Safety and feasibility of laparoscopic surgery for appendiceal mucocele: a multicenter study.

BACKGROUND: Although laparoscopic appendectomy has been widely performed since 1987, concerns over potential spillage of mucus into the peritoneal cavity during laparoscopic manipulation have prevented the use of laparoscopic surgery (LS) for appendiceal mucocele. The purpose of the present study was to evaluate the safety, feasibility, and short-term perioperative outcomes of LS for appendiceal mucocele. METHODS: A retrospective review was performed to identify patients diagnosed with appendiceal mucocele based on their imaging studies and who underwent surgery at one of six Hallym-University-affiliated hospitals between January 2007 and June 2016. Patient demographics, surgical outcomes, and postoperative outcomes were retrospectively analyzed. RESULTS: A total of 96 patients were evaluated, of whom 58 underwent LS (LS group) and 38 underwent open surgery (OS; OS group). There were no significant differences in patient characteristics between groups. The operation time was similar in both groups (P = 0.399). Intraoperative rupture occurred in two patients in each group (no significant difference, P = 0.647). Time to flatus, time to soft food intake, and length of hospital stay were shorter in the LS group than in the OS group (2.4 vs. 3.2 days, P = 0.003; 3.6 vs. 4.5 days, P = 0.024; 6.5 vs. 8.8 days, P = 0.011, respectively). The rate of postoperative complications was similar between the groups (P = 0.786). Univariate analysis revealed that rupture of appendiceal mucocele was associated with white blood cell count > 10,000/µL (P = 0.032) but not with LS (P = 0.647). CONCLUSIONS: The results showed that LS is safe and feasible for the surgical treatment of appendiceal mucocele. An elevated WBC count was associated with a risk of appendiceal mucocele rupture.

Invasion Depth Measured in Millimeters is a Predictor of Survival in Patients with Distal Bile Duct Cancer: Decision Tree Approach.

BACKGROUND: AJCC staging system is unreliable for predicting survival in distal bile duct (DBD) cancer patients, due to inter-observer variation. Measured depth of invasion (DOI) is suggested to be more accurate to predict patients' clinical outcome in extra-hepatic cholangiocarcinomas, but its significance in DBD cancer and cutoff values are still debatable. This study aimed to identify the optimal cutoff value of DOI in relation to prognosis in DBD cancer patients. METHODS: Data of 179 patients with DBD adenocarcinoma treated in three institutions were investigated. Under microscopic review, DOI was measured. The relationships between the clinicopathological parameters and the groups based on DOI (≤3; 3-10; >10 mm) were evaluated, and the survival times of each group based on DOI and T classification were compared. RESULTS: Deeply invading tumors exhibited a greater tendency toward the infiltrative type, high histological grade, AJCC stage, and pancreatic, duodenal, lymphovascular and perineural invasion. The measured DOI was significantly correlated with worse relapse-free and overall survival (all p < 0.05). In multivariate analyses, the DOI remained as one of the prognostic factors (all p < 0.05), while T classification was not a significant prognostic factor. The new prognostic models (low, intermediate, and high risk) that applied DOI and nodal metastasis showed significant difference in recurrence and survival rate (all p < 0.05). CONCLUSIONS: On the basis of the proposed cutoff value, the DOI could be clear and meaningful, overcoming the vagueness of the T classification for predicting clinical outcomes in patients with DBD carcinoma.

TCL1 expression predicts overall survival in patients with mantle cell lymphoma.

