Gheeyoung Choe

Screening of Anaplastic Lymphoma Kinase Rearrangement by Immunohistochemistry in Non-small Cell Lung Cancer: Correlation with Fluorescence In Situ Hybridization

Background: The use of a standard immunohistochemistry (IHC) assay to detect the anaplastic lymphoma kinase (ALK) protein in lung cancer is challenging. There are no universally accepted, evidence-based guidelines on identifying patients with ALK-rearranged lung cancer using IHC. Methods: We retrospectively reviewed 465 resected specimens of non-small cell lung cancer using a tissue microarray as a test set. ALK protein expression using IHC with 5A4 monoclonal antibody (Novocastra) and ALK gene rearrangement using fluorescence in situ hybridization (FISH) with dual-color break-apart probes (Abbott molecular) were examined. Immunoreactivity was scored as 0, 1, 2, or 3, and the results were compared with the FISH results. A diagnostic algorithm was derived from the correlation of the IHC and FISH results and applied to an additional 187 adenocarcinoma samples used as a validation set. Results: In the test set, ALK protein expression was detected in 40 patients (40/465, 8.6%), consisting of IHC scores of 1 (n = 14), 2 (n = 10), and 3 (n = 16), whereas 19 patients (19/453, 4.2%) were FISH-positive. All the FISH-positive patients were assigned IHC scores of 2 or 3. All the patients with ALK IHC scores of 3 were FISH-positive, those with scores of 0 or 1 were FISH-negative, and those with scores of 2 were FISH variable. In the validation set, ALK protein expression was detected in 14 patients (scores of 1, n = 2; scores of 2, n = 6; and scores of 3, n = 6), of which nine patients (9/187, 4.8%) were FISH-positive. All the patients with IHC scores of 0 or 1 were FISH-negative, and those with scores of 3 were FISH- positive. Among the patients with IHC scores of 2, three (3/6, 50%) were FISH-positive. Conclusions: The sensitivity and specificity of IHC was 100% and 95.8%, respectively. These data supported an IHC scoring algorithm in which ALK IHC scores of 0, 1, or 3 were highly compatible with FISH results, and IHC scores of 2 were variable. Based on these findings, the IHC assay using the 5A4 antibody reliably detected non-small cell lung cancer with ALK rearrangement and may be useful as a screening method to identify these tumors.

Predictors of surgical outcome and pathologic considerations in focal cortical dysplasia

Background: Although surgical resection has been an important alternative treatment for patients with intractable epilepsy related to focal cortical dysplasia (FCD), the prognostic relevance of the degree of pathologic severity is controversial and there has been only limited information regarding the prognostic factors involved in the surgical treatment of refractory epilepsy in patients with FCD. Methods: We undertook the present study to assess whether the pathologic subtypes of FCD affect surgical outcomes in patients with drug-resistant epilepsy. We also studied the prognostic roles of clinical factors and various diagnostic modalities in the surgical treatment. Results: A total of 166 consecutive patients were included. By univariate analysis, incomplete resection of epileptogenic area (p < 0.001), mild pathologic features (p = 0.01), and the presence of secondary tonic clonic seizures (2GTCS) (p = 0.05) were associated with poor surgical outcomes. There was a strong tendency for patients with severe pathologic features to have MRI abnormalities (p < 0.001). Incomplete resection of epileptogenic area (p < 0.001) and mild pathologic features (p = 0.02) were poor independent outcome predictors on multivariate analysis. The results of MRI, scalp EEG, fluorodeoxyglucose–PET, and ictal SPECT were not associated with surgical outcomes. Conclusions: Our study shows that there is a strong tendency for patients with severe pathologic features to have MRI abnormalities, and patients with incomplete resection, mild pathologic features, or the presence of secondary tonic clonic seizures have a high chance of a poorer surgical outcome.

Clinicopathologic implication of ALK rearrangement in surgically resected lung cancer: A proposal of diagnostic algorithm for ALK-rearranged adenocarcinoma

BACKGROUND To characterize the clinicopathologic features of ALK-rearranged lung cancer, and suggest a molecular test protocol for lung adenocarcinoma in the small biopsy specimen. METHODS In 735 NSCLC surgical specimens, clinicopathologic features, ALK protein over-expression by immunohistochemistry (IHC), and ALK rearrangement by fluorescence in situ hybridization (FISH) as well as EGFR and KRAS mutation studies were analyzed. RESULTS Of the 735 NSCLC cases, 28 (3.8%) were ALK FISH-positive. ALK rearrangement, EGFR and KRAS mutation were mutually exclusive. ALK rearrangement was significantly higher in adenocarcinomas (6.8%, p<0.001), younger age (p<0.0007), women (7.6%, p<0.001), and never-smokers (8.9%, p<0.001) with no gender difference in the adenocarcinoma or never-smoker subgroup. ALK FISH-positivity was not associated with disease recurrence (HR, 0.79; 95% CI, 0.42-1.49) or overall survival (HR, 0.61; 95% CI, 0.24-1.55). However, ALK-rearranged lung cancer tended to show more frequent lymph node metastasis despite its lower T stage. Similar to EGFR-mutated lung cancer, ALK-rearranged lung cancer was enriched in adenocarcinoma, women, and never-smokers. The results of ALK IHC and FISH obtained from tissue microarray (TMA)/biopsy specimens and whole sections after resection were concordant. CONCLUSION ALK rearrangement was not a significant prognostic factor in surgically resectable NSCLC. The clinical profiles of ALK-rearranged lung cancer patients overlapped with those of EGFR-mutated patients. Therefore, we suggest that simultaneous tests for ALK IHC and EGFR mutation (Chungs SNUBH molecular test protocol), which has important implications for the storage and use of small biopsy or cytology samples for genetic analysis.

