Lobular carcinoma ''in situ'' (LCIS) is an incidental microscopic finding with characteristic cellular morphology and multifocal tissue patterns. The condition is a
laboratory diagnosis
Clinical pathology is a medical specialty that is concerned with the diagnosis of disease based on the laboratory analysis of bodily fluids, such as blood, urine, and tissue homogenates or extracts using the tools of chemistry, microbiology, h ...
and refers to unusual cells in the
lobules of the
breast
The breast is one of two prominences located on the upper ventral region of a primate's torso. Both females and males develop breasts from the same embryological tissues.
In females, it serves as the mammary gland, which produces and sec ...
.
The lobules and acini of the terminal duct-lobular unit (TDLU), the basic functional unit of the breast, may become distorted and undergo expansion due to the abnormal proliferation of cells comprising the structure.
These changes represent a spectrum of atypical epithelial lesions that are broadly referred to as
lobular neoplasia (LN).
One subset of LN can be defined as LCIS based on specific cellular traits and tissue changes seen histologically. These lesions are preceded by atypical lobular
hyperplasia and may follow a linear progression to
invasive lobular carcinoma (ILC), with specific genetic aberrations.
This process coincides with the progression of ductal neoplasia to
ductal carcinoma in situ
Ductal carcinoma in situ (DCIS), also known as intraductal carcinoma, is a pre-cancerous or non-invasive cancerous lesion of the breast. DCIS is classified as Stage 0. It rarely produces symptoms or a breast lump one can feel, typically being d ...
and invasive carcinoma. Rarely, terminal ducts may be involved in lobular neoplasia, known as
pagetoid spread.
Many do not consider LCIS to be a true case of
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
, but it can indicate an increased risk of future cancer.
In 2018, the eighth edition of the American Joint Committee on Cancer (AJCC) removed LCIS from tumor staging and considers it a benign entity.
Causes
Genetics
Cells of Lobular Neoplasia (LN), including both Atypical Lobular Hyperplasia and LCIS, and ILC share common genetic alterations, perhaps accounting, in part, for the similarities in histologic appearance. Classic LCIS and invasive lobular lesions are low-grade ER and PR-positive cancers, referring to the positive expression of Estrogen and Progesterone receptors on the neoplastic cells (determined via immunohistochemistry).
These entities are also both classically negative for HER2 (human epidermal growth factor receptor 2). These hormone and growth factor receptors are clinically significant, as they represent targets for chemotherapy. Chromosomal alterations have also been consistently observed between LCIS and ILC – namely, loss of 16q and gain of 1q, referring to the loss of the long arm (designated q) of chromosome 16 and an extra copy of the long arm of chromosome 1. Furthermore,
e-cadherin
Cadherin-1 or Epithelial cadherin (E-cadherin), (not to be confused with the APC/C activator protein CDH1) is a protein that in humans is encoded by the ''CDH1'' gene. Mutations are correlated with gastric, breast, colorectal, thyroid, and ovarian ...
, the
transmembrane
A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequent ...
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
mediating
epithelial
Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercell ...
cell adhesion, exhibits loss of expression on LN cells, and P120 Catenin exhibits cytoplasmic reactivity.
The mechanism for these findings is explained by E-cadherin normally interacting with p120 catenin in the cytoplasm. When e-cadherin is lost, p120 cadherin builds up in the cytoplasm of the neoplastic cells – thus, producing a positive reaction in immunohistochemical testing.
LCIS often have the same genetic alterations (such as loss of heterozygosity on chromosome 16q, the locus for the e-cadherin gene) as the adjacent area of invasive carcinoma.
These observations, along with genomic analysis for clonal relationships between the cells of LCIS and ILC, support LCIS as being a precursor to ILC, and that the lesions encompassed by the broader category of Lobular Neoplasia (LN) fall on a linear spectrum of progression. LCIS is often found concurrently with foci of invasive carcinoma and multiple studies have shown, using genetic sequencing techniques, that synchronous LCIS and ILC share clonal cell populations, or originate from the same line of mutated cells.
Diagnosis
Lobular lesions are incidental findings without reliable clinical correlations. Routine mammograms showing suspicious radiologic findings warrant a core needle biopsy in the abnormal area seen radiologically, and may or may not show lobular neoplasia histologically.
Morphology
Classically, LN, including LCIS, is characterized by enlargement and distension of acini making up the TDLU by proliferation of monomorphic, dyshesive, small, round, or polygonal cells with loss of polarity and inconspicuous cytoplasm. Essentially, groups of round, almost identical looking cells that fill and expand the lobule spaces, occasionally extending into the adjacent terminal ducts – termed Pagetoid extension.
Like the cells of atypical lobular hyperplasia and invasive lobular carcinoma, the abnormal cells of LCIS consist of small cells with oval or round nuclei and small nucleoli detached from each other.