OBJECTIVES: Mantle cell lymphoma (MCL) has a heterogeneous clinical course. Although most cases show a poor prognosis, a minority has an indolent course. It is difficult to identify indolent MCL cases prospectively. T-cell leukemia/lymphoma protein 1 (TCL1) is expressed by several B-cell lymphomas, including MCL. This study examined the expression of TCL1 and its prognostic relevance for MCL. METHODS: Clinical data for 162 patients with MCL were collected. Of these, 144 cases with available tissues for tissue microarray construction and immunostaining were included in the analysis. TCL1 staining was quantified using the Nuclear Quant application with Pannoramic™ Viewer v. 1.14. High TCL1 expression was defined as moderate to strong nuclear and/or cytoplasmic staining in 40% or more of the cells. RESULTS: High TCL1 expression was observed in 39 of 144 samples (27.1%). Patients with low TCL1 expression were more likely to present with blastoid/pleomorphic morphology (P = 0.010). Low TCL1 expression was associated with significantly shorter overall survival (OS, P = 0.006). Multivariate analysis identified low TCL1 expression (P = 0.003), high-risk MIPI (P = 0.027), and anemia (P = 0.018) as adverse prognostic factors. CONCLUSIONS: Our study suggests that TCL1 expression profile may have a role in the prediction of overall outcome in patient with MCL and call for prospective studies.

Incremental value of cell block preparations over conventional smears alone in the evaluation of EUS-FNA for pancreatic masses.

BACKGROUND/AIMS: The effectiveness of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) has been established for a definite pathological diagnosis of pancreatic solid masses. We investigated the usefulness of cell block preparations in EUS-FNA, by evaluating the added value of cell block preparations over conventional smears alone. METHODOLOGY: Between March 2011 and June 2013, 61 patients were retrospectively evaluated who underwent EUS-FNA for pancreatic solid masses. Diagnostic values for diagnosing pancreatic malignancy were compared for a combination of the conventional smear and cell block (CSCB) and the conventional smear alone (CS). RESULTS: The addition of the cell block technique increased the sensitivity of conventional smear for diagnosing the pancreatic malignancy from 79% (CS) to 90% (CSCB, p=0.0313) and the accuracy from 81% to 91% (p=0.0313). The specificity and positive predictive value were 100% in both methods. The negative predictive value was increased from 33% (CS) to 50% (CSCB), but this difference was not statistically significant (p=0.0833). CONCLUSION: The addition of the cell block method after a conventional smear may increase the sensitivity and negative predictive value for diagnosing the pancreatic malignancy in patients with pancreatic masses who undergo EUS-FNA. Further study may be warranted to determine whether the cell block method can replace the conventional smear.

FLI-1 is expressed in a wide variety of hematolymphoid neoplasms: a special concern in the differential diagnosis.

Friend Leukemia Virus Integration 1 (FLI-1) is a member of E26 transformation-specific family of transcription factors that participates in hematopoietic and vascular endothelial cell development. Immunohistochemical detection of FLI-1 has been widely used to diagnose vascular tumors or, more evidently, Ewing's sarcoma. However, the expression pattern of FLI-1 in hematolymphoid neoplasms remains unclear. Therefore, in this study, we aimed to investigate the expression of FLI-1 in these tumors, focusing on high-grade lesions, which presents a diagnostic challenge by mimicking Ewing's sarcoma. We evaluated the expression FLI-1 in various types of lymphoid and plasmacytic tumors, including 27 plasmablastic lymphomas, 229 diffuse large B-cell lymphomas, 22 precursor T- or B-lymphoblastic lymphomas, 24 angioimmunoblastic-type nodal T-follicular helper cell lymphomas, 52 peripheral T-cell lymphomas, NOS, 18 Burkitt lymphomas, 18 non-gastric lymphomas of mucosa-associated lymphoid tissue, 38 chronic lymphocytic leukemia/small lymphocytic lymphomas, 15 mantle cell lymphomas, 23 gastric MALT lymphomas, 50 plasma cell myelomas, and 38 follicular lymphomas. We calculated the H-scores of FLI-1 immunostaining, ranging from 0 to 200, and used the scores to analyze the clinicopathological significance of FLI-1 statistically. FLI-1 was expressed to varying degrees in all types of hematological tumors. FLI-1 expression was detected in 84.1% of patients (466/554). FLI-1 was highly expressed in precursor T- or B-lymphoblastic lymphomas. Follicular lymphomas exhibited low FLI-1 expression. In plasmablastic lymphoma, 85.2% of the patients were focally positive for FLI-1. FLI-1 expression did not correlate with clinicopathological variables, such as demographic data or disease stage, in patients with plasmablastic lymphoma and diffuse large B-cell lymphoma. However, FLI-1 overexpression was associated with poorer overall survival in patients with plasmablastic lymphoma. This study demonstrates that FLI-1 is expressed in various hematolymphoid neoplasms. FLI-1 expression can lead to diagnostic confusion, especially in small blue round cell tumors, such as lymphoblastic lymphoma, plasmablastic lymphoma, and plasma cell myeloma, when distinguishing tumors positive for CD99 and CD56 without CD3, CD20, or CD45. Our findings also suggested the possibility of FLI-1 as a potential prognostic biomarker for plasmablastic lymphoma.