Intramedullary spinal cord astrocytoma in adults : postoperative outcome

Intramedullary spinal cord astrocytomas are relatively rare and usually low-grade lesions with a long natural history. The rarity of the condition and its indolent clinical course has made the evaluation of treatment efficacy difficult. To clarify postoperative outcome and prognostic factors, we performed a retrospective analysis of intramedullary spinal cord astrocytomas in a single institute. Twenty-eight patients were surgically treated between 1978 and 1999; of median age 36 years (range, 19–68 years); nineteen patients were males and nine females. All patients presented with pain and neurological deficits. The cervical cord was involved in fifteen patients, cervico-thoracic in five, thoracic in six and thoraco-lumbar in two. Gross total removal was performed in three patients, subtotal removal in six, partial removal in fourteen and biopsy only in five. Nineteen patients received radiation therapy postoperatively. The mean follow-up period was 31.9 months (range, 0.5–184 months). Low-grade astrocytomas were found in 18 cases, anaplastic astrocytoma in three cases and glioblastomas in seven cases. The median survivals of patients with low- and high-grade astrocytoma were 184 months and 8 months, respectively (p < 0.05). The median survivals of irradiated and non-irradiated patients with low-grade astrocytoma were 184 months and 102 months. Neither the extent of resection, nor radiation influenced the survival rate. In summary, the histological grade was the most significant predictor of survival in patients with astrocytoma of the spinal cord.

Dysembryoplastic neuroepithelial tumor: radiological findings (including PET, SPECT, and MRS) and surgical strategy.

In order to elucidate the radiological features of dysembryoplastic neuroepithelial tumor (DNT), and to clarify the optimal surgical strategy for this tumor, the authors retrospectively analyzed 20 cases of DNT treated at our institution.Magnetic resonance (MR) imaging (all cases), 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) (eight cases), ictal/interictal Tc99m-HMPAO single photon emission computed tomography (SPECT) (seven and five cases respectively) and proton magnetic resonance spectroscopy (1H MRS) (one case) were performed preoperatively. Invasive monitoring/intraoperative electrocorticography (ECoG) was performed in four cases in order to determine the epileptogenic zone. A well-demarcated lobulating tumor located in the cortical with/without subcortical area was the typical MR finding. 18F-FDG PET showed glucose hypometabolism in all cases. Ictal Tc99m-HMPAO SPECT showed hyperperfusion of the lesion in three cases and interictal Tc99m-HMPAO SPECT showed hypoperfusion of the lesion in one case. 1H MRS showed nonspecific findings. Gross total resection was performed in all cases. Histologically, associated cortical dysplasia was found in 11 cases. The mean duration of follow-up after surgery was 37.9 months, and the overall seizure free rate was 90%. Follow-up MR imaging was performed in 14 cases (mean duration of follow-up: 21.6 months) and showed no recurrence of tumor in any of these cases. lnvasive monitoring/intraoperative ECoG and the presence of cortical dysplasia showed no significant relationship with seizure control rate (p=1.25 and p=1.62 respectively).

Prevalence and Risk Factors of Atrophic Gastritis and Intestinal Metaplasia in a Korean Population Without Significant Gastroduodenal Disease

Background and Aim: The prevalence of gastric cancer and Helicobacter pylori infection is unacceptably high in Korea. This study was performed to evaluate the prevalence of atrophic gastritis (AG) and intestinal metaplasia (IM) and to identify their risk factors with respect to H. pylori virulence factors, and environmental and host factors, in Korean population without significant gastroduodenal disease.

