Differential Expression of Glut1 in Pulmonary Neuroendocrine Tumors: Correlation with Histological Grade

Background : Increased glucose uptake, a process that is mediated by glucose transporter (Glut1) proteins, is an important metabolic feature in a variety of cancer cells. The overexpression of Glut1 in human cancers is known to be related to a variety of histopathological parameters, including histological grade, proliferation rate, and lymphatic invasion. The principal objective of this study was to evaluate Glut1 expression in the spectrum of pulmonary neuroendocrine (NE) tumors including typical carcinoid tumor (TC), atypical carcinoid tumor (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell carcinoma (SCC), and to characterize the relationship between Glut1 expression and the histologic grade of NE tumors. Methods : 19 TC, 7 AC, 13 LCNEC, and 6 SCC patients were included in this study. The percentages of Glut1-positive tumor cells in these patients were determined. For statistical analysis, Glut1 expression was subdivided into a Glut1-low expression group (0-30%) and a Glut1-high expression group (31-90%). Results : In our subgroup analyses, the histological grade of pulmonary neuroendocrine (NE) tumors was significantly correlated with Glut1 expression; TC (n=19, 3.6 +/- 4.2%), AC (n=7, 20.0 +/- 4.9%), LCNEC (n=13, 60.0 +/- 21.1%), and SCC (n= 6, 74.2 +/- 16.9%). Glut1-high expression was significantly associated with high-grade NE tumors such as LCNEC and SCC (n=19, 62.6 +/- 21.0%) (p=0.000). Conclusions: The results of this study appear to indicate that Glut1 overexpression is a consistent feature of high-grade NE lung tumors.This work was supported by grant no 02-2008-029 from the SNUBH Research Fund and partly supported by the Korean Science & Engineering Foundation (KOSEF) through the Tumor Immunity Medical Research Center at Seoul National University College of Medicine.Song YS, 2008, LUNG CANCER, V61, P54, DOI 10.1016/j.lungcan.2007.11.012Nguyen XC, 2007, EUR J RADIOL, V62, P214, DOI 10.1016/j.ejrad.2006.12.008Khandani AH, 2007, NUCL MED COMMUN, V28, P173Chung JH, 2004, J NUCL MED, V45, P999TRAVIS WD, 2004, WHO INT HISTOLOGICALKalir T, 2002, CANCER, V94, P1078, DOI 10.1002/cncr.10280Wong CYO, 2001, EUR J NUCL MED, V28, P1702Wang BY, 2000, CANCER, V88, P2774Brown RS, 1999, J NUCL MED, V40, P556Ito T, 1998, MODERN PATHOL, V11, P437Travis WD, 1998, HUM PATHOL, V29, P272Baer SC, 1997, J AM ACAD DERMATOL, V37, P575Younes M, 1997, CANCER, V80, P1046Voldstedlund M, 1997, APMIS, V105, P537Haber RS, 1997, THYROID, V7, P363Younes M, 1997, CANCER EPIDEM BIOMAR, V6, P303Younes M, 1996, CLIN CANCER RES, V2, P1151Younes M, 1996, CANCER RES, V56, P1164Younes M, 1995, ANTICANCER RES, V15, P2895NAGASE Y, 1995, J UROLOGY, V153, P798MELLANEN P, 1994, INT J CANCER, V56, P622BROWN RS, 1993, CANCER, V72, P2979TAKATA K, 1992, CELL TISSUE RES, V267, P407PESSIN JE, 1992, ANNU REV PHYSIOL, V54, P911PARDRIDGE WM, 1990, J BIOL CHEM, V265, P18035ISSELBAC.KJ, 1972, NEW ENGL J MED, V286, P929

CD5-undetected by immunohistochemistry, t(11;14)(q13;q32)-positive conjunctival mantle cell lymphoma: a case report

Most primary ocular adnexal lymphomas are extranodal marginal zone B-cell lymphomas of mucosa-associated lymphoid tissue (MALT). A few cases of ocular adnexal mantle cell lymphomas have been reported in the literature. We present a case of mantle cell lymphoma presenting as conjunctival mass. A 58-year-old man presented with a palpable mass in the left lower tarsal conjunctiva incidentally detected one month previously. Histopathologic examination showed proliferation of monomorphous small-to-medium sized lymphoid cells. On immunohistochemistry, tumor cells were positive for CD20, bcl-2, and cyclin D1, and negative for CD5. PCR analysis for immunoglobulin heavy chain gene rearrangement showed monoclonal B-cell proliferation. t(11;14)(q13;q32), involving the CCND1 and IGH genes, was detected in interphase fluorescent in situ hybridization using formalin-fixed, paraffin-embedded tissue; however, MALT1 gene translocation was not observed. The final diagnosis was mantle cell lymphoma. There was no lymphadenopathy; however, bone marrow involvement of the lymphoma was suspected. The patient has been receiving systemic chemotherapy. This case emphasizes the differential diagnosis of conjunctival mantle cell lymphoma from extranodal marginal zone B-cell lymphomas of MALT regarding the clinical and pathological aspects