Comparison of histological and molecular features of pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma.

Pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma are pediatric B cell lymphomas with similar clinical characteristics but distinct histological features. We investigated the differences between pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma by comparing their histological and molecular characteristics. A total of 5 pediatric-type follicular lymphoma and 11 pediatric nodal marginal zone lymphoma patients were included in the study. In the histological review, 5 of the 16 cases showed overlapping morphological features of pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma; hence, they were reclassified as "mixed type." In molecular analysis, using panel-based massively parallel sequencing, MAP2K1, TNFRSF14, and IRF8 mutations were found in 6, 3, and 2 of the 11 pediatric nodal marginal zone lymphoma patients, respectively, and IRF8 mutation was found in one of the five pediatric-type follicular lymphoma patients. There were no significant differences in genetic alterations established from the histologically reclassified diagnosis as well as the initial diagnosis. Pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma showed morphological overlap in some cases, and no difference between the two was found upon molecular analysis. These findings suggest the possibility that pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma are single entity pediatric B-cell lymphoma with broad morphological spectrum.

Intimal angiosarcoma presenting with common femoral artery aneurysm.

Intimal angiosarcoma is a rare malignant vascular tumor with an aggressive natural history. Presenting symptoms vary according to the location of the lesion, but symptoms are typically due to intravascular obstruction or embolization. We present a case of an intimal angiosarcoma presenting with a common femoral artery aneurysm.

Coexpression of MCT1 and MCT4 in ALK-positive Anaplastic Large Cell Lymphoma: Diagnostic and Therapeutic Implications.

In solid tumors, glycolytic cancer or stromal cells export lactates through monocarboxylate transporter (MCT) 4, while oxidative cancer or stromal cells take up lactates as metabolic fuels or signaling molecules through MCT1. CD147 acts as a chaperone of MCT1 or MCT4. Unlike solid tumors, malignant lymphomas have a peculiar tumor microenvironment. To investigate the metabolic phenotype of malignant lymphoma associated with lactate transport, we analyzed immunohistochemical expressions of MCT1, MCT4, and CD147 in 247 cases of various malignant lymphomas. Surprisingly, both MCT1 and MCT4 were diffusely expressed on tumor cell membranes in all cases (11/11, 100%) of anaplastic lymphoma kinase (ALK) (+) anaplastic large cell lymphoma (ALCL). In contrast, only MCT1 was diffusely expressed in tumor cells of ALK(-) ALCL, as well as in B-cell, natural killer/T-cell, T-cell, and classic Hodgkin lymphomas. In these lymphomas, MCT4 expression was mostly localized to adjacent stromal cells. The pattern of diffuse membranous MCT1 and partial MCT4 expressions in tumor cells was observed in 1 case each of peripheral T-cell lymphoma (1/15, 6.7%) and multiple myeloma (1/34, 2.9%). CD147 was diffusely expressed in all types of lymphoma tumor and/or stromal cells. In conclusion, ALK(+) ALCL has a unique metabolism showing high coexpression of MCT1 and MCT4 in tumor cells. Because only ALK(+) ALCL overexpresses MCT4, immunostaining for MCT4 together with ALK is very useful for differential diagnosis from ALK(-) ALCL or peripheral T-cell lymphoma. Moreover, dual targeting against MCT1 and MCT4 would be an appropriate therapeutic approach for ALK(+) ALCL.

