Journal of Pathology and Translational Medicine

Original Articles

Membranous Insulin-like Growth Factor-1 Receptor (IGF1R) Expression Is Predictive of Poor Prognosis in Patients with Epidermal Growth Factor Receptor (EGFR)-Mutant Lung Adenocarcinoma: Eunhyang Park, Soo Young Park, Hyojin Kim, Ping-Li Sun, Yan Jin, Suk Ki Cho, Kwhanmien Kim, Choon-Taek Lee, Jin-Haeng Chung; J Pathol Transl Med. 2015;49(5):382-388. Published online August 4, 2015; DOI: https://doi.org/10.4132/jptm.2015.07.10

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Background
Insulin-like growth factor-1 receptor (IGF1R) is a membrane receptor-type tyrosine kinase that has attracted considerable attention as a potential therapeutic target, although its clinical significance in non-small cell lung cancer (NSCLC) is controversial. This study aimed to clarify the clinical significance of IGF1R expression in human NSCLC. Methods: IGF1R protein expression was evaluated using immunohistochemistry in 372 patients with NSCLC who underwent curative surgical resection (146 squamous cell carcinomas [SqCCs] and 226 adenocarcinomas [ADCs]). We then analyzed correlations between expression of IGF1R and clinicopathological and molecular features and prognostic significance. Results: Membranous and cytoplasmic IGF1R expression were significantly higher in SqCCs than in ADCs. In patients with SqCC, membranous IGF1R expression was associated with absence of vascular, lymphatic, and perineural invasion; lower stage; and better progression-free survival (PFS) (hazard ratio [HR], 0.586; p = .040). In patients with ADC, IGF1R expression did not have a significant prognostic value; however, in the subgroup of epidermal growth factor receptor (EGFR)-mutant ADC, membranous IGF1R expression was associated with lymphatic and perineural invasion, solid predominant histology, and higher cancer stage and was significantly associated with worse PFS (HR, 2.582; p = .009). Conclusions: Lung ADC and SqCC showed distinct IGF1R expression profiles that demonstrated prognostic significance. High membranous IGF1R expression was predictive of poor PFS in EGFR-mutant lung ADC, while it was predictive of better PFS in SqCC. These findings will help improve study design for subsequent investigations and select patients for future anti-IGF1R therapy.

Citations

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Relationship between Insulin Secretory Capacity and Mitochondrial Morphology in Pancreatic beta-Cell.: Seung Won Yang, Jae Hyuk Lee, Chang Soo Park, Min Young Chung; Korean J Pathol. 1999;33(5):326-336.

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Abstract PDF: To investigate the relationship between insulin response and morphometric changes of the mitochondria of pancreatic beta-cell, this study was performed using hyperglycemia and streptozotocin as oxidative stresses. Adult and neonatal rats were used. Intravenous glucose tolerance test (IVGTT) and morphologic examination of pancreas using immunohistochemical stain, in situ end-labeling method and electron microscopic study were performed. Various mitochondrial parameters were measured by image analyzer. Immunohistochemical stain revealed a markedly reduced islet size and decreased number of beta-cells and the increased number of non-beta-cell in adult and neonatoal streptozotocin group, and the appearance of insulin positive cells throughout the exocrine parenchyma in neonatal streptozotocin group. Three days after injection of streptozotocin in adult streptozotocin group, TUNEL stain showed increased apoptotic cells in islets. Ultrastructurally, beta-cells in adult streptozotocin group showed increase in number and size of mitochondria, and disruption of mitochondrial structures. Hyperglycemic group and neonatal streptozotocin group showed preserved mitochondrial ultrastructure. Ultrastructural morphometric study revealed increase in size and number of mitochondria and decrease in mitochondrial contour index in adult streptozotocin-treated rats, which suggested mitochondrial degeneration. Hyperglycemic group showed mild increase in size of mitochondria. Increased number of mitochondria was also observed in neonatal streptozotocin group. IVGTT revealed marked decrease in insulin response in adult streptozotocin group, and non-insulin-dependent diabetes mellitus pattern in glucose and insulin response in neonatal streptozotocin group. Hyperglycemic group showed a glucose and insulin response similar to control group. The above results suggest that a severe oxidative injury may cause degeneration and disruption of mitochondria of pancreatic beta-cell, and may be associated with substantial apoptotic cell death. The changes in the morphology and the number of mitochondria may result from streptozotocin treatment within neonatal period and hyperglycemia treatment, which may be associated with changes in insulin response.

