Lobular Carcinoma In Situ



Lobular Carcinoma In Situ












LCIS is characterized by a neoplastic proliferation of small, uniform, dyshesive cells that expand the acini of the terminal ductal lobular unit image. Signet ring cells are often present image.






A characteristic of both in situ and invasive lobular neoplasia is the loss of E-cadherin expression in tumor cells image. The surrounding myoepithelial cells show weak E-cadherin positivity image.


TERMINOLOGY


Abbreviations



  • Lobular carcinoma in situ (LCIS)


Synonyms



  • Lobular intraepithelial neoplasia (LIN), includes atypical lobular hyperplasia (ALH) and LCIS


Definitions



  • Neoplastic proliferation of epithelial cells lacking cell adhesion, confined to ducts and lobules, and filling and expanding at least 1/2 of 1 lobular unit


ETIOLOGY/PATHOGENESIS


Molecular Pathology



  • Hallmark molecular feature of all lobular neoplasia (ALH, LCIS, and ILC) is loss of cellular cohesion



    • In > 95% of lesions, this is due to loss of expression of E-cadherin (CDH11) located on chromosome 16q



      • E-cadherin plays major role in intercellular adhesion and cell polarity


      • Cytoplasmic portion of E-cadherin is attached to actin cytoskeleton by binding β- or γ-catenin


    • Absence of E-cadherin is due to combinations of mechanisms leading to biallelic inactivation of gene



      • Allelic deletion (loss of heterozygosity 16q), CDH1 gene mutation, promoter silencing (hypermethylation)


    • In rare cases, loss of cohesion is due to defects in catenins or possibly other related proteins



      • Carcinomas have typical morphology, but nonfunctional E-cadherin is present


      • Other proteins, such as catenins, may have abnormal expression patterns


  • Distribution of LCIS suggests association with germline mutation



    • LCIS is not specifically associated with mutations in BRCA1, BRCA2, or CDH11 (E-cadherin)



      • Families with germline mutations in CDH11 are predominantly at risk for signet ring cell carcinomas of the stomach, with fewer cases of lobular carcinoma


    • Association with other genes is being investigated


CLINICAL ISSUES


Epidemiology



  • Incidence



    • 0.5-4% of breast biopsies


  • Age



    • Mean age: 44-46 years; 80-90% are premenopausal


Site



  • LCIS is frequently found as multiple foci within the same or both breasts



    • Up to 50% of patients have bilateral LCIS


    • Multicentric foci have been described in up to 80% of patients undergoing mastectomy for LCIS


Presentation



  • Classic LCIS is incidental finding



    • Does not form palpable mass or mammographic lesion


  • Variant forms of LCIS may be associated with calcifications detected by mammography


Natural History



  • LCIS, ALH, and flat epithelial atypia/columnar cell change share similar molecular and cytogenetic features



    • Columnar cell change often coexists with LCIS


    • May be part of morphologic continuum in low-grade neoplasia pathway


  • Genetic studies have found similar or identical mutations in LCIS and corresponding invasive lobular carcinomas




    • Similarities between LCIS and invasive carcinoma provide evidence that LCIS can be direct precursor of invasive carcinoma


  • Natural history for variants of LCIS is unknown


Treatment



  • Surgical approaches



    • Due to multicentric nature of LCIS, effective risk reduction requires bilateral mastectomy



      • However, majority of women with LCIS will never develop invasive carcinoma


  • Adjuvant therapy



    • Adjuvant endocrine therapy (chemoprevention) reduces subsequent risk of ER-positive carcinomas


    • Associated with significant side effects in some women


  • Surveillance



    • Women can be followed with close surveillance using imaging modalities


    • Risk of dying of breast cancer with careful follow-up is very low


  • Optimal treatment for variants of LCIS is unclear



    • Some authors feel that variant forms of LCIS are better managed like DCIS


Prognosis



  • Increased long-term risk of subsequent invasive carcinoma after diagnosis of classic LCIS



    • Subsequent invasive carcinomas more likely to be lobular than in general population but are most commonly of no special type


    • Magnitude of risk after variant types of LCIS is unknown but is presumed to be higher


  • Risk applies to both breasts



    • Slightly greater in ipsilateral than in contralateral breast


    • Relative risk is 7-10x or about 25-30% lifetime risk



      • Corresponds to approximately 1% of patients diagnosed with invasive carcinoma per year of follow-up