Somatic Mutations of TP53 Identified by Targeted Next-Generation Sequencing Are Poor Prognostic Factors for Primary Operable Breast Cancer: A Single-Center Study.

Few studies have reported on the clinical utility of targeted next-generation sequencing (NGS) for breast cancer in Korea. We retrospectively reviewed the targeted NGS data of 219 patients with breast cancer who underwent surgical resection between August 2018 and April 2021. Here, we described the mutational profiles of breast cancer and examined their prognostic implications. The most frequently mutated gene was PIK3CA (n = 97/219, 44.3%), followed by TP53 (n = 79/219, 36.1%), AKT1 (n = 23/219, 10.5%), and GATA3 (n = 20/219, 9.1%). TP53 mutations were associated with aggressive histologic features. We followed up for 31 (range, 1-39) months and observed 11 (5.0%) recurrences: nine were TP53 mutant and two were TP53 wild-type. Multivariable analysis revealed that TP53 mutation was an independent prognostic factor for recurrence (p = 0.012). Although no drug is currently available for TP53 mutations, it is valuable to know the mutational status of TP53 for the precise management of breast cancer.

Proteomic and biochemical analyses reveal the activation of unfolded protein response, ERK-1/2 and ribosomal protein S6 signaling in experimental autoimmune myocarditis rat model.

BACKGROUND: To investigate the molecular and cellular pathogenesis underlying myocarditis, we used an experimental autoimmune myocarditis (EAM)-induced heart failure rat model that represents T cell mediated postinflammatory heart disorders. RESULTS: By performing unbiased 2-dimensional electrophoresis of protein extracts from control rat heart tissues and EAM rat heart tissues, followed by nano-HPLC-ESI-QIT-MS, 67 proteins were identified from 71 spots that exhibited significantly altered expression levels. The majority of up-regulated proteins were confidently associated with unfolded protein responses (UPR), while the majority of down-regulated proteins were involved with the generation of precursor metabolites and energy metabolism in mitochondria. Although there was no difference in AKT signaling between EAM rat heart tissues and control rat heart tissues, the amounts and activities of extracellular signal-regulated kinase (ERK)-1/2 and ribosomal protein S6 (rpS6) were significantly increased. By comparing our data with the previously reported myocardial proteome of the Coxsackie viruses of group B (CVB)-mediated myocarditis model, we found that UPR-related proteins were commonly up-regulated in two murine myocarditis models. Even though only two out of 29 down-regulated proteins in EAM rat heart tissues were also dysregulated in CVB-infected rat heart tissues, other proteins known to be involved with the generation of precursor metabolites and energy metabolism in mitochondria were also dysregulated in CVB-mediated myocarditis rat heart tissues, suggesting that impairment of mitochondrial functions may be a common underlying mechanism of the two murine myocarditis models. CONCLUSIONS: UPR, ERK-1/2 and S6RP signaling were activated in both EAM- and CVB-induced myocarditis murine models. Thus, the conserved components of signaling pathways in two murine models of acute myocarditis could be targets for developing new therapeutic drugs or methods aimed at treating enigmatic myocarditis.

Development of nano-hydroxyapatite graft with silk fibroin scaffold as a new bone substitute.

