Correlations of mRNA Levels among Efflux Transporters, Transcriptional Regulators, and Scaffold Proteins in Non-Small-Cell Lung Cancer.

Multidrug resistance (MDR) due to enhanced drug efflux activity of tumor cells can severely impact the efficacy of antitumor therapies. We recently showed that increased activity of the efflux transporter P-glycoprotein (P-gp) associated with activation of Snail transcriptional regulators may be mediated mainly by moesin in lung cancer cells. Here, we aimed to systematically evaluate the relationships among mRNA expression levels of efflux transporters (P-gp, breast cancer resistance protein (BCRP), and multidrug resistance-associated protein 2 (MRP2)), scaffold proteins (ezrin (Ezr), radixin (Rdx), and moesin (Msn); ERM proteins), and SNAI family members (Snail, Slug, and Smac) in clinical lung cancer and noncancer samples. We found high correlations between relative (cancer/noncancer) mRNA expression levels of Snail and Msn, Msn and P-gp, Slug and MRP2, and Smuc and BCRP. These findings support our previous conclusion that Snail regulates P-gp activity via Msn and further suggest that Slug and Smuc may contribute to the functional regulation of MRP2 and BCRP, respectively, in lung cancer cells. This trial is registered with UMIN000023923.

Prognostic value of extracapsular invasion of axillary lymph nodes combined with peritumoral vascular invasion in patients with breast cancer.

BACKGROUND: Extracapsular invasion (ECI) of metastatic axillary lymph nodes has been associated with aggressive nodal disease but its prognostic role in breast cancer is unclear. The present study evaluated nodal ECI as a predictor of breast cancer recurrence. METHODS: We evaluated 154 women with histologically proven node-positive breast cancer who were diagnosed with invasive ductal carcinoma, and investigated the relationships between ECI and recurrences and other clinicopathological factors, particularly vascular invasion and the number of lymph node metastases. RESULTS: The presence of ECI at positive nodes was significantly associated with the number of positive nodes, and with disease recurrence and survival in univariate (but not multivariate) analysis. Interestingly, all ECI(+) patients with distant metastases in our series had peritumoral vascular invasion (PVI), which may have reflected systemic disease; ECI with PVI of the primary tumor strongly predicted recurrent disease and shorter survival. CONCLUSION: ECI of axillary metastases combined with PVI indicates high tumor aggressiveness. Patients with ECI and PVI may be considered for stronger adjuvant therapies because of their high risk for distant recurrences.

Clinicopathological significance of decreased galectin-3 expression and the long-term prognosis in patients with breast cancer.

PURPOSE: Galectin-3 expression is modulated in cancer cells, and that finding has led to the recognition of galectin-3 as a diagnostic or prognostic marker for various cancers, including breast cancer. This study investigated the correlation between galectin-3 expression and the clinicopathological features in patients with breast cancer, in order to determine the relevance and role of galectin-3 in breast cancer progression. METHODS: Galectin-3 expression was investigated immunohistochemically in 116 patients with breast cancer, and a statistical analysis was performed. RESULTS: Galectin-3 expression in breast cancer was significantly associated with tumor vascular invasion. However, galectin-3 expression was not associated with Ki-67 expression, which reflects tumor proliferation. Disease-free survival and long-term overall survival were significantly shorter for patients with reduced galectin-3 expression. CONCLUSIONS: This study demonstrated that the galectin-3 expression was associated with tumor vascular invasion and metastasis, suggesting that galectin-3 plays a critical role in tumor progression via an invasive mechanism but not via proliferation in breast cancer. Furthermore, reduced expression of galectin-3 is useful for predicting a long-term poor prognosis in patients with breast cancer.

Accuracy of intraoperative macroscopic diagnosis of sentinel node metastases in breast cancer: is accurate prediction possible?

