[show abstract][hide abstract] ABSTRACT: Previous studies have reported that pretreatment thrombocytosis is associated with poor outcomes in several cancer types. This study was designed to evaluate the prognostic significance of preoperative thrombocytosis in patients with non-small cell lung cancer (NSCLC) who undergo surgery.
We retrospectively reviewed the records of 199 patients who underwent R0 resection for NSCLC between May 2003 and July 2006 at Seoul National University Bundang Hospital, Seongnam, Korea.
The frequency of preoperative thrombocytosis was 7.5% (15/199). Patients with preoperative thrombocytosis had shorter overall survival (OS, P = 0.003) and disease-free survival (DFS, P = 0.005) than those without thrombocytosis. In multivariable analysis, patients with preoperative thrombocytosis had a significantly greater risk of death and recurrence than those without preoperative thrombocytosis (risk of death: hazard ratio (HR) 2.98, 95% confidence interval (CI) 1.39 to 6.37, P = 0.005; risk of recurrence: HR 2.47, 95% CI 1.22 to 5.01, P = 0.012). A tendency towards a shorter OS and DFS was observed in three patients with persistent thrombocytosis during the follow-up period when compared with those of patients who recovered from thrombocytosis after surgery.
Preoperative thrombocytosis was valuable for predicting the prognosis of patients with NSCLC. Special attention should be paid to patients with preoperative and postoperative thrombocytosis.
World Journal of Surgical Oncology 02/2014; 12(1):37. · 1.09 Impact Factor
[show abstract][hide abstract] ABSTRACT: Activating mutations in the epidermal growth factor receptor (EGFR) kinase domain are correlated with dramatic clinical responses in non-small cell lung cancer patients treated with EGFR-tyrosine kinase inhibitors (TKIs). The two most common EGFR mutations, representing 85-90% of EGFR mutations, are the E746_A750 deletion in exon 19 and the L858R point mutation in exon 21. We conducted this study to evaluate the suitability of mutation-specific antibodies that can detect E746_A750 deletion and L858R mutant EGFR proteins by immunohistochemistry (IHC).
In a cohort of consecutive patients with surgically resected lung adenocarcinomas (n=240), mutant EGFR protein expression was assessed by IHC using specific antibodies (clone SP111 and SP125) to the 2 major forms of EGFR mutations. Immunoreactivity was scored as 0-3, and the results were compared with the EGFR-mutational status.
With a cutoff value of IHC 2+ for SP 111 (anti-EGFR E746_A750 del antibody) and SP 125 (anti-EGFR L858R antibody), both antibodies showed high specificity (99.0% and 89.7%, respectively) and sensitivity (70.6% and 80.4%, respectively). While cases with IHC scores of 3 using these 2 antibodies positively correlated with the EGFR-mutational status, cases with IHC scores lower than 3+ showed variable results regarding EGFR-mutational status.
Although each antibody showed relatively high specificity, some EGFR-mutant cases were not detected by the mutation-specific antibodies. Various forms of exon 19 deletions, except E746_A750, were rarely detected by the mutant-specific antibody. Therefore, IHC-negative cases require further molecular analysis to confirm the presence of EGFR mutations.
Lung cancer (Amsterdam, Netherlands) 12/2013; · 3.14 Impact Factor
[show abstract][hide abstract] ABSTRACT: The discovery of the chromosomal fusion product of anaplastic lymphoma kinase (ALK) with echinoderm microtubule-associated protein-like 4 (EML4) (EML4-ALK) has changed the treatment paradigm of lung cancer. In this study, we analysed the clinical characteristics, including bronchoscopic findings, of patients with EML4-ALK-positive adenocarcinoma and compared them with those of EGFR mutation-positive patients.
In this retrospective cohort study, the clinical characteristics and bronchoscopic findings of patients with ALK fusion-positive lung cancers were compared to patients with EGFR-mutant lung cancers.
Among the 440 patients with adenocarcinoma of lung screened for this study, 46 (10.4%) harboured the EML4-ALK fusion, 90 (20.4%) harboured an activating EGFR mutation, and all had adenocarcinoma. In univariate analysis, ALK-positive patients were significantly younger than EGFR-positive patients (p = 0.004) and were more commonly male (p = 0.021). An initial status of stage IV metastatic cancer was more frequently noted in EML4-ALK-positive patients (p = 0.012), with initial brain metastasis frequently observed (p = 0.007). Compared with EGFR-positive patients, EML4-ALK-positive patients were significantly more likely to have positive bronchoscopic findings, which suggested a more centralized origin (p = 0.001). EML4-ALK patients also had significantly more positive bronchoscopic findings and were more commonly male in multivariate analysis.
