Mixed neuroendocrine-non-neuroendocrine carcinoma (MiNEN) in gallbladder with liver metastasis of neuroendocrine carcinoma component: a case report.

Mixed neuroendocrine-non-neuroendocrine neoplasms of the gallbladder are rare with a lack of established standardized therapeutic strategies. We report a case of gallbladder mixed neuroendocrine-non-neuroendocrine neoplasm with liver metastasis of neuroendocrine carcinoma. A patient who underwent radical cholecystectomy for gallbladder adenocarcinoma was detected with increasing liver mass, and hepatectomy was performed. Pathological report revealed neuroendocrine carcinoma. To find primary origin, pathological review of the old specimen from previous cholecystectomy with a slightly different perspective was conducted, where the neuroendocrine component was positively dyed. In conclusion, though it might be impossible to review every pathological result in cases with ambiguous findings, reviewing the previous specimen can be a useful option in diagnosis.

Albumin, filamin-A and cytokeratin 19 help distinguish intrahepatic cholangiocarcinoma from extrahepatic adenocarcinoma.

BACKGROUND: The differential diagnosis of intrahepatic cholangiocarcinomas (iCCAs) from metastatic adenocarcinomas from organs adjacent to the liver (gallbladder, pancreas, and stomach) is difficult due to histopathological similarity and a lack of specific markers. This study aimed to develop a method to differentiate iCCA and adenocarcinomas originated from extrahepatic organs adjacent to the liver. METHODS: We retrospectively enrolled surgically resected iCCA (n = 181) and adenocarcinomas from extrahepatic organs (n = 30, n = 28, and n = 38 from gallbladder, pancreas, and stomach, respectively) between 2007 and 2013. The albumin mRNA in situ hybridization (ISH) and immunohistochemistry (IHC) of filamin-A and cytokeratin 19 (CK19) were performed using tissue microarray. Using logistic regression analysis of three markers, iCCA-score was developed, and its diagnostic performance was evaluated. RESULTS: The iCCAs were more frequently positive for albumin ISH (23.2% vs. 0%), filamin-A IHC (47.5% vs. 12.5%) and CK19 (68.5% vs. 40.6%) than extrahepatic adenocarcinomas (p < 0.001 for all). The iCCA-score consisting of these three markers was developed, and it showed higher diagnostic performance (area under the curve [AUC], 0.798 vs. 0.616, p < 0.001). Taking an iCCA-score of 2 or higher as the threshold for iCCA, the sensitivity was substantially higher than albumin ISH alone (45.9% and 23.2%, respectively; p < 0.001), but maintained high specificity (94.8% and 100%, respectively). CONCLUSION: Albumin ISH and IHC staining for filamin-A and CK19 showed distinct expression patterns between iCCA and extrahepatic adenocarcinomas from gallbladder, pancreas, and stomach. We developed iCCA-score that consisted of those three markers, and it showed better diagnostic performance than albumin ISH alone.

Revisiting extraprostatic extension based on invasion depth and number for new algorithm for substaging of pT3a prostate cancer.

Extraprostatic extension (EPE) is a factor in determining pT3a stage in prostate cancer. However, the only distinction in EPE is whether it is focal or non-focal, causing diagnostic and prognostic ambiguity. We substaged pT3a malignancies using classification of EPE to improve personalized prognostication. We evaluated 465 radical prostatectomy specimens with a digital image analyzer by measuring the number, radial distance and two-dimensional square area of the EPE. The most significant cut-off value was proposed as an algorithm for the pT3a substaging system to predict biochemical recurrence (BCR). A combination of the radial distance and the number of EPEs predicted BCR the most effectively. The optimal cut-off criteria were 0.75 mm and 2 mm in radial distance and multifocal EPE (hazard ratio: 2.526, C-index 0.656). The pT3a was subdivided into pT3a1, < 0.75 mm and any number of EPEs; pT3a2, 0.75-2 mm and one EPE; and pT3a3, > 2 mm and any number of EPEs or 0.75-2 mm and ≥ 2 EPEs. This combined tier was highly significant in the prediction of BCR-free survival. The combination of radial distance and number of EPEs could be used to subdivide pT3a prostate cancer and may aid in the prediction of BCR.

Genomic Profiling and Clinicopathological Characteristics of Neuroendocrine Tumors of the Lung in East Asian Patients.

