Soomin Ahn

Persistent pure ground-glass opacity lung nodules ≥ 10 mm in diameter at CT scan: histopathologic comparisons and prognostic implications.

BACKGROUNDnLittle is known about the histopathology and prognosis of persistent pure ground-glass opacity nodules (GGNs) of ≥ 10 mm in diameter. We aimed to compare the morphologic features of persistent pure GGNs of ≥ 10 mm in diameter at thin-section CT (TSCT) scan with histopathology and patient prognosis.nnnMETHODSnA total of 46 resected GGNs that were evaluated with TSCT scan and followed up for ≥ 3 years were included in this study. Correlations between histopathology (adenocarcinoma in situ [AIS], minimally invasive adenocarcinoma [MIA], and invasive adenocarcinoma) and CT scan characteristics were examined. CT scan and clinicodemographic data were investigated by univariate and multivariate analyses to identify features that helped distinguish invasive adenocarcinoma from AIS or MIA. Disease recurrence was also evaluated.nnnRESULTSnThe nodules included 19 AISs (41%), nine MIAs (20%), and 18 invasive adenocarcinomas (39%). On univariate analysis, the presence of air bronchogram (P = .012), size of nodule (P = .032, cutoff = 16.4 mm in diameter), and mass of nodule (P = .040, cutoff = 0.472 g) were significant factors that differentiated invasive adenocarcinoma from AIS or MIA. On multivariate analysis, size (P = .010) and mass of nodule (P = .016) were significant determinants for invasive adenocarcinoma. There were no cases of recurrence during a follow-up period of ≥ 3 years after surgical resection.nnnCONCLUSIONSnIn persistent pure GGNs of ≥ 10 mm in diameter, the size and mass of the nodule are determinants of invasive adenocarcinoma, for which surgical resection leads to excellent prognosis.

MET overexpression assessed by new interpretation method predicts gene amplification and poor survival in advanced gastric carcinomas

The establishment of better selection criteria for identifying sub-populations that may benefit from treatment is a key aspect of the development and success of targeted therapy. To investigate methods for assessing MET overexpression in gastric cancer, we conducted immunohistochemistry using a new anti-Total MET monoclonal antibody in a single-institution cohort of 495 patients. As antibody is directed against a membranous and/or cytoplasmic epitope, two interpretation methods were used: (1) membranous and cytoplasmic and (2) membranous alone. In selected 120 cases, copy number gain and mRNA expression levels were measured using quantitative real-time PCR. Further in situ hybridization confirmed the presence of MET gene amplification. Among the 495 gastric cancers, simultaneous membranous and cytoplasmic overexpression of MET was found in 108 cases (21.8%) and membranous alone overexpression was observed in 40 cases (8.1%). The highest correlation was observed in membranous and cytoplasmic staining of MET: MET expression scores correlated significantly with high MET mRNA levels (r=0.465, P<0.0001), increased copy number gain (r=0.393, P=0.000002) and amplification of MET gene. Moreover, patients with MET overexpression showed shorter overall survival (HR, 1.781; 95% CI, 1.324–2.395; P<0.001) and disease-free survival (HR, 1.765; 95% CI, 1.227–2.541; P=0.002) compared with patients without MET overexpression. However, membranous overexpression of MET did not highly correlate with mRNA level (r=0.274, P=0.002), copy number gain or survival (P>0.05). We developed highly correlating interpretation methods of MET immunohistochemistry in gastric carcinomas. MET overexpression is an independent prognostic factor and could be a potential target and predictor of benefit for targeted therapy with MET inhibitors.

The prediction of malignant risk in the category “atypia of undetermined significance/follicular lesion of undetermined significance” of the Bethesda System for Reporting Thyroid Cytopathology using subcategorization and BRAF mutation results

The “atypia of undetermined significance/follicular lesion of undetermined significance” (AUS/FLUS) category in the Bethesda System for Reporting Thyroid Cytopathology is a heterogeneous category of cases that are not clearly benign or malignant.