PURPOSE: This study involves a comparison between the bone regeneration of nano-hydroxyapatite (nHA), as derived from eggshells either with or without silk fibroin scaffolds, and the unfilled control in the rabbit calvarial bony defect model. MATERIALS AND METHODS: Sixteen 4-month-old New Zealand white rabbits, with a mean weight of 2.8 kg (range, 2.5-3.0 kg), were used in this experiment. After the formation of bilateral parietal bony defects (diameter, 8.0 mm), either an nHA or an nHA+silk fibroin combination (nHA+silk) was grafted. The control was unfilled defect. The bone regeneration was evaluated by micro-computed tomography (µCT) and histomorphometric analyses at 4 and 8 weeks. RESULTS: All measured variables of the µCT analysis were significantly higher in the grafted groups (nHA and nHA+silk) than in the unfilled control groups at both 4 and 8 weeks after operation (P < .05). On histomorphometric analysis, there was no significant difference between the groups at 4 weeks after operation. However, the nHA group exerted significantly higher bone regeneration (40.16% ± 8.27%) compared with the unfilled control group (25.66% ± 10.98%) or the nHA+silk group (16.62% ± 3.05%) (P < .05). CONCLUSION: The nHA from eggshells exerted better bone formation than the unfilled control group on both µCT and histomorphometric analyses. Considering the rapid healing in bony defect and easy availability, the nHA from the eggshells could prove to be a good new bone substitute.

Differences in prognostic factors between early and advanced gastric cancer.

BACKGROUND/AIMS: The aim of this study was to assess any differences in the prognostic factors affecting long term survival in early gastric cancer (EGC) and advanced gastric cancer (AGC). METHODOLOGY: The prognostic factors affecting long term survival between EGC and AGC were evaluated. RESULTS: Based on the result of multivariate analysis, the variables related with poor prognosis in patient with EGC were ages of more than 60 (p=0.003, Relative risk [RR]:2.683) and more than 7 lymph nodes with metastasis (p=0.001, RR:12.129). The relevant variables in AGC were the presence of more than 7 lymph nodes with metastasis (p=0.002, RR:2.491), lymphovascular invasion (p=0.038, RR:1.476) and tumor depth (serosa ; p<0.001, RR:3.493, adjacent structure; p=0.005, RR:3.013). CONCLUSIONS: The prognostic factors affecting long term survival are a little different between the patients with EGC and AGC. Age of more than 60 years is one of the prognostic factors affecting long term survival in patients with EGC, but not with AGC. In AGC, lymphovascular invasion and tumor depth are prognostic factors but not in EGC.

Expression of bone morphogenic protein-4 is inversely related to prevalence of lymph node metastasis in gastric adenocarcinoma.

PURPOSE: Bone morphogenic proteins (BMPs) are the largest subfamily of the transforming growth factor-ß superfamily. Initially characterized as factors that induce bone and cartilage formation, BMPs have been found to be critical during mesoderm formation, organogenesis, and cellular differentiation. Bone morphogenic proteins are also known to modulate the morphologic alteration, adhesion, motility, and invasion of carcinoma cells derived from several organs. However, BMP-4 expression in gastric adenocarcinoma has not yet been clarified. We conducted the present study to define the clinical significance of BMP-4 expression in gastric carcinoma. METHODS: Using immunohistochemistry, we investigated the expression of BMP-4 in normal mucosae and gastric adenocarcinoma samples from 64 patients with gastric carcinoma. RESULTS: The expression of BMP-4 was significantly higher in the adenocarcinoma than in the normal mucosae. Moreover, increased BMP-4 expression was associated with the presence of Helicobacter pylori infection. By contrast, the BMP-4 expression rate in gastric carcinoma was inversely related to the prevalence of lymph node metastasis and tumor invasiveness. CONCLUSIONS: The findings of this study suggest that BMP-4 expression may be a useful prognostic factor for predicting the outcome of patients with gastric carcinoma. Continued investigation to define the pathophysiologic mechanism underlying the role of BMP-4 in gastric carcinoma is warranted.

Diagnostic Performance of EUS-Guided Sampling in Indeterminate Radiological Diagnosis of Pancreatic Disease and Intra-Abdominal Lymphadenopathy.

