Young Keum Kim

MUC5AC and MUC5B enhance the characterization of mucinous adenocarcinomas of the lung and predict poor prognosis.

From the viewpoint of histogenesis, lung adenocarcinoma can be subdivided into two groups: terminal respiratory unit (TRU) and non‐TRU types. We recently reported a non‐TRU type adenocarcinoma designated as ciliated adenocarcinoma (we now prefer central type adenocarcinoma). We suggest reasons that mucinous adenocarcinoma should encompass central type adenocarcinoma to represent its biological characteristics as non‐TRU type adenocarcinoma.

Programmed death-ligand 1 (PD-L1) expression in tumour cell and tumour infiltrating lymphocytes of HER2-positive breast cancer and its prognostic value

Immunotherapy targeting PD-1/PD-L1 axis showed benefits in cancer. Prognostic significance of tumour infiltrating lymphocytes (TILs) has been determined. We evaluated PD-L1 protein expression in tumour cells and TILs, PD-L1 mRNA level and various histopathologic factors including TILs using 167 formalin-fixed paraffin embedded tissues and 39 fresh tissue of HER2-positive breast cancer. TILs level and PD-L1 expression in tumour cells and TILs were significantly correlated one another. PD-L1 positivity in tumour cells was associated with high histologic grade and high TILs level (p < 0.001, both). High PD-L1 immunoscore in TILs and high total immunoscore (in tumour cells and TILs) of PD-L1 were correlated with high histologic grade (p = 0.001 and p < 0.001, respectively), absence of lymphovascular invasion (p = 0.012 and p = 0.007, respectively), negative hormone receptor expression (p = 0.044 and p = 0.001, respectively) and high TILs level (p < 0.001, both). High PD-L1 mRNA expression was associated with high TILs level (p < 0.001, both). PD-L1 positivity in tumour cells was associated with better disease-free survival in HR−/HER2+ breast cancer (p = 0.039). PD-L1 expression in tumour cells and TILs are significantly associated with TILs level in HER2-positive breast cancer. PD-L1 expression in tumour cells might be positive prognostic factor in HR−/HER2+ breast cancers.

Combination of immunohistochemistry, FISH and RT-PCR shows high incidence of Xp11 translocation RCC: comparison of three different diagnostic methods.

We evaluated the frequency of translocation renal cell carcinoma (RCC) by reverse transcription polymerase chain reaction (RT-PCR) and how well the TFE3 immunoreactivity is concordant with TFE3 gene translocation status proved by fluorescence in situ hybridization (FISH) assay and RT-PCR. TFE3 and Cathepsin K expression was analyzed by immunohistochemistry in 185 RCC cases, and 48 cases either of more than weak expression of TFE3 or of positivity for Cathepsin K were done for FISH analysis and RT-PCR. All the RT-PCR positive cases were confirmed by cloning and sequencing. Of the 14 cases with strong nuclear TFE3 expression, 12 showed a break-apart signal by FISH. ASPL- and PRCC-TFE3 translocations were detected in 13 and one case, respectively, by RT-PCR. Of 21 cases with weak TFE3 expression, five were translocation-positive by FISH. ASPL-, PRCC-, and PSF-TFE3 translocations were detected by RT-PCR (n=3, 3, and 1, respectively). All 13 TFE3-negative/cathepsin K-positive cases were negative by FISH and two each harbored ASPL- and PRCC-TFE3 translocations that were detected by RT-PCR. A high rate of TFE3 immunoreactivity (8.6%) was confirmed by RT-PCR (13.5%) and FISH (9.7%). Higher translocation rate of RT-PCR means RT-PCR detected translocation in TFE3 weak expression group and only cathepsin K positive group more specifically than FISH. Thus, RT-PCR would complement FISH analysis for detecting translocation RCC with fusion partners.

Gastric poorly cohesive carcinoma: a correlative study of mutational signatures and prognostic significance based on histopathological subtypes

Genome‐wide next‐generation sequencing has revealed several driver mutations and has allowed the establishment of a molecular taxonomy of gastric cancer. However, there are few detailed studies on the mutational spectrum of poorly cohesive gastric carcinoma. Thus, this study aim to investigate its mutation profile based on clinicopathological characteristics.

Endoscopic submucosal dissection for papillary adenocarcinoma of the stomach: is it really safe?

