atypical lobular hyperplasia

Definition :

ALH is a part of the spectrum of lobular neoplasia, which also includes LCIS.

Images

 Atypical lobular hyperplasia (or LCIS) growing in a pagetoid distribution

• https://twitter.com/brstpathology/status/715911692891373568

 Atypical Lobular Hyperplasia (ALH) at breastpathology.info

• http://www.breastpathology.info/adh-and-alh.html#CCC_atypia2

Clinical

 Usually not associated with specific mammographic findings.
 ALH is frequently associated with columnar cell lesions and flat epithelial atypia.

 ALH does not form a palpable mass.
 ALH is an ncidental finding on core biopsy with no reliable radiological features.
 Usually an incidental finding at biopsy, not a palpable mass.
 ALH is 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)

Microscopy

 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)

 The acinar lumen are not completely obliterated.

 monotonous cell population

• The cells are not as monotonous and are less regularly spaced than those seen in lobular neoplasia.
• The cell population can appear somewhat monotonous, not all the lumen are completely obliterated.

 The cells appear more pleomorphic and cohesive than those seen in lobular neoplasia LIN2.
 The acini are less distended than that seen in lobular neoplasia, and the lumen are not completely filled by cells.
 The cells are not regularly spaced, and the cells have a somewhat variable appearance.

 Ductal involvement by cells of atypical lobular hyperplasia

• Cells of atypical lobular hyperplasia can involve a terminal duct lobular unit (TDLU)
• Can involve ducts: alteration occurs around the duct as outpouchings producing a clover-leaf pattern
• When malignant cells spread in a nodular fashion, a clover-leaf pattern is produced.
• possibly displaying pagetoid involvement of a terminal duct
• The cells spread between the luminal epithelium and underlying myoepithelial layer.

 Cells of atypical lobular hyperplasia can also involve sclerosing adenosis

• There is an increase in glandular elements as well as stromal proliferation.
• If viewed at low power, the overall lobular architecture would be retained.

 May be no/minimal inflammatory response

• no surrounding inflammatory response.
• The inflammatory response is usually minimal or absent in atypical lobular hyperplasia and LCIS as compared to ductal carcinoma in situ (DCIS).

 ALH can also be observed in a fibroadenoma, in slerozing adenosis, an atrophic unit, a papilloma or micropapilloma.

 Lacks intracytoplasmic mucin

Immunochemistry

 E-cadherin-

• The E-cadherin stain is focally negative in cells of atypical lobular hyperplasia.

 ER+ (ER alpha stronger than ER beta, Virchows Arch 2007;451:893)
 CK34betaE12+ (polarized)
 p120catenin+ (cytoplasmic, not membranous staining, Am J Surg Pathol 2007;31:427)
- PR+

 alpha-catenin- and beta-catenin-

Cytology

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

Differential diagnosis

 Solid ductal intraepithelial neoplasias (DCINs)

• usually cohesive cells with multiple secondary lumina,
• rosette-like nuclei,
• E-cadherin+

Cytogenetics

  diploid

Prognosis

 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)
 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)

Management

If present at core biopsy, is surgical excision appropriate?

 Many studies support excision due to risk of subsequent in situ carcinoma or invasive carcinoma.
 Yes because:

• ductal carcinoma in situ (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, 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)

 No, unless:

• radiologic-pathologic discordance suggests that the targeted lesion was not excised,
• other high risk lesions such as atypical ductal hyperplasia (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),
• if diffuse lobular neoplasia at core biopsy (Breast J 2007;13:55)

 Lifelong follow up is recommended.

Images

 http://www.hsc.stonybrook.edu/breast-atlas/I-22.htm

See also

 mammary lobular neoplasias
 mammary precursor lesions

Microscopy

 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
   Atypical cells with focal preservation of luminal spaces
   Can involve sclerosing adenosis
   pagetoid ductal involvement and clover leaf pattern
   The distended lobules are occupied by atypical lobular cells with round to oval nuclei and small nucleoli. Rare myoepithelial cells with small dark nuclei remain.

Associations

 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)

Clinical synopsis

 Usually not associated with specific mammographic findings.
 Does not form a palpable mass.
 Incidental finding on core biopsy with no reliable radiological features.
 Usually an incidental finding, not a palpable mass.

Prognosis

 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)
 Lifelong follow up is recommended.
 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? (PO)

• 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)

CGH (16897748)

 gains

• 2p11.2 gain

 losses

• 7p11-p11.1 loss
• 22q11.1 loss
• 16q21-q23.1 loss

References

 Mastracci TL, Shadeo A, Colby SM, Tuck AB, O’Malley FP, Bull SB, Lam WL, Andrulis IL. Genomic alterations in lobular neoplasia: a microarray comparative genomic hybridization signature for early neoplastic proliferationin the breast. Genes Chromosomes Cancer. 2006 Nov;45(11):1007-17. PMID: 16897748