining

Fig. 6: LCIS - aberrant
E-cadherin staining

Immunoprofile of E-cadherin, p120 catenin and their cocktail in LCIS

LCIS is E-cadherin negative

E-cadherin negative (Fig. G) and p120 catenin positive (Fig. J)

Cytology description
  • Neoplastic cells in classic LCIS are commonly described as cells with scant cytoplasm and small, round, bland nuclei
  • Cells are present in loose cohesive groups, with occasional intracytoplasmic lumina and eccentric nuclei; cells are associated with myoepithelial cells
  • Lobular carcinoma may be suspected in an FNA sample if signet ring cells are identified associated with detached fragments of lobular epithelium; however definitive diagnosis in these sparely cellular samples is rarely possible and aspiration samples cannot distinguish between in situ and invasive lesions
  • ThinPrep: tight or loosely cohesive clusters of crowded mildly enlarged nuclei with at least moderate cellularity; occasional single epithelial cells, small but prominent nucleoli, intracytoplasmic lumina (Diagn Cytopathol 2005;32:276)
  • In this setting, E-cadherin is very useful; it is negative in both classic and pleomorphic LCIS
Positive stains
Negative stains
Molecular / cytogenetics description
  • Comparative genomic hybridization studies of synchronous LCIS and invasive lobular carcinoma have consistently demonstrated loss of 16q and gain of 1q (88%); recent molecular data, using next generation sequencing technology have supported clonal relatedness between the two
  • Loss of 16q (Breast Cancer Res Treat 2005;90:249, Hum Pathol 2001;32:292) and gain of 1q (Cancer Res 1998;58:4721, Mol Pathol 2000;53:118)
    • Loss of 16q and gain of 1q are also seen other ER positive proliferations, including columnar cell lesions and well differentiated, invasive ductal carcinoma, including tubular carcinoma, low grade DCIS and atypical ductal hyperplasia
    • This has led to an understanding of LCIS belonging to a group lesions in a low grade, ER positive pathway of breast carcinogenesis (Histopathology 2011;59:549, Arch Pathol Lab Med 2017 Jun 2 [Epub ahead of print])
  • Mutations in the CDH1 (tumor suppressor gene), entirely somatic, can result due to loss of the wild type allele / premature truncation of the translation / CDH1 promotor methylation, which eventually result in loss of membranous E-cadherin expression
  • Other tumor suppressor genes located on #16, which have shown loss of expression in LCIS:
    1. CCCTC binding factor (CTCF) gene, a transcriptional regulator of several genes linked to tumorigenesis
    2. Dipeptidase 1 (DPEP1) gene, which is involved in the metabolism of an important glutathione, which may have a role in the degradation of the surrounding extracellular matrix
  • Other recurrent chromosomal alterations have been inconsistently seen in LCIS: losses of 17q (home of ERBB2 and NF1), 17p (home of TP53), 16p (home of CCNF [cyclin F]),13q (home of RB [RB binding protein]), 12q, 11q (home of CCND1 [cyclin D1], MEN1 [multiple endocrine neoplasia 1] , ATM [ATM serine / threonine kinase]); also losses of 9p and 8p and gains of 6p and 8p

  • Recurrent alterations observed in florid LCIS include amplification of 11q13.3 (CCDN1 gene), loss of 8p, loss of 17p and loss of 11q
    • HER2 was amplified in 10% of florid LCIS cases
    • Florid LCIS showed a more complex genome, with more aberrations than classic LCIS; it also had a greater similarity in its genetic complexity to apocrine pleomorphic LCIS (Arch Pathol Lab Med 2017 Jun 2 [Epub ahead of print])
Videos

Histopathology breast - lobular carcinoma in situ

Differential diagnosis
  • Atypical lobular hyperplasia: < 50% acini in a lobule are involved, normal central lumina in some acini are still visible, sized lobule
  • Clear cell change: variant of apocrine metaplasia, both may be combined in a single lobule
  • DCIS:
    1. Cancerization of lobules by DCIS: cohesive cells with high grade cytology, comedo necrosis, background of invasive ductal carcinoma
    2. Cribriform DCIS and collagenous spherulosis involved by LCIS: lumen of DCIS are empty or contain calcifications, necrosis; myoepithelial cells in DCIS surround the periphery of the involved lobule; collagenous spherulosis is made of hyaline fibrillary material and is lined by myoepithelial cells
    3. In situ carcinoma with mixed ductal and lobular phenotype: mixed architectural and cytological features; heterogeneous expression of E-cadherin
    4. Solid low grade DCIS: cohesive cells, microacini with cells polarized around microlumen, no intracytoplasmic vacuoles, no pagetoid ductal involvement, E-cadherin positive
  • Myoepithelial hyperplasia: normal glandular cells are surrounded by cells with clear cytoplasm, small, round, dark nuclei; myoepithelial markers positive
  • Pseudolactational hyperplasia: postmenopausal women, vacuolated cytoplasm, apical apocrine tufts, hyperchromatic / atypical nuclei, psammoma-like calcifications
Board review question #1
What is the Rosen triad?

  1. LCIS, flat epithelial atypia, columnar cell hyperplasia
  2. Tubular carcinoma, DCIS, apocrine metaplasia
  3. Tubular carcinoma, LCIS, columnar cell hyperplasia
  4. Tubular carcinoma, LCIS, flat epithelial atypia
Board review answer #1
C. Tubular carcinoma, LCIS, columnar cell hyperplasia
Board review question #2
Which of the following is false?

  1. E-cadherin is inactivated via CDH1 gene mutation located on chromosome 16
  2. Generalized risk includes risk of subsequent invasive ductal or lobular carcinoma
  3. LCIS belongs to group lesions in a low grade, ER+ pathway of breast carcinogenesis
  4. Loss of nuclear expression of E-cadherin is the defining immunohistochemical feature of LCIS
Board review answer #2
D. Loss of nuclear expression of E-cadherin is the defining immunohistochemical feature of LCIS
Board review question #3
Which of the following is NOT a feature of LCIS?

  1. Intracytoplasmic lumen / vacuoles
  2. Intranuclear inclusions
  3. Loosely cohesive cells
  4. Plasmacytoid cells
  5. Signet ring cells
Board review answer #3
B. Intranuclear inclusions