BACKGROUND: Endoscopic ultrasound (EUS)-guided sampling has been widely used for pathologic diagnosis of pancreatic lesions and intra-abdominal lymphadenopathy. However, its effectiveness for diagnostic decision making in indeterminate radiological diagnosis has not been well determined. MATERIALS AND METHODS: From March 2012 to October 2015, 98 consecutive patients who underwent EUS-guided FNA for solid intra-abdominal lesions were retrospectively analyzed (100 procedures). The purpose of EUS-guided sampling was classified as (1) confirmation of a high-confidence radiological diagnosis (High-confidence group) or (2) decision making in the differential diagnostic dilemma for indeterminate radiological diagnosis (Indeterminate group). The accuracies of EUS-guided sampling according to the purpose were analyzed and then compared. RESULTS: Of the 100 procedures, 22 procedures (22%) came under the Indeterminate group, whereas 78 came under the High-confidence group. The accuracies did not differ between the Indeterminate and the High-confidence groups (86.4% vs. 88.5%, p = 1.000). Clinical conditions that required EUS-guided sampling for indeterminate radiological diagnosis were (1) pancreatic cancer vs. benign disease (n = 8; e.g., pancreatic cancer vs. mass-forming pancreatitis), (2) recurrence of previous/pre-existing cancer vs. benign disease (n = 5; e.g., recurrent gastric cancer vs. reactive lymph node), (3) pathologic differentiation of presumed malignancy (n = 6; e.g., lymphadenopathies in the previous history of esophageal cancer and colon cancer), or (4) miscellaneous (n = 3; e.g., tuberculous lymphadenopathy vs. other condition). CONCLUSIONS: EUS-guided sampling demonstrated an accuracy of 86.4% in the clinical setting of indeterminate radiological diagnosis, which was not different from that of the confirmation of high-confidence diagnosis.

A multicenter study of interobserver variability in pathologic diagnosis of papillary breast lesions on core needle biopsy with WHO classification.

BACKGROUND: Papillary breast lesions (PBLs) comprise diverse entities from benign and atypical lesions to malignant tumors. Although PBLs are characterized by a papillary growth pattern, it is challenging to achieve high diagnostic accuracy and reproducibility. Thus, we investigated the diagnostic reproducibility of PBLs in core needle biopsy (CNB) specimens with World Health Organization (WHO) classification. METHODS: Diagnostic reproducibility was assessed using interobserver variability (kappa value, κ) and agreement rate in the pathologic diagnosis of 60 PBL cases on CNB among 20 breast pathologists affiliated with 20 medical institutions in Korea. This analysis was performed using hematoxylin and eosin (H&E) staining and immunohistochemical (IHC) staining for cytokeratin 5 (CK5) and p63. The pathologic diagnosis of PBLs was based on WHO classification, which was used to establish simple classifications (4-tier, 3-tier, and 2-tier). RESULTS: On WHO classification, H&E staining exhibited 'fair agreement' (κ = 0.21) with a 47.0% agreement rate. Simple classifications presented improvement in interobserver variability and agreement rate. IHC staining increased the kappa value and agreement rate in all the classifications. Despite IHC staining, the encapsulated/solid papillary carcinoma (EPC/SPC) subgroup (κ = 0.16) exhibited lower agreement compared to the non-EPC/SPC subgroup (κ = 0.35) with WHO classification, which was similar to the results of any other classification systems. CONCLUSIONS: Although the use of IHC staining for CK5 and p63 increased the diagnostic agreement of PBLs in CNB specimens, WHO classification exhibited a higher discordance rate compared to any other classifications. Therefore, this result warrants further intensive consensus studies to improve the diagnostic reproducibility of PBLs with WHO classification.