BackgroundPapillary adenocarcinoma of the stomach has been treated according to the same endoscopic submucosal dissection (ESD) indication criteria as other differentiated-type adenocarcinomas. We aimed to compare lymph node metastasis (LNM) in patients with early gastric cancer (EGC) with papillary adenocarcinoma (EGC-P) with that in patients with EGC with nonpapillary adenocarcinoma (EGC-NP) and to consider the potential limitation of current ESD indication criteria in the treatment of EGC-P.MethodsIn total, 1583 patients who underwent gastrectomy for EGC from 2005 to 2014 were included. Clinicopathologic characteristics of 56 patients with EGC-P were compared with those of 1527 patients with EGC-NP. The safety of ESD was evaluated, by application of current ESD indication criteria to EGC-P.ResultsThe frequency of submucosal invasion was significantly higher in EGC-P than in both EGC-NP with differentiated-type histologic appearance and EGC-NP with undifferentiated-type histologic appearance (71.4% vs 50.8% and 37.6%, respectively). In addition, the frequency of LNM in EGC-P was 17.9%, higher than that in both EGC-NP with differentiated-type histologic appearance and EGC-NP with undifferentiated-type histologic appearance (9.7% and 11.1%, respectively). When the current ESD indication criteria were applied to the 56 patients with EGC-P, 17 patients met the current indications. Of these patients, two (11.8%) had LNM and three (17.6%) had lymphovascular invasion (LVI). When LNM and LVI were combined, one of seven patients (16.7%) meeting the absolute ESD indications and three of ten patients (30.0%) meeting the expanded ESD indications would not be cured after ESD.ConclusionsThe use of ESD should be more carefully applied in patients with EGC-P meeting the ESD indication criteria, especially the expanded indication criteria, after pretreatment workup compared with other differentiated-type adenocarcinomas, owing to the higher frequencies of submucosal invasion, LNM, and LVI in EGC-P.

VEGFR2 but not VEGFR3 governs integrity and remodeling of thyroid angiofollicular unit in normal state and during goitrogenesis

Thyroid gland vasculature has a distinguishable characteristic of endothelial fenestrae, a critical component for proper molecular transport. However, the signaling pathway that critically governs the maintenance of thyroid vascular integrity, including endothelial fenestrae, is poorly understood. Here, we found profound and distinct expression of follicular epithelial VEGF‐A and vascular VEGFR2 that were precisely regulated by circulating thyrotropin, while there were no meaningful expression of angiopoietin–Tie2 system in the thyroid gland. Our genetic depletion experiments revealed that VEGFR2, but not VEGFR3, is indispensable for maintenance of thyroid vascular integrity. Notably, blockade of VEGF‐A or VEGFR2 not only abrogated vascular remodeling but also inhibited follicular hypertrophy, which led to the reduction of thyroid weights during goitrogenesis. Importantly, VEGFR2 blockade alone was sufficient to cause a reduction of endothelial fenestrae with decreases in thyrotropin‐responsive genes in goitrogen‐fed thyroids. Collectively, these findings establish follicular VEGF‐A–vascular VEGFR2 axis as a main regulator for thyrotropin‐dependent thyroid angiofollicular remodeling and goitrogenesis.

Three cases of adrenocortical tumors mistaken for hepatocellular carcinomas/diagnostic pitfalls and differential diagnosis

Adrenocortical adenomas and carcinomas in other parenchyma are extremely rare, with few cases reported and because of the rarity of these tumors, they occasionally cause problems during diagnosis. Adrenal cortical neoplasms in liver parenchyma can be present in 3 forms, including direct invasion or adhesion to liver parenchyma, tumors arising in adrenohepatic fusion tissue or in ectopic adrenal gland tissue. We report 3 cases of adrenal cortical tumors that were misdiagnosed as hepatocellular carcinoma in the preoperative state. The first case involved an adrenocortical adenoma arising in adrenohepatic fusion tissue. The remaining 2 cases involved an adrenocortical carcinoma and an adrenocortical oncocytoma arising in ectopic adrenal tissue in the liver. We describe the clinical presentations, gross, microscopic findings, immunohistochemical findings with respect to each case, with emphasis on differential diagnosis from hepatocellular carcinoma.

