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The clinical characteristics of malignant melanoma are highly variable between patient populations of different ethnicities. To explore the underlining genetic variations, we reviewed the clinical data of 242 malignant melanoma cases from Taiwan and among them submitted formalin-fixed paraffin-embedded tissue samples from 37 patients for whole-exome sequencing to identify the mutational signatures, tumor mutation burden and specific gene mutations. The genomic profiles and clinical outcomes were compared with the information derived from the publicly available TCGA and TGEN databases. Mutation signature 12 was the dominant signature in Taiwanese patients and represented approximately 45% of the mutation signatures observed. In contrast, mutation signature 7 was the most prominent among cases available in the TCGA database. Common gene mutations found in the TCGA melanoma dataset were not frequently found in melanomas from Taiwanese patients. There were a significant number of specific gene mutations that exclusively occurred in acral subtype but not in non-acral subtype melanomas, and vice versa. While certain common mutations form a shared core of genetic features, there appear to be specific genetic pathways that are involved in the occurrence of melanomas that grow in non-UV-exposed areas. Our findings have shed light on the tumorigenesis pathways involved in malignant melanoma.

BACKGROUND Immune checkpoint inhibitor therapy has revolutionized lung adenocarcinoma therapy. Treatment with antibodies against the immune checkpoint molecules programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) can induce a durable response in a subset of patients. Immunohistochemistry characterization of tumor PD-L1 expression using either a histopathology specimen or a cytopathology specimen has been shown to correlate with treatment response. However, the current practice relies on pathologists' visual estimation of tumor PD-L1 staining, which can be variable in certain conditions. Highlighting tumor cells via double immunostaining with PD-L1 and thyroid transcription factor-1 (TTF-1) may improve estimation accuracy. METHODS We performed PD-L1 single staining and PD-L1/TTF-1 double staining in 42 pairs of cytopathology and histopathology specimens from lung adenocarcinoma patients. An experienced pathologist visually estimated PD-L1 expression in each case and placed tumor PD-L1 expression into 1 of 3 categories

OBJECTIVES Cytokeratins (CKs) are mainly expressed in epithelial carcinomas and are valuable for making diagnoses and identifying metastatic status. Changes in the expression of individual CKs in certain carcinoma may be relevant to establishing a prognosis. However, the prognostic significance of CKs in head and neck squamous cell carcinoma (HNSCC) remains elusive. Herein, we investigated the diverse and unique expression patterns of Cytokeratin 13 (CK13) and Cytokeratin 17 (CK17) and assessed the role of CK17 as a predictor for HNSCC metastasis and prognosis. METHODS CK13 and CK17 expressions were evaluated using immunohistochemical tissue microarray (TMA) analysis with 106 patients of HNSCC. To clarify the characterisation of CK17 expression with respect to its ability in predicting metastatic disease, an in vitro study of cells migration/invasion assays was conducted. Furthermore, the correlation of CK17 expression to clinicopathologic variables and prognosis was analyzed using a serial statistical method. RESULTS CK13 was predominately expressed in non-cancerous tissues and was lost in HNSCC. Decreasing expression of CK17 correlated with cancerous cell migration and invasion (P

Background and objective Therapeutic responses of lung adenocarcinoma patients to tyrosine kinase inhibitors (TKIs) of epidermal growth factor receptor (EGFR) are closely associated with activating mutations within the EGFR tyrosine kinase domain. Screening activating EGFR mutations prior to selection for therapeutic strategy has been considered extremely valuable for clinical management of lung adenocarcinoma patients in Asian countries including Taiwan, where the EGFR mutation rate is higher than in the rest of the world. Currently there is no consensus on the method of choice to assess EGFR mutations in tumour tissue. Methods We enrolled 445 lung adenocarcinoma patients for analysis of tumour EGFR mutations using polymerase chain reaction (PCR)-direct sequencing, scorpion/amplified refractory mutation system (ARMS) technology and immunohistochemistry with mutation-specific antibodies. Results Two hundred forty-five patients (245/445; 55%) were found to harbour activating EGFR mutations using PCR-direct sequencing method, with a majority of patients (233/245; 95%) carrying exon 19 deletion or p.L858R point mutations. One hundred three of 200 patients were negative for EGFR mutations from PCR-direct sequencing were further analysed using Scorpion/ARMS technology. Up to 30% of the PCR-direct sequencing negative patients turned out to be positive in the Scorpion/ARMS EGFR mutation tests. For immunohistochemistry analysis of EGFR mutations, the p.E746_A750del specific antibody showed a sensitivity of 57% and a specificity of 100% for exon 19 deletions while the p.L858R point mutation specific antibody showed a sensitivity of 68% and a specificity of 95%. Conclusions Based on this study, we proposed an algorithm for comprehensive and efficient testing of EGFR mutations on lung adenocarcinoma patients in Asia.

