KOLUMNAR HÜCRELİ DEĞİŞİM, BENİGN PROLİFERATİF MEME LEZYONLARI VE MEME KARSİNOMLARINDA PI3K/AKT/MTOR YOLAK AKTİVASYONUNUN İMMÜNOHİSTOKİMYASAL DEĞERLENDİRMESİ

Abstract

Columnar cell lesions (CCL) are clonal alterations of the terminal duct lobular unit (TDLU) characterized by enlarged, variably dilated acini lined by columnar epithelial cells. Flat epithelial atypia (FEA) –columnar cell lesion with atypia- is a non-obligatory preneoplastic lesion for breast carcinoma and is considered as the first line for low-grade breast carcinogenesis. Here, the immunohistochemical profile of the components of the PI3K/AKT pathway -the most frequently mutated pathway in breast carcinogenesis- is investigated in columnar cell lesion (CCL), benign proliferative breast lesions containing CCL, preneoplastic lesions and breast carcinomas. 452 lesions from 188 cases with the diagnosis of CCL, benign breast lesions, preneoplastic lesions, in-situ and invasive carcinoma were examined in Hacettepe University Faculty of Medicine, Pathology Department. Tissue microarrays were stained immunohistochemically with antibodies against pAKT, INPP4B, pSGK3, and PTEN. 61/380 (16%) and 306/408 (75%) of the lesions were pAKT and pSGK3 positive, respectively. PTEN loss was seen in 205/376 (54.5%) cases and INPP4B loss was observed in 131/416 (31.5%) cases. pAKT expression was most common in lobular carcinoma (70%) and was not found in any cases of intraductal papillary carcinoma, encapsulated papillary carcinoma, sclerosing adenosis, and florid ductal epithelial hyperplasia. Intraductal papilloma (77.7%) and biphasic lesions (63.6%) showed the highest nuclear pAKT expression rate. Loss of INPP4B was greater in malignant lesions than in benign lesions (19.1% vs. 49.1%, p<0.05); INPP4B loss was seen in all metaplastic carcinomas and complex apocrine metaplasias and 60.7% of invasive lobular carcinomas in particular. Loss of PTEN in CCL was more common in FEA near the tumor (22.2%) than in FEA without a tumor (5.1%) (p=0.049). In FEA, pAKT expression (9.9%), PTEN loss (53%), INPP4B loss (6%) are lower and pSGK3 expression (93%) was more common than atypical ductal hyperplasia and low-grade invasive carcinoma. Compared to papillary lesions and biphasic lesions containing columnar cells, more PTEN loss (52.5%) and less INPP4B loss (5.9%) were observed in CCL. pSGK3 expression in CCLs (94.1%) was similar to that in biphasic lesions (96.9%) and higher than in papillary lesions (70%). In INPP4B positive lesions, pSGK3 expression (85.9%) was high (p<0.05) while pAKT expression (13.5%) decreased (p=0.023). As a result, the role of the FEA in low-grade breast carcinogenesis is emphasized by the immunoexpression pattern which differs both spatially and temporally from the later steps in tumorigenesis. INPP4B exhibits an ambivalent role in the PI3K/AKT pathway: the tumor suppressor role by pAKT inactivation and the oncogenic role by pSGK3 expression has been uncovered.