Molecular Evidence for Progression of Microglandular Adenosis (MGA) to Invasive Carcinoma

Abstract

Microglandular adenosis (MGA) is an uncommon, benign breast lesion that is characterized by a proliferation of small uniform, round glands lined by a single layer of epithelial cells around open lumina with haphazard infiltrative growth in fibrous and fatty breast tissue. Although MGA usually has an indolent course, there is morphologic evidence that MGA can be a precursor for the development of intraductal and invasive ductal carcinoma. To investigate the possibility of such a transition, we studied 17 cases of MGA or atypical MGA some of which had given rise to carcinoma in situ (CIS) and/or invasive ductal carcinoma using the reticulin stain, immunohistochemistry (S-100, p63, Ki-67, and p53), and a molecular approach involving microdissection and high-resolution comparative genomic hybridization and MYC chromogenic in situ hybridization. MGA and carcinomas arising from MGA were typically negative for p63 and positive for S-100 and Ki-67 and occasionally positive for p53. High-resolution comparative genomic hybridization identified recurrent gains and losses in MGA (2q+, 5q-, 8q+, and 14q-) and atypical MGA (1q+, 5q-, 8q+, 14q-, and 15q-). Some examples of MGA and carcinomas arising from MGA harbored few gross chromosomal abnormalities whereas others had considerable genetic instability with widespread aberrations affecting numerous chromosomal arms. Such widespread genetic changes, together with recurrent loss of 5q and gain of 8q were reminiscent of those reported specifically for basal-like, estrogen receptor-negative, and BRCA1-associated breast tumors. Concordant genetic alterations were identified between MGA, atypical MGA, and higher risk lesions (CIS and invasive ductal carcinoma) and in some cases there was an accumulation of genetic alterations as cases "progressed" from MGA to atypical MGA, CIS, and invasive ductal carcinoma. The molecular data suggests that MGA, atypical MGA, and carcinoma arising in MGA in a single case were clonally related. This result implicates MGA as a nonobligate precursor for the development of intraductal and invasive ductal carcinoma.

Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists

“…The majority of invasive cancers developing in microglandular adenosis is of triple-negative phenotype [108][109][110][111][112] and show metaplastic elements or is of adenoid cystic morphology. [109][110][111][112] It has been recently shown that microglandular adenosis may be a nonobligate precursor of triple-negative and basallike breast cancers.…”

“…[109][110][111][112] It has been recently shown that microglandular adenosis may be a nonobligate precursor of triple-negative and basallike breast cancers. 108,113 A stepwise progression in the number of gross chromosomal changes from microglandular adenosis to invasive carcinoma has been observed. 108 However, given the rarity of microglandular adenosis, it is unlikely to be the precursor lesion for most triple-negative cancers.…”

“…108,113 A stepwise progression in the number of gross chromosomal changes from microglandular adenosis to invasive carcinoma has been observed. 108 However, given the rarity of microglandular adenosis, it is unlikely to be the precursor lesion for most triple-negative cancers.…”

Expression of claudin, paxillin and FRA-1 in non-nodular breast lesions in association with microcalcifications

“…[5][6][7] Recently, microarray analysis on the triple negative subtype of ductal invasive carcinomas has indicated that actually there is a subset of these cases that does not express claudins. These cases were described as "claudin-low" and were characterized by statistically significantly worse prognosis.…”

Small Glandular Proliferations of the Breast With Absent or Attenuated Myoepithelial Reactivity by Immunohistochemistry: A Review Focusing on the Differential Diagnosis and Interpretative Pitfalls

“…Although benign, carcinoma can arise within MGA, and there is morphologic, immunohistochemical, and molecular evidence that supports its role as a precursor lesion to some invasive triple-negative breast carcinoma. [1][2][3][4][5][6] Microglandular adenosis has been reported over a wide age range, but most cases occur in women in their 40s to 60s. 1,[7][8][9][10] It most often presents as a palpable mass, but it may also be discovered on screening imaging or as an incidental histologic finding.…”