Mucin
Mucins () are a family of high molecular weight, heavily glycosylated proteins (glycoconjugates) produced by epithelial tissues in most animals. Mucins' key characteristic is their ability to form gels; therefore they are a key component in most ...
-containing signet-ring cells are commonly seen. LCIS generally leaves the underlying architecture intact and recognisable as lobules.
Estrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal ac ...
and
progesterone receptors are present and
HER2/neu
Receptor tyrosine-protein kinase erbB-2 is a protein that in humans is encoded by the ''ERBB2'' gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The human protein is also frequently refer ...
overexpression is absent in most cases of LCIS.
Cell borders are indistinct and neither mitotic activity or necrosis are seen. In addition, in situ and invasive lesions exhibit loss of cellular adhesion, considered a characteristic histologic feature, due to the fact that e-cadherin expression is lost (transmembrane protein involved in epithelial cell adhesion).
ALH and LCIS are cytologically indistinguishable, so a quantitative threshold is used to classify lesions into either category. A diagnosis of LCIS requires more than half of the acini in an involved lobular unit to be filled with LN cells and the central lumen of the acini should not be visible.
Proliferation of LN cells that do not meet these histological characteristics are either Atypical Lobular Hyperplasia or simply lobular distension. Small degrees of cytologic variation can be observed and subsequent subtypes have been described. However, these subtypes have not been shown to be of clinical usefulness and does not have bearing on whether or not LCIS will progress to full invasive carcinoma.
[
]
Immunohistochemistry
Lobular Carcinoma In Situ may mimic low grade Ductal Carcinoma In Situ histologically. In these scenarios, pathologists may employ immunohistochemical testing to differentiate between entities.
This involves using marked antibodies synthetically developed to bind to target proteins expressed on or inside cells. Specifically, in LCIS, antibodies targeting the e-cadherin protein (or lack thereof) and p120 catenin proteins are used to differentiate LCIS from DCIS. Due to the fact that LCIS shows lack of e-cadherin expression on cell membranes and subsequent p120 catenin buildup in the cytoplasm, lesions that show positive membrane immunoreactivity for e-cadherin are diagnosed as DCIS.
Treatment
Lobular Carcinoma In-situ is both a risk factor and precursor of invasive carcinoma. Furthermore, it is a non-obligate precursor. In other words, LCIS represents a distinct entity in the developmental pathway of cancer that does not guarantee invasive carcinoma. That being said, the historical approach of radical mastectomy (surgical removal of entire breast and axillary lymph nodes) has been substituted by more conservative approaches.
Observation is the preferred management option if LCIS is found to occur alone without accompanying infiltrating or invasive carcinoma. LCIS may be treated with close
clinical follow-up (frequent scheduled checkups) and
mammographic screening,
tamoxifen
Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and treat breast cancer in women and men. It is also being studied for other types of cancer. It has b ...
or related hormone controlling drugs to reduce the risk of developing cancer, or, if patients and providers would like a less conservative option, bilateral
prophylactic
Preventive healthcare, or prophylaxis, consists of measures taken for the purposes of disease prevention.Hugh R. Leavell and E. Gurney Clark as "the science and art of preventing disease, prolonging life, and promoting physical and mental hea ...
mastectomy
Mastectomy is the medical term for the surgical removal of one or both breasts, partially or completely. A mastectomy is usually carried out to treat breast cancer. In some cases, women believed to be at high risk of breast cancer have the operat ...
.
Some surgeons consider bilateral prophylactic mastectomy to be overly aggressive treatment except for certain high-risk cases.
This is in part due to the fact that multiple studies have shown no significant different in mortality due to breast cancer between women who underwent surveillance and those who elected for the mastectomy.
When Lobular Neoplasia, or specifically, LCIS, is found on core needle biopsy during routine workups, the National Comprehensive Cancer Network (NCCN) recommends the surgeon perform an excisional biopsy of the region to allow pathologists to rule out concurrent DCIS or invasive cancer. It has been widely reported in the literature that 10-30% of patients with a diagnosis of LCIS on core needle biopsy will receive an upstaged diagnosis after excisional.
If LCIS remains the only diagnosis after the excisional biopsy, NCCN guidelines recommend clinical follow-up every 6–12 months with annual diagnostic mammograms.
Prognosis
![Histopathology of invasive lobular carcinoma, next to lobular carcinoma in situ, annotated](https://upload.wikimedia.org/wikipedia/commons/f/f2/Histopathology_of_invasive_lobular_carcinoma%2C_next_to_lobular_carcinoma_in_situ%2C_annotated.jpg)
Lobular neoplasia is considered pre-cancerous, and LCIS is an indicator (marker) for increased risk of developing invasive breast cancer in women. This risk extends more than 20 years. Most of the risk relates to subsequent
invasive ductal carcinoma
Invasive carcinoma of no special type (NST) also known as invasive ductal carcinoma or ductal NOS and previously known as invasive ductal carcinoma, not otherwise specified (NOS) is a group of breast cancers that do not have the "specific different ...
rather than to
invasive lobular carcinoma.
