Sun Och Yoon

Current Trends of the Incidence and Pathological Diagnosis of Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs) in Korea 2000-2009: Multicenter Study.

Purpose As a result of various independently proposed nomenclatures and classifications, there is confusion in the diagnosis and prediction of biological behavior of gastroenteropancreatic neuroendocrine tumors (GEP-NETs). A comprehensive nationwide study is needed in order to understand the biological characteristics of GEP-NETs in Korea. Materials and Methods We collected 4,951 pathology reports from 29 hospitals in Korea between 2000 and 2009. Kaplan-Meier survival analysis was used to determine the prognostic significance of clinicopathological parameters. Results Although the GEP-NET is a relatively rare tumor in Korea, its incidence has increased during the last decade, with the most significant increase found in the rectum. The 10-year survival rate for well-differentiated endocrine tumor was 92.89%, in contrast to 85.74% in well differentiated neuroendocrine carcinoma and 34.59% in poorly differentiated neuroendocrine carcinoma. Disease related death was most common in the biliary tract (62.2%) and very rare in the rectum (5.2%). In Kaplan-Meier survival analysis, tumor location, histological classification, extent, size, mitosis, Ki-67 labeling index, synaptophysin expression, lymphovascular invasion, perineural invasion, and lymph node metastasis showed prognostic significance (p<0.05), however, chromogranin expression did not (p=0.148). The 2000 and 2010 World Health Organization (WHO) classification proposals were useful for prediction of the prognosis of GEP-NET. Conclusion The incidence of GEP-NET in Korea has shown a remarkable increase during the last decade, however, the distribution of tumors in the digestive system differs from that of western reports. Assessment of pathological parameters, including immunostaining, is crucial in understanding biological behavior of the tumor as well as predicting prognosis of patients with GEP-NET.

MYC translocation and an increased copy number predict poor prognosis in adult diffuse large B-cell lymphoma (DLBCL), especially in germinal centre-like B cell (GCB) type.

Aims:  Diffuse large B‐cell lymphoma (DLBCL) is a heterogeneous disease with various genetic alterations. The aim was to investigate MYC, Bcl‐2 and Bcl‐6 translocations and copy number changes in adult DLBCLs to evaluate their clinicopathological features and prognostic implications.

Prognostic implications for high expression of oncogenic microRNAs in advanced gastric carcinoma

Aberrant expressions of specific microRNAs are recently known in many malignancies, including gastric carcinoma. The prognostic implication of oncogenic microRNA dysregulation was investigated in advanced gastric carcinomas undergoing radical resection and adjuvant systemic chemotherapy, and observed on long‐term follow‐up.

Deregulated expression of microRNA-221 with the potential for prognostic biomarkers in surgically resected hepatocellular carcinoma☆

Aberrant expression of specific microRNAs in hepatocellular carcinomas has recently been reported. We examined expression patterns of 4 microRNAs (microRNA-221, microRNA-222, microRNA-21, and microRNA-155) to evaluate their potential as relevant biomarkers by quantitative real-time reverse transcriptase-polymerase chain reaction using formalin-fixed, paraffin-embedded tissues of 115 surgically resected hepatocellular carcinoma and paired nonneoplastic liver cases as well as 21 normal liver samples from cancer-free individuals. MicroRNA-221, microRNA-222, and microRNA-21 were differentially overexpressed in hepatocellular carcinoma compared with nonneoplastic and normal livers (P < .001). The mean fold changes in microRNA-221, microRNA-222, and microRNA-21(hepatocellular carcinoma to matched nonneoplastic liver) were 4.00, 4.44, and, 3.67, respectively. In addition, nonneoplastic liver tissues displayed higher levels of microRNA-221, microRNA-222, microRNA-21, and microRNA-155 than normal livers (P < .001, respectively). However, the overexpression of the 4 microRNAs showed no consistent relevance to the known prognostic clinicopathologic parameters. High expression of microRNA-221 in hepatocellular carcinomas was significantly related to shorter time to local recurrence (P < .001) and determined as an independent predictor for local recurrence (P = .001). The fold changes in microRNA-221 (hepatocellular carcinoma to matched nonneoplastic liver) less than 1 were more commonly detected in cases of distant metastases than those of disease-free and local recurrence (P = .009). The fold changes less than 1 were related to reduced metastasis-free survival (P = .006) and thus can be used as an independent predictor of distant metastasis after surgical resection (P = .027). Based on these results, we propose the possible role of microRNA-221, microRNA-222, microRNA-21, and microRNA-155 dysregulation in hepatocarcinogenesis and the potential of microRNA-221 dysregulation for predicting local recurrence and distant metastasis after curative surgery.