The prognostic significance of tumor-associated stroma in invasive breast carcinoma

Fibroblasts in the stromal component of a tumor may influence tumor progression in various organs. The prognostic significance of tumor-infiltrating lymphocytes is also frequently reported. However, the prognostic significance of the stromal component in breast cancers, particularly those of high grade, has not been established. In this study, we analyzed surgically resected specimens from 545 patients with breast carcinoma, including 193 high-grade tumors, for tumor–stroma ratio, dominant stroma type [collagen (C), fibroblast (F), or lymphocyte (L) dominant type], and central fibrosis on hematoxylin–eosin-stained histological sections. We correlated these features with clinical prognosis. Among the 533 specimens examined, 127 (23.3xa0%) were of C type, 292 (53.6xa0%) of F type, and 114 (20.9xa0%) of L type. Central fibrosis was found in 99 tumors (18xa0%). The dominant stroma type was a significant prognostic factor on univariate and multivariate analyses, together with T classification, nodal status, and Bloom–Richardson grade. Tumor–stroma ratio and central fibrosis did not predict survival on multivariate analysis. Even in high-grade tumors, relapse-free intervals differed significantly according to dominant stroma type. Thus, conventional hematoxylin–eosin-stained tumor slides may contain more prognostic information than previously thought; in particular, the dominant stroma type in invasive breast cancer may potentially be used to predict outcome.

Expression of Fibroblast Growth Factor 19 Is Associated with Recurrence and Poor Prognosis of Hepatocellular Carcinoma

BackgroundFibroblast growth factor 19 (FGF19)-mediated activation of mitogen-activated protein kinase and the β-catenin pathway may be involved in the development and progression of hepatocellular carcinoma. This study aimed to elucidate the prognostic significance of FGF19 protein expression in hepatocellular carcinoma patients.MethodsBy immunohistochemistry, we investigated the expression of FGF19 protein in tumor tissue from 281 hepatocellular carcinoma patients who underwent curative hepatectomy. Univariate and multivariate analyses were performed to evaluate its predictive value for tumor recurrence and survival of patients. The median follow-up period was 75.6xa0months.ResultsFGF19 protein expression was observed in 135 (48.0xa0%) of the 281 hepatocellular carcinomas. FGF19 expression was significantly associated with larger tumor size (Pxa0<xa00.001), and higher BCLC stage (Pxa0=xa00.001). FGF19 expression was correlated with the early recurrence (Pxa0<xa00.001), but not with the late recurrence (Pxa0=xa00.582). FGF19 expression (Pxa0=xa00.002), viral etiology (Pxa0=xa00.028), and intrahepatic metastasis (Pxa0<xa00.001) were independent predictors of early recurrence. Multivariate analyses of survival revealed that FGF19 expression (Pxa0<xa00.001), intrahepatic metastasis (Pxa0<xa00.001), and liver cirrhosis (Pxa0=xa00.019) were independent predictors of shorter disease-free survival. FGF19 expression (Pxa0=xa00.005), larger tumor size (Pxa0=xa00.038), major portal vein invasion (Pxa0=xa00.048), intrahepatic metastasis (Pxa0<xa00.001), lower albumin level (Pxa0=xa00.024), and liver cirrhosis (Pxa0=xa00.031) were independent predictors of shorter disease-specific survival.ConclusionsFGF19 protein expression might be an effective predictor of early recurrence and a marker for poor prognosis of hepatocellular carcinoma after curative hepatectomy, indicating that FGF19 might be a potential preventive target in hepatocellular carcinoma patients.