Diagnostic Value of Galectin-3, HBME-1, Cytokeratin 19, High Molecular Weight Cytokeratin, Cyclin D1 and p27kip1 in the Differential Diagnosis of Thyroid Nodules

The distinction between benign and malignant thyroid tumors is critical for the management of patients with thyroid nodules. We applied immunohistochemical staining for galectin-3, HBME-1, cytokeratin 19 (CK19), high molecular weight cytokeratin (HMWCK), cyclin D1 and p27kip1 in 295 thyroid lesions to determine their diagnostic accuracy. The expression of all markers was significantly associated with differentiated thyroid carcinoma (DTC).The sensitivity for the diagnosis of DTC was 94.7% with galectin-3, 91.3% with HBME-1, and 90.3% with CK19. The specificities of these markers were 95.5%, 69.7%, and 83.1%, respectively. Combining these markers, co-expression of galectin-3 and CK19 or galectin-3 and HBME-1 was seen in 93.2% of carcinomas but in none of the benign nodules. Comparing follicular variant of papillary carcinoma (FVPC) with follicular carcinoma (FC), the expression of galectin-3, CK19, and HMWCK was significantly higher in FVPC. When comparing FC with FA, the expression of galectin-3 and HBME-1 was significantly higher in FC. These results suggest that 1) galectin-3 is a useful marker in the distinction between benign and malignant thyroid tumors, 2) the combined use of HBME-1 and CK19 can increase the diagnostic accuracy, and 3) the use of CK19 and HMWCK can aid in the differential diagnosis between PC and FC.

The Role of Serum Pepsinogen and Gastrin Test for the Detection of Gastric Cancer in Korea

Background and Aim:  This study was performed to determine whether serum pepsinogen (PG) and gastrin testing can be used to detect gastric cancer in Korea.

The effect of chromosome 17 polysomy on HER-2/neu status in breast cancer

Aim: To investigate the effect of polysomy 17 on HER-2 status as evaluated by immunohistochemistry (IHC), dual-colour fluorescence in situ hybridisation (FISH) and chromogenic in situ hybridisation (CISH). Methods: Dual-probe FISH and single-probe CISH were performed to detect HER-2 gene amplification, and IHC to detect HER-2 expression, on 309 invasive breast cancers. Results: Polysomy 17 was detected in 32.0% of the total number of breast cancers; it was detected in 12.3% of the IHC 0 or 1+ cases, 42.8% of the IHC 2+ cases and 66.0% of the IHC 3+ cases (p<0.001). In addition, there was a substantially higher rate of polysomy 17 in the IHC 2+ or 3+/FISH-negative cases than in the IHC 0 or 1+ cases (40.8% vs 12.3%; p<0.001). The FISH and CISH results were concordant in 299 cases (96.8%). Of the 10 discordant cases, FISH suggested amplification in five with disomy 17 and one with monosomy 17, whereas CISH pointed to borderline copy numbers in each of these six cases. The remaining four cases had high polysomy 17; CISH, but not FISH, indicated amplification. Conclusions: Results suggest that an increase of HER-2 gene copy number secondary to polysomy 17 leads to HER-2 overexpression in some IHC 2+/3+ breast cancers, without gene amplification. The high level of concordance between FISH and CISH suggests that CISH is a valid alternative to FISH for assessing HER-2 gene amplification. However, cases in which CISH indicates the presence of borderline copy numbers or low levels of amplification may need FISH to rule out polysomy 17 and to determine HER-2 gene amplification status accurately.

Epidermal Growth Factor Receptor Mutation and Pathologic-Radiologic Correlation Between Multiple Lung Nodules with Ground-Glass Opacity Differentiates Multicentric Origin from Intrapulmonary Spread

Introduction: No standard guidelines detailing recommendations for the selection and treatment for multiple lung nodules with ground-glass opacity (GGO) have been established. For treatment decision, we analyzed epidermal growth factor receptor (EGFR)/K-ras somatic aberrations and pathologic-radiologic correlation in multiple lung nodules presented as GGO to differentiate multifocal lesions from intrapulmonary spread. Methods: Twenty-four patients with multiple lung nodules presented as GGO were identified to investigate somatic mutations of EGFR (exon 18–21) and K-ras (codons 2, 13, and 61). This series included 18 atypical adenomatous hyperplasias (AAH), 15 bronchioloalveolar carcinomas (BAC), and 23 adenocarcinomas (ADC) obtained from 24 patients. Results: High frequency of discordant EGFR mutations (17 of 24, 70.8%) could discriminate tumor clonality (18 of 24, 75%) of multiple lung neoplastic nodules presented as GGO. EGFR mutations were common in AAH (38.9%), BAC (46.7%), and ADC (39.1%). In case 4, AAH and BAC had different mutational changes, and in case 10, the BAC lesion contains EGFR mutation that is not in the invasive ADC. In case 17, the BAC had more mutational changes than the carcinoma. The pure GGO appearance in the radiologic examination corresponded preinvasive pathologic change. Conclusions: This study showed that synchronous BAC and/or ADC can have different EGFR or K-ras mutational profiles suggesting these lesions arise as independent events rather than intrapulmonary spread or systemic metastasis. This has significant implication in staging and treatment. These findings might be a clue to establish guidelines of the multiple neoplastic lung nodules with GGO.