Histopathologic Findings of Mastopathy in Diabetes Mellitus.: Jae Ho Han, Hee Jung Kim, Woo Hee Jung, Ki Keun Oh; Korean J Pathol. 1999;33(7):503-506.

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Abstract PDF: Diabetic mastopathy is a clinicopathologic entity which was first described as a dense fibrous breast mass in insulin-dependent diabetes mellitus. The purpose of this article was to document diabetic mastopathy histologically which had been diagnosed as fibrocystic disease and to avoid unnecessary surgical procedures in breast mass simulating malignancy in diabetic patients. We examined eight excisional breast biopsies from seven patients. Three diabetic patients with type I insulin-dependent diabetes mellitus presented with bilateral (2 patients) or unilateral (1 patient) rapidly growing palpable breast masses. Four patients with type II noninsulin-dependent diabetes mellitus presented with bilateral (2 patients) or unilateral breast mass (1 patient). One patient had no symptoms. All of them had late complications of diabetes mellitus such as nephropathy, neuropathy and retinopathy. Mammographic findings such as ill- defined mass density and asymmetric increased density suggested malignancy. However, all of them had been diagnosed as fibrocystic disease. On review, the most consistent pathologic finding was keloid-like stromal fibrosis. Others were ductitis or ductulitis, thickening of basement membrane of ducts or ductules, mononuclear perivasculitis and lobulitis. Six of eight breast satisfied all five criteria for diabetic mastopathy.

Expression of Insulin-like Growth Factor-I-Receptor in Colorectal Adenomas and Carcinomas.: Young Chae Chu, Hye Seung Han, Jee Young Han, Joon Mee Kim, Young Bae Kim, Tae Sook Hwang; Korean J Pathol. 2000;34(3):199-207.

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Abstract PDF: The activation of the insulin-like growth factor-I-receptor system (IGF-IR) has recently emerged as critical events in transformation and tumorigenicity of several human tumors. In this study we investigated the expression of IGF-IR in 33 colorectal adenomas, 88 primary colorectal carcinomas, and 30 normal colonic mucosa adjacent to the carcinoma. Immunohistochemical staining (IHC) for IGF-IR was performed on paraffin embedded sections using an anti-IGF-IR rabbit polyclonal antibody. IHC stains for IGF-IR were scored using a semiquantitative scoring system. The relationship of IGF-IR staining to clinicopathologic variables and proliferating cell nuclear antigen (PCNA) staining was also analysed. The mean IHC scores for IGF-IR of normal glands, adenoma, intramucosal carcinoma, node-negative carcinoma, and node-positive carcinoma were 0.41 0.96, 0.76 1.23, 2.0 1.48, 2.83 2.0 and 5.93 1.58, respectively. These scores for each category were statistically significant except between normal glands and adenoma and between intramucosal carcinoma and node-negative carcinomas. The mean PCNA indexes of normal glands, adenoma, intramucosal carcinoma, node-negative carcinoma, and node-positive carcinoma were 2.48 2.60, 6.94 11.03, 27.21 11.42, 43.36 9.9 and 57.60 10.01, respectively. The PCNA index for each category was statistically significant except between normal and adenoma. IGF-IR scores and PCNA indexes were higher with tumor progression and also correlated each other (sr=0.65, p=0.0001). Higher IGF-IR scores and PCNA indexes were seen in tumors with advanced stage, infiltrative growth pattern, poor differentiation, nerve invasion, lymphovascular invasion, and moderate fibrosis. Our results suggest that IGF-IR plays an important role in tumorigenicity and tumor progression.

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