Notchl and Notch4 are markers for poor prognosis of hepatocellular carcinoma

BACKGROUNDnNotch signaling is critical to physiologic angiogenesis and has been implicated in tumor angiogenesis and metastasis. Notch signaling was reported to exert either oncogenic or tumor-suppressive function in hepatocellular carcinoma (HCC) tumorigenesis. However, the prognostic significance of Notch receptors in HCC remains uncertain. In this study, we investigated the roles of Notch receptors in the prognosis of HCC.nnnMETHODSnWe investigated the expressions of Notch receptors in tumor tissue microarrays of 288 patients with primary HCC who had undergone curative resection using immunohistochemistry. Additionally, prognostic factors of HCC were examined by univariate and multivariate analyses. The median follow-up period was 97.1 months. Tumor recurrence was detected in 189 patients (65.6%), and 99 (34.4%) died of HCC.nnnRESULTSnCytoplasmic expression of Notch1, cytoplasmic expression of Notch3, coexistent nuclear expression of Notch3, and cytoplasmic Notch4 overexpression were observed in 145 (50.3%), 60 (20.8%), 17 (5.9%), and 172 (59.7%) of the 288 HCCs, respectively. Multivariate analyses revealed that Notch1 expression (P=0.029), Edmondson grade III (P=0.038), and higher BCLC stage (P<0.001) were independent predictors of shorter disease-free survival. Cytoplasmic Notch3 expression tended to be an independent predictor of shorter disease-free survival (P=0.055). Notch1 expression (P=0.039), Notch4 overexpression (P=0.012), and higher BCLC stage (P<0.001) were independent predictors of shorter disease-specific survival. On univariate analysis, Notch1 expression tended to show an unfavorable influence on disease-specific survival (P=0.063) and Notch4 overexpression did not show an unfavorable influence on disease-specific survival (P=0.103).nnnCONCLUSIONSnNotch1 expression might be an independent predictor of both shorter disease-free survival and shorter disease-specific survival in HCC patients after curative resection. Notch4 overexpression might be an independent predictor of shorter disease-specific survival. Notch1 could be used as an immunohistochemical biomarker to detect patients with a high-risk of recurrence. Notch1 and Notch4 could be used as immunohistochemical biomarkers to detect patients with a shorter disease-specific survival.

Changes in tumour expression of programmed death-ligand 1 after neoadjuvant concurrent chemoradiotherapy in patients with squamous oesophageal cancer

BACKGROUNDnProgrammed death-ligand 1 (PD-L1) expression has been suggested as a potential predictive biomarker of response to anti-PD-1/PD-L1 therapy. In this study, we investigated whether the expression of PD-L1 in tumour cells is affected by neoadjuvant concurrent chemoradiotherapy (CCRT) or chemotherapy in oesophageal squamous cell carcinoma.nnnPATIENTS AND METHODSnBetween 2004 and 2014, we collected the medical records of locally advanced oesophageal cancer patients consecutively diagnosed and treated with neoadjuvant CCRT or chemotherapy, followed by curative resection. PD-L1 expression in acquired tissue specimens was evaluated by immunohistochemistry using the H-score. The changes in PD-L1 expression between paired samples were evaluated and we also analysed PD-L1 expression in surgical tumour specimens to evaluate its prognostic role.nnnRESULTSnTwenty-eight paired tumour tissues that were acquired before and after neoadjuvant therapy were available: 19 patients with CCRT and 9 with chemotherapy before complete oesophagectomy. The PD-L1 H-score increased significantly from baseline tumour tissues to surgical tumour tissues after neoadjuvant CCRT (P = 0.007, median H-score from 28 to 52), whereas it decreased significantly after neoadjuvant chemotherapy (P = 0.048, median H-score from 53 to 22). In a total of 73 patients, including 45 additional cases for the prognosis analysis, patients with higher PD-L1 H-scores (≥ 20) had poorer overall survival (median 16.7 versus 32.9 months, P = 0.02) than those with lower H-scores (<20).nnnCONCLUSIONSnPD-L1 expression in tumour cells increased in oesophageal cancer patients who received neoadjuvant CCRT. Further studies with more cases are necessary to validate these findings.