BACKGROUND/AIM: In recent years, the genomic landscape of neuroendocrine tumors (NETs) of the lung has been investigated. However, more data are necessary to elucidate the heterogeneous nature of NETs, especially in East Asian patients. PATIENTS AND METHODS: A total of 64 patients who underwent surgical resection for lung NETs [26 typical or atypical carcinoid tumors, 21 large-cell neuroendocrine carcinomas (LCNECs), and 19 small-cell lung carcinomas (SCLCs)] were enrolled, and samples from 46 patients were subjected to targeted next-generation sequencing. RESULTS: Co-mutations of tumor protein p53 (TP53) and RB transcriptional corepressor 1 (RB1) were detected in 15%, 42%, and 93% of carcinoid tumors, LCNECs, and SCLCs, respectively. Oncogenic or targetable genetic alterations identified in this study included mutations of KRAS proto-oncogene (KRAS), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), ALK receptor tyrosine kinase (ALK), mitogen-activated protein kinase kinase 1 (MAP2K1), and isocitrate dehydrogenase 1 (IDH1), as well as amplifications of erb-b2 receptor tyrosine kinase 2 (ERBB2), fibroblast growth factor receptor 1 (FGFR1), CD274 molecule (CD274), and MYCN proto-oncogene (MYCN). These alterations were more frequently found in high-grade NETs than in carcinoid tumors (33.3% vs. 7.7%). Programmed cell death-ligand 1 expression was strongly associated with the LCNEC subtype among NETs (p=0.002). CONCLUSION: The mutational status of TP53 and RB1 was significantly associated with NET subtypes in East Asian patients. Targeted therapy or immunotherapy may serve as a treatment option in a subset of patients with high-grade NETs.

Expression of V-set immunoregulatory receptor in malignant mesothelioma.

Malignant mesothelioma is a highly lethal cancer. V-set immunoregulatory receptor (VSIR, also known as V-domain Ig suppressor T-cell activation, VISTA), a negative immune checkpoint regulator, was reported to be expressed in malignant mesothelioma; however, its detailed expression pattern and clinicopathological significance have not been elucidated. We examined the expression of VSIR and CD274 and CD8+ tumor-infiltrating lymphocytes in a total of 124 samples from 66 patients with malignant mesothelioma and analyzed the clinicopathological characteristics and their relationship with the immunohistochemical findings. A total of 553 non-small cell lung carcinomas were also evaluated for VSIR expression. VSIR expression was higher in epithelioid type mesothelioma (p < 0.001), whereas CD274 expression was higher in sarcomatoid type (p < 0.001). CD8+ tumor-infiltrating lymphocytes were more abundant in sarcomatoid mesotheliomas (p < 0.001), VSIR-low tumors (p = 0.045), and CD274-high tumors (p < 0.001). VSIR and CD274 were differentially expressed in each histological component of the biphasic type. VSIR expression was associated with favorable survival (p = 0.008). Two patients with VSIR-high tumors had received pembrolizumab; however, they showed progressive disease. No VSIR expression was observed in tumor cells of non-small cell lung carcinomas. In conclusion, VSIR expression may define a unique class of mesothelioma, characterized by predominantly epithelioid type and favorable prognosis. VSIR expression may be used as an immunohistochemical diagnostic marker for epithelioid mesothelioma. CD274 expression was associated with sarcomatoid mesothelioma and high infiltration of CD8+ lymphocytes. Because VSIR is a negative immune regulator and expressed in malignant mesothelioma, further study is warranted to investigate the therapeutic significance of VSIR blockade in this deadly cancer.

Prognostic factors of acinar- or papillary-predominant adenocarcinoma of the lung.

OBJECTIVE: Histologic types are correlated with prognosis in lung adenocarcinoma. The acinar/papillary type is most common, although this group comprises heterogeneous tumor types. However, the prognostic factors in this group have not been well studied. Therefore, we investigated the prognostic factors of acinar/papillary lung adenocarcinomas and attempted to define the so-called "intermediate grade" group of lung adenocarcinoma. MATERIALS AND METHODS: We classified surgically resected invasive non-mucinous adenocarcinomas of the lung and analyzed their clinicopathological features and prognostic factors, focusing on the acinar/papillary type. RESULTS: A total of 301 cases with stage I-III lung adenocarcinoma were enrolled, of which 193 were acinar/papillary type (64.1%). In survival analysis of the entire cohort, acinar/papillary types showed intermediate survival compared with lepidic and micropapillary/solid types. In the univariate survival analysis for acinar/papillary types, stage, age, lymphovascular invasion, spread through air spaces, presence of micropapillary or solid pattern, and programmed death-ligand 1 (PD-L1) positivity were associated with poor recurrence-free survival and overall survival. In multivariate analysis, spread through air spaces and PD-L1 expression were independent poor prognostic factors of recurrence-free survival and overall survival in the acinar/papillary cohort, respectively. CONCLUSIONS: Evaluation of spread through air spaces and PD-L1 expression may be useful to stratify patients with acinar/papillary lung adenocarcinomas in terms of prognosis.