The EML4-ALK fusion defines a new molecular subset of NSCLC that has distinct clinical and bronchoscopic findings suggesting more proximal origin when compared to tumours harbouring EGFR mutations.
Respiratory medicine 12/2013; · 2.33 Impact Factor
[show abstract][hide abstract] ABSTRACT: Although IL-1beta is believed to be crucial in the pathogenesis of osteoarthritis (OA), the IL-1beta blockade brings no therapeutic benefit in human OA and results in OA aggravation in several animal models. We explored the role of a cytokine signaling 1 (SOCS1) suppressor as a regulatory modulator of IL-1beta signaling in chondrocytes.
Cartilage samples were obtained from patients with knee OA and those without OA who underwent surgery for femur neck fracture. SOCS1 expression in cartilage was assessed by immunohistochemistry. IL-1beta-induced SOCS1 expression in chondrocytes was analyzed by quantitative polymerase chain reaction and immunoblot. The effect of SOCS1 on IL-1beta signaling pathways and the synthesis of matrix metalloproteinases (MMPs) and aggrecanase-1 was investigated in SOCS1 over-expressing or knockdown chondrocytes.
SOCS1 expression was significantly increased in OA cartilage, especially in areas of severe damage (P <0.01). IL-1beta stimulated SOCS1 mRNA expression in a dose-dependent pattern (P <0.01). The IL-1beta induced production of MMP-1, MMP-3, MMP-13, and ADAMTS-4 (aggrecanase-1, a disintegrin and metalloproteinase with thrombospondin motifs 4) was affected by SOCS1 over-expression or knockdown in both SW1353 cells and primary human articular chondrocytes (all P <0.05). The inhibitory effects of SOCS1 were mediated by blocking p38, c-Jun N-terminal kinase (JNK) and nuclear factor kappaB (NF-kappaB) activation, and by downregulating transforming growth factor-beta activated kinase 1 (TAK1) expression.
Our results show that SOCS1 is induced by IL1-beta in OA chondrocytes and suppresses the IL-1beta induced synthesis of matrix degrading enzymes by inhibiting IL-1beta signaling at multiple levels. It suggests that the IL-1beta-inducible SOCS1 acts as a negative regulator of the IL-1beta response in OA cartilage.
Arthritis research & therapy 11/2013; 15(6):R191. · 4.27 Impact Factor
[show abstract][hide abstract] ABSTRACT: MET gene copy number gain (CNG) and protein overexpression have been reported in lung cancer, but the clinical implications in early stage adenocarcinoma remain unclear.
We investigated MET gene copy number and protein expression in 141 cases of surgically resected stage I pulmonary adenocarcinoma. MET gene CNG was determined by silver in situ hybridization, and MET protein expression was assessed by immunohistochemistry. The correlation between MET gene CNG/protein expression and clinicopathologic parameters and prognostic significance was analyzed.
MET gene CNG was found in 24.1 % (34 of 141) of the cases and was associated with larger tumor size, pleural invasion, and lymphatic vessel invasion. MET gene CNG was inversely correlated with the presence of lepidic subtype (r = -0.17, p = 0.045) and was not associated with EGFR, KRAS mutation, or ALK gene rearrangement. In addition, MET gene CNG was significantly associated with shorter disease-free survival (DFS) (49 vs. 75 months; p < 0.001) and shorter overall survival (OS) (65 vs. 78 months; p = 0.01). Multivariate analysis confirmed that MET gene CNG was significantly associated with poorer DFS [p < 0.001; hazard ratio (HR) 5.5; 95 % confidence interval (CI) 2.2-13.9] but was not significantly associated with OS. MET overexpression was observed in 71.3 % of cases (97 of 136), but it was not correlated with gene CNG.
MET gene CNG is an independent poor prognostic factor in patients with stage I lung adenocarcinoma. It is associated with aggressive pathologic features and is inversely correlated with the presence of lepidic subtype.
Annals of Surgical Oncology 11/2013; · 4.12 Impact Factor
[show abstract][hide abstract] ABSTRACT: The implication of eosinophilic inflammation in chronic rhinosinusitis (CRS) has not been sufficiently studied in Asians. The aim of this study was to evaluate the relationship between eosinophilic inflammation in sinonasal tissues and the surgical outcome of functional endoscopic sinus surgery (FESS) in Koreans.