Gastrointestinal malignancies harbor actionable MET exon 14 deletions

Recently, MET exon 14 deletion (METex14del) has been postulated to be one potential mechanism for MET protein overexpression. We screened for the presence of METex14del transcript by multiplexed fusion transcript analysis using nCounter assay followed by confirmation with quantitative reverse transcription PCR with correlation to MET protein expression by immunohistochemistry (IHC) and MET amplification by fluorescence in situ hybridization (FISH). We extracted RNAs from 230 patients enrolled onto the prospective molecular profiling clinical trial (NEXT-1) (NCT02141152) between November 2013 and August 2014. Thirteen METex14del cases were identified including 3 gastric cancer, 4 colon cancer, 5 non-small cell lung cancer, and one adenocarcinoma of unknown primary. Of these 13 METex14del cases, 11 were MET IHC 3+ and 2 were 2+. Only one out of the 13 METex14del cases was MET amplified (MET/CEP ratio > 2.0). Growths of two (gastric, colon) METex14del+ patient tumor derived cell lines were profoundly inhibited by both MET tyrosine kinase inhibitors and a monoclonal antibody targeting MET. In conclusion, METex14del is a unique molecular aberration present in gastrointestinal (GI) malignancies corresponding with overexpression of MET protein but rarely with MET amplification. Substantial growth inhibition of METex14del+ patient tumor derived cell lines by several MET targeting drugs strongly suggests METex14del is a potential actionable driver mutation in GI malignancies.

Ideal number of biopsy tumor fragments for predicting HER2 status in gastric carcinoma resection specimens

Intratumoral heterogeneity of HER2 expression is common in gastric cancers and pose a challenge for identifying patients who would benefit from anti-HER2 therapy. The aim of this study is to compare HER2 expression in biopsy and resection specimens of gastric carcinoma by immunohistochemistry (IHC) and to find the ideal number of biopsy tumor fragments that can accurately predict HER2 overexpression in the corresponding surgically resected specimen. The HER2 IHC results of 702 paired biopsy and resection specimens of gastric cancer were compared. The mean number of biopsy fragments among all cases was 4.3 (range 1–11). HER2 was positive in 130 (18.5%) endoscopic biopsies and in 102 (14.5%) gastrectomy specimens. Intratumoral heterogeneity of HER2 was found in 80 (61.5%) biopsies and 70 (68.6%) resection specimens. Out of the 70 surgical specimens with intratumoral heterogeneity, 24 (34.3%) of the corresponding biopsies were categorized as negative (positive conversion). In the 86 (12.3%) discrepant cases, negative conversion was observed in 57 (66.3%) cases and positive conversion in 29 (33.7%). The fragment numbers were significantly correlated with the discrepancy of results and positive predictability (P = 0.0315 and P = 0.0052). ROC curve analysis and positive predictability showed that 4 fragments should be obtained to minimize the differences in HER2 scores between biopsy and resection specimen. In gastric carcinomas with discrepant HER2 results between biopsy and surgical resection specimens, intratumoral heterogeneity is common with most of them showing positive conversion. To predict HER2 status precisely, at least 4 biopsy fragments containing tumor cells are required.

Apparent Diffusion Coefficient in Estrogen Receptor–Positive Invasive Ductal Breast Carcinoma: Correlations with Tumor-Stroma Ratio

PURPOSEnTo determine whether apparent diffusion coefficient (ADC) values vary according to tumor-stroma ratio, dominant stroma type, or presence of central fibrosis in estrogen receptor-positive breast cancer.nnnMATERIALS AND METHODSnInstitutional review board approval was obtained, and patient consent was waived. Sixty-one patients with estrogen receptor-positive invasive ductal carcinoma-not otherwise specified who underwent breast magnetic resonance (MR) imaging with diffusion-weighted (DW) imaging were included in this study. The ADC values of the lesions were measured. Two pathologists evaluated the tumor-stroma ratio, dominant stroma type (collagen, fibroblast, lymphocyte), and central fibrosis. Detectability on DW images was compared between the two groups according to the tumor-stroma ratio (stroma rich or stroma poor). Mean ADC values were retrospectively compared with the tumor-stroma ratio, dominant stroma type, and presence of a central fibrosis. Multiple linear regression analysis was performed to determine variables independently associated with ADC.nnnRESULTSnOn DW images, detectability was not significantly different between stroma-rich and stroma-poor groups (P = .244). ADC values were significantly lower in the stroma-poor group (P < .001). The mean ADC values in the collagen-dominant type were lower than in fibroblast-dominant or lymphocyte-dominant types (P = .021). In multiple linear regression analysis, tumor-stroma ratio (P = .007), tumor size (P = .007), and dominant stroma type (collagen dominant, P = .029) were independently correlated with ADC.nnnCONCLUSIONnIn estrogen receptor-positive breast cancers, ADC values showed significant differences according to the tumor-stroma ratio and dominant stroma type.