Overexpression of the M2 isoform of pyruvate kinase is an adverse prognostic factor for signet ring cell gastric cancer

AIM To investigate M2 isoform of pyruvate kinase (PKM2) expression in gastric cancers and evaluate its potential as a prognostic biomarker and an anticancer target. METHODS All tissue samples were derived from gastric cancer patients underwent curative gastrectomy as a primary treatment. Clinical and pathological information were obtained from the medical records. Gene expression microarray data from 60 cancer and 19 non-cancer gastric tissues were analyzed to evaluate the expression level of PKM2 mRNA. Tissue microarrays were constructed from 368 gastric cancer patients. Immunohistochemistry was used to measure PKM2 expression and PKM2 positivity of cancer was determined by proportion of PKM2-positive tumor cells and staining intensity. Association between PKM2 expression and the clinicopathological factors was evaluated and the correlation between PKM2 and cancer prognosis was evaluated. RESULTS PKM2 mRNA levels were increased more than 2-fold in primary gastric cancers compared to adjacent normal tissues from the same patients (log transformed expression level: 7.6 ± 0.65 vs 6.3 ± 0.51, P < 0.001). Moreover, differentiated type cancers had significantly higher PKM2 mRNA compared to undifferentiated type cancers (log transformed expression level: 7.8 ± 0.70 vs 6.7 ± 0.71, P < 0.001). PKM2 protein was mainly localized in the cytoplasm of primary cancer cells and detected in 144 of 368 (39.1%) human gastric cancer cases. PKM2 expression was not related with stage (P = 0.811), but strongly correlated with gastric cancer differentiation (P < 0.001). Differentiated type cancers expressed more PKM2 protein than did the undifferentiated ones. Well differentiated adenocarcinoma showed 63.6% PKM2-positive cells; in contrast, signet-ring cell cancers showed only 17.7% PKM2-positive cells. Importantly, PKM2 expression was correlated with shorter overall survival (P < 0.05) independent of stage only in signet-ring cell cancers. CONCLUSION PKM2 expression might be an adverse prognostic factor for signet-ring cell carcinomas. Its function and potential as a prognostic marker should be further verified in gastric cancer.

TTF-1 mRNA-positive circulating tumor cells in the peripheral blood predict poor prognosis in surgically resected non-small cell lung cancer patients

Circulating tumor cells (CTCs) have been identified in peripheral blood of cancer patients, and reproducible detection of CTCs has demonstrated the potential as useful diagnostic and prognostic tools in several cancers. Present study aimed to determine the clinical relevance of CTCs in surgically resected non-small cell lung cancer (NSCLC) patients. CTC status in presurgery and postsurgery peripheral blood samples from 79 surgically resected NSCLC patients was investigated using thyroid transcription factor-1 (TTF-1) and cytokeratin19 (CK19) mRNA markers by nested real-time RT (reverse transcription)-PCR assay. Detection of TTF-1((+))CTCs was found to be specific to NSCLC patients. TTF-1((+))CTCs were detected in 36.1% (22/61) of patients before surgery and in 37.5% (18/48) after surgery. For CK19 mRNA-expressing CTCs (CK19((+))CTCs), the detection rate was 42.6% (26/61) before surgery, and 25.0% (12/48) after surgery. Cases with postsurgery TTF-1((+)) and/or CK19((+))TCs was more associated with disease progression (P=0.004) and shorter disease progression-free survival (P=0.006) as compared to those without postsurgery CTCs. As an individual marker, postsurgery TTF-1((+))CTCs-positive status was more associated with disease progression (P=0.004) and shorter disease progression-free survival (P=0.004) as compared to postsurgery TTF-1((+))CTCs-negative status. Particularly, patients with postsurgery TTF-1((+))CTCs, but not presurgery (Pre((-))Post((+)) cases) showed marked shorter disease progression-free survival than other patients (P<0.001). On the other hand, a CK19((+))CTC status individually did not show significant clinical relevance, and presurgery CK19((+))CTC status did not either. Present study suggests that TTF-1 mRNA-expressing CTCs might be a useful surrogate predictor of disease progression before clinical manifestations are apparent, and that monitoring of TTF-1((+))CTCs status after surgery may be useful for identifying high-risk patients among surgically resected NSCLC cases.