Significance of druggable targets (PD-L1, KRAS, BRAF, PIK3CA, MSI, and HPV) on curatively resected esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) still remains intractable disease with few therapeutic options. Programmed death-ligand 1 (PD-L1), which is essential for immune evasion, is involved in the pathogenesis of ESCC and thus is a potential therapeutic target. PIK3CA, KRAS, and BRAF mutations, microsatellite instability (MSI) caused by deficient mismatch repair (dMMR), and human papillomavirus (HPV) can potentially upregulate PD-L1 expression, which might contribute to the clinical outcome of patients with ESCC. METHODS: We investigated the significance of the present druggable markers [PD-L1, PIK3CA, KRAS, and BRAF mutations, MSI caused by deficient dMMR, and HPV] in 64 curatively resected ESCCs, using immunohistochemistry (PD-L1 and MMR protein expression), direct sequencing (KRAS, BRAF, and PIK3CA mutations), real-time PCR (HPV infection), and MSI using quasi-monomorphic markers. RESULTS: PD-L1 expression, PIK3CA mutation, and MSI/dMMR were detected in 35.9, 12.5, and 17.2% of ESCCs, respectively. HPV was rarely detected (1.6%) (high-risk HPV68), whereas KRAS and BRAF mutations were not detected in ESCCs. PD-L1-positive tumors were not correlated with PIK3CA mutation or MSI/dMMR (all P > 0.05). PD-L1, PIK3CA mutation, and MSI/dMMR characterized the patients associated with light smoking, female and younger age, and younger age and well-differentiated tumors, respectively (all P < 0.05). In multivariate analysis, only PD-L1-positivity was an independent favorable prognostic factor for overall survival (OS) and disease-free survival (DFS) (P = 0.023, P = 0.014). In the PD-L1-negative ESCCs, PIK3CA mutation had a poor prognostic impact on both OS and DFS (P = 0.006, P = 0.002). CONCLUSIONS: PIK3CA mutation may be an alternative prognostic biomarker in PD-L1-negative curatively resected ESCCs that can be optional to identify high-risk patients with worse clinical outcome who require more intensive therapy and follow-up.

Comparative pathologic analysis of mediastinal B-cell lymphomas: selective expression of p63 but no GATA3 optimally differentiates primary mediastinal large B-cell lymphoma from classic Hodgkin lymphoma.

BACKGROUND: Interpretation of mediastinal biopsy is often challenging even for experienced pathologists especially when a hematolymphoid neoplasm is suspected. Primary mediastinal large B-cell lymphoma (PMLBCL) and classic Hodgkin lymphoma (CHL) represent two major types of mature B-cell lymphomas of the mediastinum. Although PMLBCL and mediastinal CHL share many clinicopathologic characteristics, their treatment strategies and responses are remarkably different. We therefore aimed to find distinctive histologic or protein markers to better differentiate these two lesions. METHODS: Search for primary mediastinal B-cell lymphomas found 52 consecutive cases from 3 university hospitals of Korea during 2005 to 2012. Among them, 32 cases that were available for additional immunohistochemistry (IHC) assessment were enrolled in this study. These cases consisted of the following: CHL (N = 13), PMLBCL (N = 16), and B-cell lymphoma unclassifiable, with features intermediate between diffuse large B-cell lymphoma and CHL (gray zone lymphoma, N = 3). Along with the clinicopathologic findings, the expression of p63, GATA3 and cyclin E was investigated by IHC in the three categorized lesions mentioned above. RESULTS: Most clinical features overlapped between PMLBCL and CHL except for the increased disease progression and mortality found in PMLBCL. In the pathologic review, the presence of epithelioid granuloma favored a diagnosis of CHL, whereas reticulated or alveolar patterns of fibrosis were characteristic of PMLBCL. For protein markers, p63 was predominantly positive in PMLBCL (15/16) compared with CHL (2/13), which indicates that p63 is a marker of the highest diagnostic accuracy when calculated by the area under the ROC curve. GATA3 was expressed in the majority of CHL cases (10/13) compared with PMLBCL (0/16), while the expression of cyclin E was only rarely present in a minor population of PMLBCL. CONCLUSIONS: P63 expression in tumor cells, even focal expression, and no GATA3 is the most helpful feature in distinguishing PMLBCL from mediastinal CHL.