A retrospective review of medical records was performed for 347 patients who had undergone bilateral FESS. During FESS, nasal polyp (NP) or sinonasal pathological mucosa was obtained and histopathological analyses were performed. For analyses of surgical outcomes, 173 patients whose follow-up was >12 months were included. The sinonasal cavity was evaluated by endoscopic examination at the last follow-up using a Lund-Kennedy endoscopic scoring system.
Of 347 patients whose tissues were histologically evaluated, 250 (72%) had noneosinophilic CRS. The patients were categorized into four groups according to the presence of NP and eosinophilic inflammation. Of 173 patients, 43 patients (24.9%) had eosinophilic CRS with NP, 15 (8.7%) had eosinophilic CRS without NP, 74 (42.7%) had noneosinophilic CRS with NP, and 41 (23.7%) had noneosinophilic CRS without NP. There were no statistically significant differences in prevalence of allergic rhinitis and asthma and in their preoperative Lund-Mackay scores among four groups. Also, there was no statistically significant difference in the postoperative Lund-Kennedy score between eosinophilic and noneosinophilic CRS groups.
The results suggest that eosinophilic inflammation in CRS may not be related to the surgical outcome in Koreans.
American Journal of Rhinology and Allergy 11/2013; 27(6):166-9.
[show abstract][hide abstract] ABSTRACT: Small cell lung cancer (SCLC) transformation during epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment in lung cancer has been suggested as one of possible resistance mechanisms.
We evaluated whether SCLC transformation or neuroendocrine (NE) differentiation can be found in the cell line model. In addition, we also investigated its effect on responses to conventional chemotherapeutic drugs of the SCLC treatment.
Resistant cell lines to various kinds of EGFR-TKIs such as gefitinib, erlotinib, CL-387,785 and ZD6474 with A549, PC-9 and HCC827 lung adenocarcinoma cell lines were established. Among them, two resistant cell lines, A549/GR (resistant to gefitinib) and PC-9/ZDR (resistant to ZD6474) showed increased expressions of CD56 while increased synaptophysin, Rb, p16 and poly(ADP-ribose) polymerase were found only in A549/GR in western blotting, suggesting that NE differentiation occurred in A549/GR. A549/GR cells were more sensitive to etoposide and cisplatin, chemotherapeutic drugs for SCLC, compared to parental cells. Treatment with cAMP and IBMX induced synaptophysin and chromogranin A expression in A549 cells, which also made them more sensitive to etoposide and cisplatin than parental cells. Furthermore, we found a tissue sample from a patient which showed increased expressions of CD56 and synaptophysin after development of resistance to erlotinib.
NE differentiation can occur during acquisition of resistance to EGFR-TKI, leading to increased chemosensitivity.
Tuberculosis and Respiratory Diseases 09/2013; 75(3):95-103.
[show abstract][hide abstract] ABSTRACT: Survivin is a member of the inhibitors of apoptosis and frequently overexpressed in various cancer cells. Overexpression of survivin in lung cancer cells attenuates antitumor effect of tyrosine kinase inhibitors. However, data from the previous studies on the clinicopathologic implication of survivin in non-small-cell lung carcinoma (NSCLC) are inconsistent. We investigated the expression of survivin in 373 cases of surgically resected NSCLC. Correlations between the expression of survivin and clinicopathologic, molecular features and prognostic significance were analyzed. In adenocarcinoma, the increased expression of survivin was associated with the presence of vascular invasion, lymph node metastasis, and tumor recurrences, but we didn't find any correlation with survivin expression and clinicopathological parameters in squamous cell carcinoma. Patients with high survivin expression had significantly shorter disease-free survival (DFS; 42.2 vs. 58.8 months; p = 0.001) and shorter overall survival (OS; 60.8 vs. 71.5 months; p = 0.009) than those with low survivin expression group in adenocarcinoma. In squamous cell carcinoma, the expression of survivin was not associated with prognosis of the patients (DFS; 48.9 vs. 48.7 months; p = 0.837, OS; 61.0 vs. 62.4 months; p = 0.771). Multivariate analysis confirmed that survivin was an independent poor prognostic factor in adenocarcinoma (DFS: hazard ratio (HR), 1.687; 95 % confidence interval (CI), 1.123-2.532; p = 0.012; OS: HR, 1.965; 95 % CI, 1.108-3.486; p = 0.021). There was no statistically significant difference in the expression of survivin among different molecular subgroups (p > 0.05). Our results suggest that survivin is an independent negative prognostic factor in adenocarcinoma, but not in squamous cell carcinoma. The different prognostic roles played by survivin in adenocarcinoma and squamous cell carcinoma highlights the biological differences between these two histologic types.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 08/2013; · 2.68 Impact Factor