Prevalence of BRAFV600E Mutation in Follicular Variant of Papillary Thyroid Carcinoma and Non-Invasive Follicular Tumor with Papillary-Like Nuclear Features (NIFTP) in a BRAFV600E Prevalent Area

Background BRAFV600E mutation status and prevalence of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) has not yet been reported in Korea. The aim of this study was to investigate the significance of the BRAFV600E mutation in the follicular variant of papillary thyroid carcinoma (FVPTC) and to determine the prevalence of NIFTP in BRAFV600E mutation-prevalent Korean patients. Methods This study retrospectively analyzed 1,417 consecutive patients who underwent total thyroidectomy with routine prophylactic central lymph node dissection for papillary thyroid carcinoma (PTC). BRAFV600E mutation analysis was performed routinely using multiplex polymerase chain reaction by applying dual priming oligonucleotide. Clinicopathological characteristics and ultrasonographic findings were compared between BRAFV600E mutation-positive and -negative groups for FVPTC. Pathologists reviewed the pathology slides according to consensus diagnostic criteria for the encapsulated FVPTC and NIFTP. Results The prevalence of the BRAFV600E mutation in all subtypes of PTC was 61.0% (861/1,411). FVPTC presented a BRAFV600E mutation rate of 27.3%. The FVPTC patients with BRAFV600E mutation were older than those with no BRAFV600E mutation (P = 0.021). The prevalence of NIFTP was 0.18% among all PTC patients (2/1,411) and the proportion of NIFTP among FVPTC was 9.1% (2/22). Conclusion The BRAFV600E mutation is prevalent in Korean patients with FVPTC in a region with high frequency of the BRAFV600E mutation and very low prevalence of NIFTP compared with that reported in western studies.

The significance of tumor budding in T1 colorectal carcinoma: The most reliable predictor of lymph node metastasis especially in endoscopically resected T1 colorectal carcinoma

Endoscopic resection is widely recognized as a first-line treatment for T1 colorectal cancers (CRC), although additional surgical intervention may be indicated based on the risk of lymph node (LN) metastasis. However, risk factors for LN metastasis in T1 CRC not fully established. We investigated the clinicopathological features of T1 CRC and evaluated their association with lymph node metastasis in 133 cases of T1 CRC, consisting of 87 cases with first-line endoscopic resection (EMR) followed by additional surgery and 46 cases with primary surgical resection. Among the total 133 cases, 16 cases (12.0%) showed LN metastasis; 13 cases (13/16, 81.25%) were included in endoscopic resection cohort. These were all of the non-pedunculated gross type and most of LN+ tumors invaded submucosa over 1000 μm (surgical cohort versus endoscopic resection cohort; 3 versus 11). However, there was no statistical difference in the depth of submucosal invasion between the LN+ and LN- in both surgical cohort (2799.42 μm ± 401.56 versus 3000.00 μm ± 721.69, P = .897) and endoscopic resection cohort (2066.55 μm ± 142.96 versus 2305.77 μm ± 345.62, P = .520). Conversely, presence of and a higher number of tumor budding foci were associated with an increase in the incidence of LN metastasis in both cohort (P < .0001). Positive resection margins as well as absence of adenoma component were also an independent predictive factor for lymph node metastasis in 87 cases with first-line endoscopic resection followed by additional surgery. We found that tumor budding was the most reliable LN metastasis predictor in T1 CRC in both surgically resected and endoscopic resection specimens.

IDH1 R132C mutation is detected in clear cell hepatocellular carcinoma by pyrosequencing.

BackgroundIsocitrate dehydrogenase 1 (IDH1) mutation is common in low-grade glioma (approximately 80%) and acute myeloid leukemia (approximately 10%). Other than brain tumor or hematologic malignancies, intrahepatic cholangiocarcinoma (iCC) is a well-known solid tumor with IDH1 mutation (6.8–20%). Histologically, poor differentiation and clear cell change are associated with IDH1 mutation in iCC. Since hepatocellular carcinoma (HCC) shares histologic features with iCC, some specific subtypes of HCC might show a higher IDH1 mutation rate than reported before (0.5–1.5%).MethodsForty-six cases of iCC and 48 cases of HCC (including 20 cases of clear cell type and 13 cases of pseudoglandular pattern) were tested for IDH1 mutation by pyrosequencing.ResultsThree cases in iCC (6.5%) and five cases in HCC (10.4%) had IDH1 mutation, all of which were Arg132Cys. IDH1 mutant HCCs were all clear cell type. Although the IDH1 mutation rate between iCC and HCC demonstrated no significant difference, clear cell HCC revealed statistically increased mutation rate compared to that of HCC without clear cell change (P = 0.009). Presence of IDH1 mutation was related with poor survival in clear cell HCC patients (P = 0.004).ConclusionsClear cell HCC showed higher frequency of IDH1 mutation rate than other variants of HCC. This result consolidates the assumption that morphological features of tumors reflect molecular alterations.