General
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• Part of spectrum of lobular neoplasia, which also includes LCIS (see Breast-malignant chapter)

Terminology
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• Also called lobular intraepithelial neoplasia 1 (LIN1)

Clinical features
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• Usually not associated with specific mammographic findings
  • Frequently associated with columnar cell lesions and flat epithelial atypia; less commonly associated with low grade invasive carcinomas which may have mammographically-detectable calcifications, density or mass targeted on biopsy (Am J Surg Pathol 1998;22:1521, Am J Surg Pathol 2007;31:417)
• Does not form a palpable mass
• 19% develop invasive cancer at mean 15 years after diagnosis (4-5x usual risk), 42% are special subtypes with good prognosis (Cancer 2006;107:1227)

Radiology
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• Incidental finding on core biopsy with no reliable radiological features

Prognostic factors
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• 4-5x usual risk of carcinoma, higher in ipsilateral breast, higher if age < 50 years (Am J Surg Pathol 2002;26:421, Cancer 2007;109:180); risk increased further if ductal involvement (Hum Path 1988;19:201)
• If present at core biopsy, is surgical excision appropriate?
  • Many studies support excision due to risk of subsequent in situ or invasive carcinoma
  • Yes: DCIS/invasive carcinoma occurs in 6-8% (Archives 2008;132:979, Am J Surg Pathol 2007;31:717), invasive ductal/lobular carcinoma occurs in 25% (Am J Surg Pathol 2005;29:534, AJR Am J Roentgenol 2008;190:637)
  • No, unless: radiologic-pathologic discordance suggests that the targeted lesion was not excised, other high risk lesions such as ADH are present that would warrant further surgery, ALH has features resembling DCIS (Am J Surg Pathol 2002;26:1095), ALH has pleomorphic features (Mod Pathol 2008;21:1208, Cancer 2008;112:2152), or there is diffuse lobular neoplasia at core biopsy (Breast J 2007;13:55)
  • No: because there is no significantly increased risk and any subsequent cancer is diffuse, bilateral and not at location of biopsy (Am J Surg 2009;198:792)

Treatment
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• Lifelong follow up is recommended

Gross description
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• Usually an incidental finding, not a palpable mass

Micro description
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• Criteria of Page et al: (Schnitt and Collins: Biopsy Interpretation of the Breast, 2nd Edition)
  • Distends 50% or more acini within a lobule (so resembles LCIS), but not uniformly present throughout entire lobule OR
  • Involves all acini in a TDLU (so resembles LCIS) but does not distend the acini (i.e. caliber of the involved acini is similar to that of uninvolved acini)
• May be no/minimal inflammatory response
• Can involve ducts: alteration occurs around the duct as outpouchings producing a clover-leaf pattern)
• Lacks intracytoplasmic mucin

Micro images
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Atypical cells with focal preservation of luminal spaces

Simple type, courtesy of Dr. Mark R. Wick

Courtesy of Dr. Mark R. Wick

Involving sclerosing adenosis

     

Pagetoid ductal involvement and clover leaf pattern

Low power

Less regularly spaced cells

Not all the lumen are obliterated (arrow)

H&E

Pleomorphic and cohesive cells

No surrounding inflammatory response

Variable appearance to cells

Involving a terminal duct lobular unit

Increase in glandular units

Monotonous cell population

Unusual clear cells and secretory features

ALH in fibroadenoma

ALH and LCIS

Microglandular adenosis with adjacent ALH

Tubular adenoma with ALH

E-cadherin is focally negative

Focal preservation of luminal spaces

Neoplastic cells occupy <50% of acini

Loss of cell cohesion, disorderly spread and pagetoid involvement into normal acini (but <50% of acini involved)

Haphazardly dispersed atypical cells (arrows) have partially replaced normal lobular cells

Expansion of acini on left side

Tumor cells with loss of cohesion have almost entirely filled lumina

Clover-leaf pattern of proliferation around terminal duct with preservation of normal epithelium centrally

Ill defined glandular proliferation around terminal duct

Cytology description
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• Loosely cohesive cell clusters composed of uniform cells with occasional intracytoplasmic lumina, minimal nuclear atypia but frequent eccentric nuclei

Positive stains
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• ER (ER alpha stronger than ER beta, Virchows Arch 2007;451:893)
• CK 34betaE12 (polarized)
• p120catenin (cytoplasmic, not membranous staining, Am J Surg Pathol 2007;31:427)
• Also PR

Negative stains
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• E-cadherin (Mod Path 2005;18:741), HER2
• Negative for alpha and beta catenin
  
  
  

  Absent E-cadherin staining in lobular hyperplasia

Electron microscopy descriptions
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• Intracytoplasmic lumina, microvilli with secretory droplets; basement membrane and myoepithelial cells are present

Molecular / cytogenetics description
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• Diploid

Differential diagnosis
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• Solid ductal intraepithelial neoplasias: usually cohesive cells with multiple secondary lumina, rosette-like nuclei, E-cadherin+

Additional references
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• Atypical Lobular Hyperplasia of the Breast - Stanford University, Arch Pathol Lab Med 2014;138:1344

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