BRAF and NRAS mutations and antitumor immunity in Korean malignant melanomas and their prognostic relevance: Gene set enrichment analysis and CIBERSORT analysis.

Cutaneous malignant melanomas (CMMs) are rare but are the cause of the highest skin cancer-related mortality in Korea. Very few studies have investigated the associations between KRAS, NRAS, BRAF, and PIK3CA mutations and TICs, as well as their prognostic impact on Korean CMMs. Peptide nucleic acid-mediated polymerase chain reaction clamping and Mutyper and immunohistochemistry were used to detect these mutations in 47 paraffinized CMMs. BRAF and NRAS mutations were detected in 21.3% and 12.8% of CMMs, respectively. No KRAS or PIK3CA mutations were identified. NRAS mutations correlated with low FOXP3 (regulatory T lymphocyte marker) and indoleamine 2,3-dioxygenase (IDO) (activated dendritic cell marker) TICs in CMMs, which is consistent with the negative correlation of regulatory T cells with NRAS mutations in TCGA data, while BRAF mutations were not associated with any TICs. In gene set enrichment analysis, BRAF and NRAS mutations were enriched in decreased CD8 (suppressor/cytotoxic T lymphocyte marker) T cell-linked and increased CD4 (helper/inducer T lymphocyte marker) T cell-linked gene signatures, respectively, confirming the trend in our cohort of associations only with NRAS. BRAF or NRAS mutations alone did not affect any prognosis. In the subgroup analyses, BRAF mutations, as well as high CD4, CD8, FOXP3, and IDO TICs, caused worse overall survival in NRAS-mutated melanoma. No correlation of CD163 (monocyte-macrophage-specific marker) was detected. We found that approximately one-third of our cohort had BRAF and NRAS mutations, none had KRAS or PIK3CA mutations, and most displayed decreased anti-tumor immunity. These findings may warrant further study on combined immunotherapeutic and molecular targeted therapy in Korean CMMs. Subgroup analyses according to TICs and BRAF/NRAS mutations may help to identify high-risk patients with worse prognoses.

Expression of mucins (MUC1, MUC2, MUC5AC and MUC6) in ALK-positive lung cancer: Comparison with EGFR-mutated lung cancer.

ALK-positive (ALK+) lung adenocarcinoma usually shows a more advanced-staged disease with frequent nodal metastasis and highly aggressive outcomes compared with EGFR-mutated lung cancers. The aim of this study was to investigate the expression profiles of several mucins in ALK + lung cancers to gain insight into the relationship between the more aggressive biological nature of ALK + lung cancers and the role of mucins. We examined the immunohistochemical profiles of mucins MUC1, MUC2, MUC5AC, and MUC6 in 19 ALK + lung cancers compared with 42 EGFR-mutated lung cancers. ALK + cancers were found to occur in younger patients and were characterized by a solid-predominant histologic subtype with frequent signet ring cells and peritumoral muciphages. By contrast, EGFR-mutated cancers lacked ALK-specific histological patterns. Although all MUC1 and MUC5AC were expressed in both subtypes, MUC1 expression in ALK + cancers was visualized exclusively through cytoplasmic staining, whereas those in EGFR-mutated cancers were predominantly membranous staining in apical area (92.9%) and focally in cytoplasmic staining (7.1%). MUC5AC expression in ALK + cancers was exclusively visualized through cytoplasmic staining (100%), whereas EGFR-mutated cancers showed predominantly perinuclear dot-like patterns (90.5%) and focal cytoplasmic staining (9.5%). MUC2 and MUC6 expression was not detected in either type of lung cancer. CONCLUSIONS: The high frequency of both MUC1 and MUC5AC cytoplasmic expression, coupled with a lack of MUC2 and MUC6 expression in ALK + lung cancer may contribute to the biologically aggressive behavior of ALK + cancer. Inhibitors to these types of mucins may thus act as a barrier to cancerous extension reducing their aggressive behavior.