Loss of PTEN Expression is an Independent Poor Prognostic Factor in Non-Small Cell Lung Cancer

Introduction: The PTEN gene acts as a tumor suppressor gene and there are various mechanisms involved to suppress its function, including mutation, homozygous deletion, and promoter methylation. Recently, the role of PTEN loss is focused on drug resistance mechanism, such as gefitinib. We investigated PTEN protein expression in non-small cell lung cancer (NSCLC) and correlated with clinicopathologic features to evaluate prognostic significance.

Reliability of chromogenic in situ hybridization for epidermal growth factor receptor gene copy number detection in non-small-cell lung carcinomas: A comparison with fluorescence in situ hybridization study

Fluorescence in situ hybridization (FISH) has been known to be the most representative and standardized test for assessing gene amplification However. FISH requires a fluorescence microscope, the signals are labile and rapidly fade over time. Recently, chromogenic in situ hybridization (CISH) has emerged as a potential alternative to FISH The aim of this study is to test the reliability of CISH technique for the detection of epidermal growth factor receptor (EGFR) gene amplification in non-small-cell lung carcinomas (NSCLC), to compare CISH results with FISH. A total of 277 formalin-fixed and paraffin embedded NSCLC tissue samples were retrieved nom the surgical pathology archives at Seoul National University Bundang Hospital CISH and FISH examinations were performed to test EGFR gene amplification status There was high concordance in the assessment of EGFR gene copy number between CISH and FISH tests (Kappa coefficient = 0.83) Excellent concordance was shown between two observers on the interpretation of the CISH results (Kappa coefficient = 0 90) In conclusion, CISH result is highly reproducible, accurate and practical method to determine EGFR gene amplification in NSCLC In addition, CISH allows a concurrent analysis of histological features of the tumors and gene copy numbers. (C) 2009 Elsevier Ireland Ltd All rights reserved.Chang JWC, 2008, LUNG CANCER, V61, P328, DOI 10.1016/j.lungcan.2008.01.009Hirsch FR, 2008, J CLIN ONCOL, V26, P3351, DOI 10.1200/JCO.2007.14.0111Ruiz MIG, 2007, HISTOPATHOLOGY, V51, P631, DOI 10.1111/j.1365-2559.2007.02854.xLambros MBK, 2007, HUM PATHOL, V38, P1105, DOI 10.1016/j.humpath.2007.04.011Hirsch FR, 2007, ANN ONCOL, V18, P752, DOI 10.1093/annonc/mdm003Jeon YK, 2006, LUNG CANCER, V54, P387, DOI 10.1016/j.lungcan.2006.08.015Cappuzzo F, 2005, J NATL CANCER I, V97, P643, DOI 10.1093/jnci/dji112Lynch TJ, 2004, NEW ENGL J MED, V350, P2129TRAVIS WD, 2004, PATHOLOGY GENETICS TTanner M, 2000, AM J PATHOL, V157, P1467FEINSTEIN MB, 2000, CHEST SURG CLIN N AM, V10, P653

A comprehensive comparative analysis of the histomorphological features of ALK-rearranged lung adenocarcinoma based on driver oncogene mutations: frequent expression of epithelial-mesenchymal transition markers than other genotype.

Molecular classification of lung cancer correlates well with histomorphological features. However, specific histomorphological features that differentiate anaplastic lymphoma kinase (ALK)-rearranged tumors from ALK-negative tumors have not been fully evaluated. Eighty ALK-rearranged and 213 ALK-negative (91 epidermal growth factor receptor-mutated; 29 K-ras-mutated; 93 triple-negative) resected lung adenocarcinomas were analyzed for several histomorphological parameters and histological subtype. ALK-rearranged tumors were associated with younger age at presentation, frequent nodal metastasis, and higher stage of disease at diagnosis. ALK-rearranged tumors were more likely to show a solid predominant pattern than ALK-negative tumors (43.8%; 35/80; p<0.001). Unlike ALK-negative tumors, a lepidic predominant pattern was not observed in ALK-rearranged tumors (p<0.001). In multivariate analysis, the most significant morphological features that distinguished ALK-rearranged tumors from ALK-negative tumors were cribriform formation (odds ratio [OR], 3.253; p = 0.028), presence of mucin-containing cells (OR, 4.899; p = 0.008), close relationship to adjacent bronchioles (OR, 5.361; p = 0.001), presence of psammoma bodies (OR, 4.026; p = 0.002), and a solid predominant pattern (OR, 13.685; p = 0.023). ALK-rearranged tumors exhibited invasive histomorphological features, aggressive behavior and frequent expression of epithelial-mesenchymal transition markers (loss of E-cadherin and expression of vimentin) compared with other genotype (p = 0.015). Spatial proximity between bronchus and ALK-rearranged tumors and frequent solid histologic subtype with p63 expression may cause diagnostic difficulties to differentiate squamous cell carcinoma in the small biopsy, whereas p40 was rarely expressed in ALK-rearranged adenocarcinoma. Knowledge of these features may improve the diagnostic accuracy and lead to a better understanding of the characteristic behavior of ALK-rearranged tumors