[show abstract][hide abstract] ABSTRACT: PURPOSE: The aim of this study is to evaluate CT, FDG PET, and clinicopathologic features of the adenosquamous carcinoma of the lung (ASC). PATIENTS AND METHODS: Twenty-six patients (M/F = 20:6; mean age, 65.0 years) who underwent surgical resection of ASC were included. The tumors were assessed in terms of size, location, morphologic characteristics, and maximum standardized uptake value (SUVmax) on CT and FDG PET. Proportion of adenocarcinoma was determined. The central and peripheral groups were compared. The differences in disease-free survival among the groups according to the observations were analyzed by Kaplan-Meier test for patients who underwent curative resection (n = 21). RESULTS: Diameter was 3.8 ± 1.9 cm. Five tumors were located centrally (19.2%) and 21 tumors peripherally (80.8%). Internal low and heterogeneous attenuation was found in all patients. Margins were lobulated in 20 (80%) patients, spiculated in 23 (92%), and ill-defined in 23 (92%). SUVmax was 8.3 ± 3.9. Adenocarcinoma proportion was 33 ± 28%. Central ASC were larger than peripheral ASC (5.7 cm vs. 3.4 cm, P = 0.007). Only SUVmax >6.3 was a poor prognostic factor. CONCLUSION: ASC was more commonly peripheral than central, and showed internal low and heterogeneous attenuation and possessed lobulated, spiculated, or ill-defined margin on CT. Mean SUVmax of ASC was 8.3 ± 3.9. Central ASC was larger than peripheral ASC. Except for tumor size, central ASC and peripheral ASC showed no significant differences in pathology, FDG PET, and survival. Higher SUVmax was a poor prognostic factor.
Clinical nuclear medicine 06/2013; · 3.92 Impact Factor
[show abstract][hide abstract] ABSTRACT: BACKGROUND: Dysregulation of the Sonic hedgehog (SHH) signaling pathway has been identified in many human malignancies. However, it remains unclear whether this pathway is activated in human lung adenocarcinoma. METHODS: We investigated the expression of the SHH ligand and its downstream molecules, such as glioma-associated oncogene homologue (GLI)-1, GLI-2, GLI-3, and ATP-binding cassette G2 (ABCG2), in 166 cases of surgically resected lung adenocarcinoma by immunohistochemistry. Correlations between the expression of SHH-related proteins and clinicopathologic parameters, histologic subtypes, and prognostic significance were statistically analyzed. RESULTS: SHH was highly expressed in the 36.1 % (60/166), GLI-1, GLI-2, and ABCG2 were found in 90/164 (54.9 %), 26/166 (15.7 %), and 139/165 (84.2 %), respectively, and GLI-3 was positive in all cases. SHH was more frequently highly expressed in nonsmokers, patients with no recurrences, lepidic predominant subtype, and with EGFR mutation (p < 0.05, respectively). The high expression of SHH and GLI-1 was related to better overall survival and progression-free survival (p < 0.05). CONCLUSIONS: The SHH signaling pathway is frequently up-regulated in a subset of lung adenocarcinoma and is significantly associated with EGFR mutation and lepidic subtype. Although SHH signaling protein expression is not an independent prognostic marker, the expression of these proteins can predict a better prognostic outcome.
Annals of Surgical Oncology 05/2013; · 4.12 Impact Factor
[show abstract][hide abstract] ABSTRACT: BACKGROUND: Epidermal growth factor receptor (EGFR) mutation alone may be insufficient to predict clinical outcomes in the response to EGFR-tyrosine kinase inhibitor (TKI) therapy. The secondary mutation T790 M and MET amplification are mechanisms of acquired resistance to EGFR-TKI in approximately 50 % of patients, but the remaining mechanisms are unknown. METHODS: Eight metastatic lesions and specimens from 41 non-small cell lung carcinoma (NSCLC) patients harbouring activating EGFR mutations who underwent surgical resection and EGFR-TKI therapy were available. Immunohistochemistry was used to evaluate E-cadherin, β-catenin, and PTEN. Chromogenic in situ hybridisation and silver-enhanced in situ hybridisation were used to evaluate EGFR and MET amplification. RESULTS: Patients with E-cadherin/β-catenin alteration showed a poor objective response rate (ORR) (p = 0.005) and shorter overall survival (p = 0.059). Additionally, β-catenin alteration was associated with a poor ORR (p = 0.012). Of the metastatic tumours, three cases (37.5 %) showed the acquisition of altered E-cadherin/β-catenin and PTEN loss and two cases (25 %) demonstrated MET/EGFR amplification. CONCLUSIONS: Altered E-cadherin/β-catenin expression in NSCLC harbouring EGFR mutations was associated with a poor response to EGFR-TKI. During metastatic progression, changes in E-cadherin/β-catenin were found. These results may suggest that E-cadherin/β-catenin alteration is related to poor TKI response and resistance.