Tumor recurrence is the most common cause of disease failure after surgical resection in early‐stage lung adenocarcinoma. Identification of clinically relevant prognostic markers could help to predict patients with high risk of disease recurrence. A meta‐analysis of available lung adenocarcinoma microarray datasets revealed that T‐LAK cell‐originated protein kinase (TOPK), a serine/threonine protein kinase, is overexpressed in lung cancer. Using stable cell lines with overexpression or knockdown of TOPK, we have shown that TOPK can promote cell migration, invasion, and clonogenic activity in lung cancer cells, suggesting its crucial role in lung tumorigenesis. To evaluate the prognostic value of TOPK expression in resected stage I lung adenocarcinoma, a retrospective analysis of 203 patients diagnosed with pathological stage I lung adenocarcinoma was carried out to examine the expression of TOPK by immunohistochemistry (IHC). The prognostic significance of TOPK overexpression was examined. Overexpression of TOPK (IHC score >3) was detected in 67.0% of patients, and these patients were more frequently characterized with disease recurrence and angiolymphatic invasion. Using multivariate analysis, patient age (>65 years old; P = 0.002) and TOPK overexpression (IHC score >3; P 3; P = 0.005) also significantly predicted a reduced time to recurrence in the patients. Our results indicate that overexpression of TOPK could predetermine the metastatic capability of tumors and could serve as a significant prognostic predictor of shortened overall survival and time to recurrence. (Cancer Sci 2012; 103: 731–738)

Background The total number of resected lymph nodes (TLN) has been shown to predict survival in esophageal cancer, but its relationship with recurrence has been rarely reported. We aim to study the prognostic factors in esophageal squamous cell carcinoma (ESCC) patients, with a particular focus on the role of TLN. Methods Two hundred sixty-eight ESCC patients who underwent transthoracic esophagectomy were selected for the study. A Cox regression model was used to identify prognostic factors. Results Recurrence occurred in 115 of 268 patients. The median time to recurrence was 10 months (range, 1–58). The recurrence-free survival at 1, 3, and 5 years was 62.3%, 32.1%, and 28.5%, respectively. Multivariate analysis identified age (P = 0.001), N stage (N1–3 vs. N0, P = 0.001), tumor length (P = 0.019), and development of recurrence (P

Adenomyosis is an oestrogen-dependent disease caused by a downward extension of the endometrium into the uterine myometrium. Epithelial-mesenchymal transition (EMT) endows cells with migratory and invasive properties and can be induced by oestrogen. We hypothesized that oestrogen-induced EMT is critical in the pathogenesis of adenomyosis. We first investigated whether EMT occurred in adenomyotic lesions and whether it correlated with serum 17β-oestradiol (E2) levels. Immunohistochemistry was performed on adenomyotic lesions and corresponding eutopic endometrium samples from women with adenomyosis. Endometria from women without endometrial disorders were used as a control. In the epithelial component of adenomyotic lesions, vimentin expression was up-regulated and E-cadherin expression was down-regulated compared to the eutopic endometrium, suggesting that EMT occurs in adenomyosis. In adenomyosis, the serum E2 level was negatively correlated with E-cadherin expression in the epithelial components of the eutopic endometrium and adenomyotic lesions, suggesting the involvement of oestrogen-induced EMT in endometrial cells. In oestrogen receptor-positive Ishikawa endometrial epithelial cells, oestrogen induced a morphological change to a fibroblast-like phenotype, a shift from epithelial marker expression to mesenchymal marker expression, increased migration and invasion, and up-regulation of the EMT regulator Slug. Raloxifene, a selective oestrogen receptor modulator, abrogated these effects. To determine the role of oestrogen-induced EMT in the implantation of ectopic endometrium, we xenotransplanted eutopic endometrium or adenomyotic lesions from adenomyosis patients into ovariectomized SCID mice. The implantation of endometrium was oestrogen-dependent and was suppressed by raloxifene. Collectively, these data highlight the crucial role of oestrogen-induced EMT in the development of adenomyosis and suggest that raloxifene may be a potential therapeutic agent for adenomyosis patients.

Yeh Y-C & Chou T-Y (2010) Histopathology 57, 112–120 Pulmonary adenocarcinoma with microcystic histology and intratumoral heterogeneity of EGFR gene polymorphism Aims: To study the clinicopathological features of pulmonary adenocarcinomas with microcystic histology. Materials and results: Two cases of pulmonary adenocarcinoma exhibiting a unique microcystic growth pattern were analysed. The 20-mm tumour of a 59-year-old woman showed a predominantly complex microcystic architecture with a focal papillary configuration, whereas the 15-mm tumour of another 46-year-old woman displayed a solely microcystic growth pattern. The first tumour was found to have metastasized to lymph nodes at surgery and, 4 years later, to the chest wall. The second tumour did not metastasize or recur over a follow-up period of 12 years. The tumour cells were immunoreactive with thyroid transcription factor-1 (TTF-1), which helped to differentiate them from salivary gland-type tumours. No mutations of epidermal growth factor receptor (EGFR) or K-ras genes were detected. However, facilitated by laser microdissection, a Q787Q polymorphism was found in the microcystic component but not in the papillary component. To our knowledge, this is the first report to illustrate intratumoral heterogeneity of EGFR gene polymorphism among different growth patterns within the same tumour. Conclusions: Pulmonary microcystic adenocarcinoma has a variable clinical outcome. The microcystic tumour cells are immunoreactive with TTF-1 and may harbour polymorphisms of the EGFR gene.

Gerzrldk& K C I I I W ~ ~ 11. Greis, I,.-Y. Dermis I h g , Melissa A. Bloinherg Teh-Yirig Chou, MatiSliiow Jiatg Llizaheth I? I ~ ~ I ~ I I I ~ ~ c , loris M. Snow, Lisa K. Kreppel, Itoberl C. Cole atid Bradley K. Hayes. Dept. Biocheni. & Molecular Genetics, University of Alabama at Birmingham, UAB Station, 1918 University Avenue, Birmingham, AL 35294-0005;Phone: (205) 934-4753; FAX: (205) 975-6685; Internet: GWHART@BMG.BHS.UAB.EDU.