PD-L1 expression on immune cells, but not on tumor cells, is a favorable prognostic factor for head and neck cancer patients

To investigate the expression of programmed death-ligand 1 (PD-L1) and immune checkpoints and their prognostic value for resected head and neck squamous cell cancer (HNSCC). PD-L1 expression on tumor cells (TC) and tumor-infiltrating immune cells (IC), abundance of tumor-infiltrating lymphocytes (TILs), and expression of the immune checkpoints were investigated in 402 HNSCC patients. PD-L1 expression on TC and IC was categorized into four groups according to the percentage of PD-L1-positive cells. PD-L1 positivity was defined as ≥5% of cells based on immunohistochemistry. High PD-L1 expression on IC, but not TC, was an independent favorable prognostic factor for RFS and OS adjusted for age, gender, smoking, stage, and HPV. High frequencies of CD3+ or CD8+ TILs, Foxp3+ Tregs, and PD-1+ TILs were strongly associated with favorable prognosis. PD-L1 was exclusively expressed on either TC or IC. Transcriptome analysis demonstrated that IC3 expressed higher levels of the effector T cell markers than TC3, suggesting that PD-L1 expression is regulated via an adaptive IFNγ-mediated mechanism. High PD-L1 expression on IC, but not TC, and high abundance of PD-1+ T cells and Foxp3+ Tregs are favorable prognostic factors for resected HNSCC. This study highlights the importance of comprehensive assessment of both TC and IC.

Signet ring cell mixed histology may show more aggressive behavior than other histologies in early gastric cancer

Signet ring cell carcinoma (SRC) of the stomach is known to have different microscopic and biologic characteristics compared to non‐SRC. The pathologic report has documented partly SRC component with main histologies. However, the clinical significance of SRC mixture has not been reported. Aim was to investigate clinicopathologic features of mixed‐SRC histology in early gastric cancer (EGC).

BRAF V600E mutation analysis of liquid-based preparation- processed fine needle aspiration sample improves the diagnostic rate of papillary thyroid carcinoma ☆

Early detection and diagnosis of papillary thyroid carcinoma are important for successful management of patients. Liquid-based preparations (Thinprep) of fine needle aspirations from thyroid nodules are now widely used and are replacing conventional smears because residual samples can be used for ancillary tests. Detection of the BRAF(V600E) mutation in cytology specimens could aid in the diagnosis of papillary thyroid carcinoma. We, therefore, analyzed the cytologic features and BRAF(V600E) mutation status of thyroid liquid-based preparation-fine needle aspiration samples. A total of 191 histologically confirmed thyroid liquid-based preparation-fine needle aspiration specimens were selected. We analyzed cytomorphological features and BRAF(V600E) mutation status in both liquid-based preparation-fine needle aspiration samples and the corresponding formalin-fixed, paraffin-embedded tissues. The Seeplex BRAF ACE detection kit (Seoul, Korea), melting curve analysis with SYBR green, and sequencing analysis were used to detect BRAF(V600E) mutations. Of 191 patients, 126 had histologically confirmed papillary thyroid carcinoma, whereas the remaining 65 lesions were benign lesions and carcinomas of other types. The sensitivity of liquid-based preparation alone for diagnosis of papillary thyroid carcinoma was 71.4%. When BRAF(V600E) mutation analyses results were considered in conjunction with the cytologic diagnosis, the diagnostic sensitivity for detecting papillary thyroid carcinoma increased to 84.9% regardless of the method used to detect BRAF mutations. BRAF(V600E) mutation analysis using residual liquid-based preparation cytologic samples is, therefore, a powerful additional diagnostic tool for diagnosis of papillary thyroid carcinoma.

Ki-67 expression as a prognostic factor in diffuse large B-cell lymphoma patients treated with rituximab plus CHOP

Background:  Assessment of tumor cell proliferation based on Ki‐67 expression yielded conflicting prognostic predictions of patients with diffuse large B‐cell lymphoma (DLBCL). The introduction of rituximab to the DLBCL treatment regime has led to alterations in the significance of previous prognostic factors.