Annals of Surgical Oncology 04/2013; · 4.12 Impact Factor
[show abstract][hide abstract] ABSTRACT: Mutations of the epidermal growth factor receptor (EGFR) are the strongest predictive factor for response to EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. EGFR TKIs are approved in Korea as a first-line treatment for lung cancer patients with mutated EGFR. Rapid and accurate EGFR mutation testing is essential for patient selection and establishing targeted therapies with EGFR TKIs. Thus, a standard set of guideline recommendations for EGFR mutation testing suitable for the Korean medical community is necessary. In this article, we propose a set of guideline recommendations for EGFR mutation testing that was discussed and approved by the Cardiopulmonary Pathology Study Group of the Korean Society of Pathologists.
The Korean Journal of Pathology 04/2013; 47(2):100-6. · 0.17 Impact Factor
[show abstract][hide abstract] ABSTRACT: BACKGROUND: Focal ground-glass opacity (GGO) is becoming a major concern because of its possible association with lung cancer. In this study, we analyzed the long-term progression of GGOs that persisted for more than 2 years. METHODS: We reviewed focal GGOs identified by thin-section computed tomography that persisted for more than 2 years. RESULTS: We enrolled a total of 114 patients with 175 GGO lesions. The median patient age was 61 years (range, 37-92 years) and 42 (36.8%) patients were male. Mean initial GGO size was 7.8 ± 4.4 mm. Median follow-up duration was 45 months. Forty-six (26.3%) GGOs had significant size increases (≥2 mm in the longest diameter) with a mean volume doubling time of 1041 days. In a multivariate analysis, large size (≥10 mm), the presence of a solid portion (mixed GGO) and old age (≥65 years) were risk factors for significant size increase, with odds ratios (95% CI) of 6.46 (2.69-15.6), 2.69 (1.11-6.95) and 2.55 (1.13-5.77), respectively. GGOs with character changes from pure to mixed or mixed to solid showed more rapid volume expansion. CONCLUSIONS: GGOs which persisted for several years showed an indolent course. Large lesions with a solid portion and GGOs in male or elderly individuals may be cause for more concern, as these factors were associated with size increase. Resection should be considered if GGOs show character changes, as these may be associated with rapid size progression.
Respiratory medicine 03/2013; · 2.33 Impact Factor
[show abstract][hide abstract] ABSTRACT: Epithelial-mesenchymal transition (EMT) is an important step in the invasion and progression of cancer and in the development of chemoresistance by cancer cells.
To address the clinical significance of the EMT pathway in lung adenocarcinoma and the association of the pathway with histological subtype, we examined 193 surgically resected lung adenocarcinoma samples for the expression of representative EMT-related proteins (E-cadherin, β-catenin, and vimentin) by immunohistochemistry. Histological subtypes were classified according to the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification. The results for EMT-related protein expression were analyzed for correlation with clinicopathological features and with survival.
The loss of E-cadherin expression and aberrant β-catenin expression were significantly associated with larger tumor size, pleural invasion, lymphatic/vascular invasion, and advanced pathological stage (p<0.05). The alteration of the E-cadherin/β-catenin complex was least frequently observed in the lepidic-predominant group, but these associations were not statistically significant. In the multivariate analysis, altered E-cadherin/β-catenin complex expression was found to be an independent poor prognostic factor (p=0.017; hazard ratio, 1.926; 95% confidence interval, 1.119 to 3.314).
The alteration of the expression of the E-cadherin/β-catenin complex was associated with aggressive tumor behavior in lung adenocarcinoma.
The Korean Journal of Pathology 02/2013; 47(1):44-51. · 0.17 Impact Factor
[show abstract][hide abstract] ABSTRACT: The aims of this study were to evaluate the abilities of direct sequencing (DS), peptide nucleic acid (PNA) clamping, and pyrosequencing methods to detect epidermal growth factor receptor (EGFR) mutations in formalin-fixed paraffin-embedded (FFPE) non-small cell lung carcinoma (NSCLC) samples and to correlate EGFR mutational status as determined by each method with the clinical response to EGFR tyrosine kinase inhibitors (TKIs).