Discordance between anaplastic lymphoma kinase status in primary non-small-cell lung cancers and their corresponding metastases

Kim H, Xu X, Yoo S-B, Sun P-L, Jin Y, Paik J H, Choe G, Jheon S, Lee C-T &amp; Chung J-H (2013) Histopathology 62, 305-314 Discordance between anaplastic lymphoma kinase status in primary non-small-cell lung cancers and their corresponding metastases Aims: The anaplastic lymphoma kinase gene (ALK) has attracted considerable attention as a potential molecular target in non-small-cell lung cancer (NSCLC). However, it is unclear whether ALK alterations are acquired during the metastatic progression of NSCLC. Methods and results: ALK status and ALK expression were evaluated in a series of 67 primary NSCLCs and their corresponding metastatic lesions using fluorescence in-situ hybridization and immunohistochemistry. ALK rearrangement was detected in 7.5% (5/67) of the primary tumours and in 9.0% (6/67) of the metastases (P &lt; 0.001). ALK copy number gain (CNG) was detected in 1.5% (1/67) of the primary tumours and in 35.8% (24/67) of the metastases. Whereas ALK rearrangement was detected only in adenocarcinomas, CNG was identified in various histological subtypes of NSCLC. ALK expression was detected in 11.9% (8/67) of the primary tumours and in 25.4% (17/67) of the metastatic lesions. Conclusions: ALK alteration and ALK expression can be acquired during metastatic progression in NSCLC, and ALK CNG is associated with ALK expression.N

Detection of ALK gene rearrangement in non-small cell lung cancer: A comparison of fluorescence in situ hybridization and chromogenic in situ hybridization with correlation of ALK protein expression

Introduction: Accurate determination of ALK rearrangement is important in lung cancer patients, especially in determining their eligibility for crizotinib therapy. Fluorescence in situ hybridization (FISH) has been regarded as the gold standard method for detecting ALK rearrangement. However, FISH requires a fluorescence microscope, and the signals are labile and rapidly fade over time. This study evaluates the concordance between ALK gene rearrangement in non-small cell lung cancer assessed by ALK FISH and a newly developed ALK chromogenic in situ hybridization (CISH) and correlates the results with ALK protein expression assessed by immunohistochemistry. Methods: A total of 465 formalin-fixed, paraffin-embedded non-small cell lung cancer samples were analyzed by ALK FISH (Path-Vysion, Vysis, Abbott) and ALK CISH. For comparison, all specimens were stained by immunohistochemistry (clone 5A4, Novocastra) and interobserver reproducibility was assessed. Results: We found that agreement between the pathologists on the CISH-determined ALK status was achieved in 449 patients (96.6%), and ALK rearrangement was identified in 18 patients (4.0%) in CISH method. Among these cases, 443 cases (95.3%) had results matching the corresponding FISH results: 17 rearranged, 425 wild types, and 1 discordant case. There was high concordance in the assessment of ALK gene rearrangement between FISH and CISH techniques (kappa = 0.92) and between observers (kappa = 0.97). In addition, there was high concordance in the ALK gene status and ALK protein expression between CISH and IHC tests (kappa = 0.82). Conclusions: CISH is a highly reproducible and practical method to detect ALK gene rearrangement and correlated well with ALK protein expression. Here, we present a diagnostic algorithm (Chung&apos;s SNUBH ALK protocol) to detect lung cancer with ALK rearrangements using IHC, FISH and CISH. Because CISH allows a concurrent analysis of histological features of the tumors and gene rearrangement, it appears to be a useful method in determining ALK gene rearrangement.Y

Histological characteristics of <i>ALK</i>-rearranged tumors.

<p>A, cribriform formation; B, mucin-containing goblet cells; C, mucin-containing signet-ring cell; D, psammoma body; E, cholesterol cleft.</p

Multivariate analysis: Factors significantly associated with <i>ALK</i> rearrangement on logistic regression analysis.

<p>Multivariate analysis: Factors significantly associated with <i>ALK</i> rearrangement on logistic regression analysis.</p