    • Time to cancer from LCIS diagnosis ranges from 15-30 years


  • Clinical follow-up should be long-term, given extended risk for late-occurring carcinoma



    • Some studies suggest risk for development of subsequent cancer diminishes with time whereas other studies do not


LCIS on Core Needle Biopsy



  • Classic LCIS may be seen as incidental finding in core needle biopsies


  • Excision is indicated for variant types of LCIS if other lesions of risk are present (e.g., ADH) or if targeted lesion may have been missed or is not well explained by pathologic findings


  • Appropriate management of incidental classic LCIS on core biopsy is debated



    • In carefully selected cases, frequency of finding more significant lesions after excision is very low


    • Subsequent cancers in these patients are often not at site of core needle biopsy


IMAGE FINDINGS


Mammographic Findings



  • Classic LCIS is not associated with mammographic findings



    • Usually incidental finding in biopsies performed for calcifications



      • Usually seen in coexisting sclerosing adenosis or columnar cell change adjacent to LCIS


  • LCIS may grow into areas of preexisting calcifications but are not source of calcifications


  • Variant forms of LCIS with necrosis &/or high-grade nuclei may be directly associated with calcifications


MR Findings



  • Some lesions may show a non-mass ductal enhancement pattern or irregular enhancing mass


  • However, difficult to correlate pathologic findings with MR lesions



MICROSCOPIC PATHOLOGY


Histologic Features



  • Classic LCIS



    • Solid and monotonous proliferation of small discohesive cells, expanding terminal duct lobular units (TDLUs) and small ducts


    • Criterion to distinguish LCIS from ALH is based on extent



      • At least 50-75% of acini in lobular unit must be filled and distended with no residual lumina


      • Involved lobules may be compared to uninvolved lobules to estimate degree of distension


    • 2 types of nuclei may be seen



      • Type A cells: Nuclei are small to slightly enlarged (1-1.5x size of lymphocyte), with uniform round nuclei and inconspicuous nucleoli


      • Type B cells: Nuclei are larger (2x size of lymphocyte) with more abundant cytoplasm and more prominent nucleoli


      • Type A and B cells can coexist in same lesion


    • Nuclei have a central or slightly eccentric position within the cell and show minimal pleomorphism


    • Intracytoplasmic vacuoles and signet ring cells are variably present



      • Special stains can be used to demonstrate mucin vacuoles


      • Cytoplasmic clearing can also be seen


    • Pagetoid spread in ducts (growth of cells between luminal and myoepithelial layers) may be present



      • Extensive ductal involvement can give “clover leaf” pattern


  • Variants of LCIS



    • Recognition of E-cadherin loss as consistent feature of lobular neoplasia broadened range of lesions included within this group



      • Often associated with classic LCIS


      • Occur in older postmenopausal age group compared with classic LCIS


      • May present as mammographic calcifications or a mass


      • Many of these lesions would have been classified and treated as DCIS in the past


      • These lesions are rare, comprising < 5% of all carcinoma in situ


      • Natural history is unknown


    • Variant LCIS has morphologic features not seen in classic LCIS



      • High nuclear grade: > 3x size of a lymphocyte, irregular membrane, prominent nucleoli


      • Central necrosis, typically with calcifications


      • Abundant cytoplasm often with apocrine or plasmacytoid appearance


      • Cohesive (solid) pattern


    • Variant LCIS has molecular features not seen in classic LCIS



      • May be ER and PR negative


      • About 1/3 overexpress HER2


      • Higher proliferative rate compared with classic LCIS


      • Share genetic changes with classic LCIS (gains of 1q and losses of 16q) but have a higher number of DNA copy number changes and more complex chromosomal rearrangements


      • Associated invasive carcinomas are similar in appearance and may belong to “molecular apocrine” group of cancers


    • Consistent terminology for these lesions has not yet been developed, but suggested terms include



      • Pleomorphic LCIS


      • Carcinoma in situ with ductal and lobular features


      • Lobular intraepithelial neoplasia grade 3 (LIN3)


      • Apocrine pleomorphic lobular carcinoma in situ


      • Mammary intraepithelial neoplasia (MIN)

Jul 6, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Lobular Carcinoma In Situ

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