Older studies have shown that the increased risk of developing invasive cancer is equal for both breasts, and more recent studies suggest that while both breasts are at increased risk of developing invasive cancer, the
ipsilateral
Standard anatomical terms of location are used to unambiguously describe the anatomy of animals, including humans. The terms, typically derived from Latin or Greek roots, describe something in its standard anatomical position. This position prov ...
(same side) breast may be at greater risk.
On the other hand, analysis of SEER data (Pooled data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results program) revealed the cumulative risk of developing invasive breast cancer after LCIS diagnosis to be 7.1% at 10 years, with equal predisposition in both breasts. The annual risk of developing invasive breast cancer after a diagnosis of LCIS ranges from 1-2%, and the invasive cancers may include intraductal carcinoma as well as intralobular carcinoma, with increased risk of developing invasive ductal.
Research regarding the cumulative risk of developing invasive cancer at 5 year intervals varies, with the risk at 10 years being 13—15%, the risk at 20 years being 26-35%, and the risk at 35 years being between 35% and over 50%. The relative risk of developing invasive carcinoma after LCIS diagnosis is 8-10 times greater than in the general population.
The overall 5-year survival rate of lobular carcinoma in situ has been estimated to be 97%.
LCIS (lobular neoplasia is considered pre-cancerous) is an indicator (marker) identifying women with an increased risk of developing invasive breast cancer. This risk extends more than 20 years. Most of the risk relates to subsequent
invasive ductal carcinoma
Invasive carcinoma of no special type (NST) also known as invasive ductal carcinoma or ductal NOS and previously known as invasive ductal carcinoma, not otherwise specified (NOS) is a group of breast cancers that do not have the "specific different ...
rather than to
invasive lobular carcinoma.
While older studies have shown that the increased risk is equal for both breasts, a more recent study suggests that the
ipsilateral
Standard anatomical terms of location are used to unambiguously describe the anatomy of animals, including humans. The terms, typically derived from Latin or Greek roots, describe something in its standard anatomical position. This position prov ...
(same side) breast may be at greater risk.
Epidemiology
![Pie chart of incidence and prognosis of histopathologic breast cancer types](https://upload.wikimedia.org/wikipedia/commons/b/bd/Pie_chart_of_incidence_and_prognosis_of_histopathologic_breast_cancer_types.png)
LCIS is identified in 0.5-1.5% of benign breast biopsies. These biopsies are often done in response to suspicious mammographic findings, as discussed in the Diagnosis section of this article. LCIS is identified in 1.8-2.5% of all breast biopsies (including those that show histologic evidence of other Lobular or Ductal Neoplasia.
The incidence of LCIS in women without prior history of breast neoplasia has increased from 0.90 per 100,000 persons in 1980 to 3.19 per 100,000 persons in 1998 – but this is likely due to the increased frequency of mammography as a screening tool. This is supported by the fact that the magnitude of increase in frequency of LCIS was greatest among women over 50 years of age (the group most likely to participate in routine mammographic screening).
History
In 1941, a seminal publication by Foote and Stewart introduced the term “Lobular Carcinoma In Situ,” using it to categorize a spectrum of cytologic changes that were precursors to invasive cancer. They described these changes as unrecognizable on gross examination, noninfiltrating, and multifocal, with the cells losing their apical-basal distinction (loss of polarity) and varying in shape but not size.
They further predicted that though still contained within the basement membrane, LCIS can indicate an increased risk of future cancer. Researchers and physicians currently treat the diagnosis as a precursor lesion and risk factor for subsequent development of breast cancer.
This article has thus far described Classical LCIS, and there are 2 other variants of LCIS: Pleomorphic LCIS (PLCIS) and Apocrine PLCIS, which may be discussed separately in a separate article.
Unlike
ductal carcinoma ''in situ'' (DCIS), LCIS is not associated with
calcification
Calcification is the accumulation of calcium salts in a body tissue. It normally occurs in the formation of bone, but calcium can be deposited abnormally in soft tissue,Miller, J. D. Cardiovascular calcification: Orbicular origins. ''Nature Ma ...
, and is typically an incidental finding in a biopsy performed for another reason. LCIS only accounts for about 15% of the ''in situ'' (ductal or lobular) breast cancers.
See also
*
Breast cancer
Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a r ...
*
Carcinoma ''in situ''
References
External links
{{Epithelial neoplasms
Breast cancer