Subepithelial myofibroblast in lung adenocarcinoma: a histological indicator of excellent prognosis

Abstract

We report here the presence of subepithelial myofibroblasts in pure bronchioloalveolar carcinoma and a subset of invasive lung adenocarcinoma. The subepithelial myofibroblasts we describe were observed in a peculiar location beneath the cancer cells in the alveolar septa. Immunohistochemically, they were positive for a-smooth muscle actin and calponin, but negative for desmin and h-caldesmon. To gain insight into their biological significance, we examined 116 surgically resected lung adenocarcinomas. The resected tumors included 13 bronchioloalveolar carcinomas, 20 mixed type adenocarcinomas with bronchioloalveolar carcinoma components, 57 papillary adenocarcinomas, 22 solid adenocarcinomas with mucin, and 4 acinar adenocarcinomas. All specimens were immunostained for a-smooth muscle actin to visualize the myofibroblasts. In all of the pure bronchioloalveolar carcinomas observed, the subepithelial myofibroblasts were completely preserved adjacent to the cancer cells. In mixed adenocarcinomas with bronchioloalveolar carcinoma components, subepithelial myofibroblasts were present in the bronchioloalveolar carcinoma components, but scanty in the invasive areas, where stromal myofibroblasts emerged between the cancer cell nests. Subepithelial myofibroblasts were retained, however, in the invasive areas of a subset of invasive adenocarcinomas. Survival analysis showed that the retention of subepithelial myofibroblasts in these invasive tumors was associated with low rates of lymphatic and vascular invasion, a low rate of lymph node involvement, and an excellent patient survival. These results suggest that subepithelial myofibroblasts increase in bronchioloalveolar carcinomas, but are gradually replaced by typical stromal myofibroblasts during progression into invasive cancer. A subset of invasive adenocarcinomas retains subepithelial myofibroblasts. Analysis of subepithelial myofibroblasts may be helpful in identifying a subset of lung adenocarcinoma with excellent prognosis.

Clinicopathological characteristics of subcentimeter adenocarcinomas of the lung

“…The presence of active fibroblastic/myofibroblastic proliferation helped this discrimination, along with the associated destruction of elastic fiber frameworks [11]. Discontinuity of subepithelial myofibroblastic layers was also frequently associated with the presence of active fibroblastic/myofibroblastic proliferation in our study as reported [12]. Briefly, it is reported that ␣-SMA positive myofibroblastic cells form the subepithelial linear continuous layer in alveolar septa of AIS, whereas in invasive adenocarcinomas the subepithelial myofibroblastic layer becomes discontinuous in areas of invasion, and is occasionally associated with random myofibroblastic proliferation [12].…”

“…Our previous study also confirmed these findings [10]. Since active fibroblastic (or myofibroblastic) proliferation is also frequently associated with destruction of elastic fiber frameworks [11] and discontinuity of subepithelial myofibroblastic layers [12], elastic fiber staining (EVG or H&E plus resorcin-fuchsin) and ␣-SMA immunostaining were performed as adjuncts to detect foci of fibroblastic/myofibroblastic proliferation. When multiple microinvasive areas were found in one tumor, the size of the largest invasive area was recorded as the largest dimension.…”

IL-6 Secreted from Cancer-Associated Fibroblasts Mediates Chemoresistance in NSCLC by Increasing Epithelial-Mesenchymal Transition Signaling

“…The SMA staining pattern of tumors obtained from patients with NSCLC after chemotherapy or chemoradiotherapy was classified into "peripheral" (cancer cells are completely surrounded by a regular layer of subepithelial SMA-positive-fibroblasts) or "diffuse" (stromal CAFs were diffusely stained by SMA in tumor stroma and tumor cells are surrounded by irregular layers of SMA-positive-fibroblasts) according to the method described by Matsubara et al. 21 If the intensity of the subepithelial area was more than twice that of the stromal area, it was defined as "peripheral" distribution; otherwise, it was defined as "diffuse" distribution.…”

Upregulation of cancer-associated myofibroblasts by TGF-β from scirrhous gastric carcinoma cells

“…Fibroblasts within the tumour stroma, known as carcinoma-associated fibroblasts (CAFs), including both fibroblasts and myofibroblasts (Semba et al , 2009), play a critical role in the regulation of tumour growth (Kalluri and Zeisberg, 2006; Guo et al , 2008; Noma et al , 2008; Shimoda et al , 2010; Yashiro and Hirakawa, 2010). Myofibroblasts, which are distinct from fibroblasts in their expression of both vimentin and α -smooth muscle actin ( α -SMA), have recently been implicated in important aspects of solid tumour progression (Olumi et al , 1999; Hasebe et al , 2000; Tomasek et al , 2002; Kalluri and Zeisberg, 2006; Tsujino et al , 2007; Matsubara et al , 2009), because myofibroblasts produce a number of important factors that can directly promote growth in the adjacent epithelium (Kalluri and Zeisberg, 2006; Brenmoehl et al , 2009). Scirrhous gastric cancer cells proliferate with fibrosis when the cancer cells invade into the submucosa containing abundant stromal cells (Nakazawa et al , 2003).…”