Sixty-one NSCLC patients treated with EGFR TKIs were identified to investigate somatic mutations in the EGFR gene (exons 18-21).
Mutations in the EGFR gene were detected in 38 of the 61 patients (62%) by DS, 35 (57%) by PNA clamping and 37 (61%) by pyrosequencing. A total of 44 mutations (72%) were found by at least one of the three methods, and the concordances among the results were relatively high (82-85%; kappa coefficient, 0.713 to 0.736). There were 15 discordant cases (25%) among the three different methods.
All three EGFR mutation tests had good concordance rates (over 82%) for FFPE samples. These results suggest that if the DNA quality and enrichment of tumor cells are assured, then DS, PNA clamping, and pyrosequencing are appropriate methods for the detection of EGFR mutations.
The Korean Journal of Pathology 02/2013; 47(1):52-60. · 0.17 Impact Factor
[show abstract][hide abstract] ABSTRACT: The purpose of this study was to evaluate the accuracy of a preoperative MRI with microscopy coils in determining the primary tumor thickness of malignant melanoma with histopathologic correlation.
Eleven patients with histopathologically confirmed malignant melanoma were included in this study. MR images of the tumors were obtained with a 47-mm microscopy coil on 1.5T MR scanners and were evaluated by two radiologists, who assessed the thickness of the primary tumor on T2-weighted images (T2WI) and gadolinium-enhanced T1-weighted images with fat suppression (Gd-T1WI) and compared the results with the histopathologic findings as the reference standard. Correlations between tumor thickness on MRI and histopathologic examination were assessed using concordance correlation coefficients (CCCs). Inter- and intraobserver variabilities of tumor measurements were also assessed by intraclass correlation coefficient (ICC).
Among the 11 cases included in the study, 10 cases from the same number of patients were managed with surgical excision and one case was confirmed with punch biopsy. The primary tumor thickness measured on T2WI showed better correlation with histopathologic results, as compared with measurements taken on Gd-T1WI: the CCC of measurements on T2WI ranged from 0.64 to 0.78, indicating a substantial agreement, whereas the CCC of measurements on Gd-T1WI ranged from 0.50 to 0.61, indicating a moderate to substantial agreement. Inter- and intraobserver agreements of readers 1 and 2 were excellent for both T2WI and Gd-T1WI, with ICC ranging from 0.86 to 0.99.
MR imaging with microscopy coils may be an accurate technique in the preoperative assessment of tumor thickness in malignant melanoma, especially on T2-weighted images.
Korean journal of radiology: official journal of the Korean Radiological Society 01/2013; 14(2):287-293. · 1.32 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
PLoS ONE 01/2013; 8(10):e76999. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Objectives
Activating mutations in the epidermal growth factor receptor (EGFR) kinase domain are correlated with dramatic clinical responses in non-small cell lung cancer patients treated with EGFR-tyrosine kinase inhibitors (TKIs). The two most common EGFR mutations representing 85% to 90% of EGFR mutations are the E746_A750 deletion in exon 19 and the L858R point mutation in exon 21. We conducted this study to evaluate the suitability of mutation-specific antibodies that can detect E746_A750 deletion and L858R mutant EGFR proteins by immunohistochemistry (IHC).
Materials and methods
In a cohort of consecutive patients with surgically resected lung adenocarcinomas (n = 240), mutant EGFR protein expression was assessed by IHC using specific antibodies (clone SP111 and SP125) to the 2 major forms of EGFR mutations. Immunoreactivity was scored as 0 to 3, and the results were compared with the EGFR-mutational status.
With a cutoff value of IHC 2+ for SP 111 (anti-EGFR E746_A750 del antibody) and SP 125 (anti-EGFR L858R antibody), each antibody showed high specificity (99.0% and 89.7%, respectively) and sensitivity (70.6% and 80.4%, respectively). While cases with IHC scores of 3 using these 2 antibodies were positively correlated with the EGFR-mutational status, cases with IHC scores lower than 3+ showed variable results of the EGFR-mutational status.
Although each antibody showed relatively high specificity, some EGFR-mutant cases were not detected by the mutation-specific antibodies. Various forms of exon 19 deletions, except E746_A750, were hardly detected by the mutant-specific antibody. Therefore, IHC-negative cases require further molecular analysis to confirm the presence of EGFR mutations.