BACKGROUND: Accurate intraoperative diagnosis of sentinel lymph node (SLN) metastases enables the selection of patients who require axillary lymph node dissection, thus avoiding an additional operation. In this study we investigated the accuracy of intraoperative macroscopic diagnosis of SLN metastases in patients with breast cancer. METHODS: SLNs from 276 breast cancer patients with clinically negative nodes were analyzed by macroscopic examination. The results of intraoperative macroscopic diagnosis were compared with those of frozen section analysis. RESULTS: The sensitivity, specificity, overall accuracy, and false negative rate of SLN biopsy in the assessment of node status were 82.1%, 100%, 96.4%, and 17.9%, respectively, for frozen section analysis, and 57.1%, 95.5%, 87.7%, and 42.9%, respectively, for macroscopic evaluation. Even in patients with node metastasis >7 mm, the false negative rate of macroscopic evaluation was 11.1%. CONCLUSIONS: Our results suggest that macroscopic diagnosis is less effective in predicting lymph node status in breast cancer than frozen section analysis. These findings imply that intraoperative macroscopic evaluation of sentinel nodes is never predictive of the final pathology.

Ramucirumab-related Oral Pyogenic Granuloma: A Report of Two Cases.

Pyogenic granuloma (PG) is a granulomatous elevated lesion that occurs on the skin and mucous membranes. We herein report two cases of intra-oral PG that developed during the administration of ramucirumab for gastric cancer. Case 1 involved a 55-year-old man with a 6-mm tumor on the right tongue, and case 2 involved a 67-year-old man with a 5-mm tumor on the upper lip. The imbalance in angiogenesis caused by ramucirumab and the deterioration in the local oral environment were suggested to have caused the PG. Medical and dental collaboration is essential during the administration of ramucirumab.

Implication of extracapsular invasion of sentinel lymph nodes in breast cancer: prediction of nonsentinel lymph node metastasis.

BACKGROUND: Accurate intraoperative diagnosis of sentinel lymph node (SLN) metastases enables the selection of patients who require axillary lymph node dissection (ALND). However, many patients with positive SLN do not show metastasis to other axillary lymph nodes. In this study, we investigated the factors that may determine the likelihood of additional positive nodes in the axilla when metastasis is found in the SLN. METHODS: SLN biopsy was performed on 276 patients with breast cancer with clinically negative nodes, of which 46 (16.6%) had positive SLNs and underwent ALND. Eleven (23.9%) of these 46 cases had additional metastasis in nonsentinel lymph nodes (NSLN). The clinical and pathological features of these cases were reviewed and statistical analysis was performed. RESULTS: All cases of positive nodes in NSLN in our series had extracapsular invasion (ECI) at the metastatic SLNs. Furthermore, the absence of ECI of SLN was significantly associated with the absence of metastasis in the NSLN (P < 0.001). As contributing factors, the absence of lymphatic invasion at the primary tumor, primary tumor size (<2 cm) and foci size in the metastatic SLN fell short of reaching statistical significance. Other factors, including histological type, pathological grade, estrogen receptor status, HER2 status, and age, were not significantly associated with metastatic involvement of NSLN. CONCLUSIONS: Our results suggest that the presence of ECI at metastatic SLNs is a strong predictor for residual disease in the axilla. These findings imply the possibility that ALND might be foregone in the treatment of patients with breast cancer without ECI at metastatic SLNs.

Metachronous bilateral breast metastases of a lung neuroendocrine tumor: A case report.

Breast metastases of primary lung neuroendocrine tumors are rarely reported. The current report presents the case of a 41-year old female with no history of smoking who initially underwent surgery for a breast fibroadenoma, during which a neuroendocrine tumor of the right lung was detected via chest X-ray. The patient underwent surgery for the tumor and developed right breast nodules after adjuvant chemotherapy. Histological and immunohistochemical examinations of biopsies from these nodules indicated breast metastasis of the primary lung neuroendocrine tumor. The patient underwent mastectomy of the right breast but subsequently developed metastases in the left breast, for which local radiotherapy was administered. The observed metachronous bilateral breast metastases indicated that the contralateral breast should be considered during an investigation of metastasis.

Moesin-Mediated P-Glycoprotein Activation During Snail-Induced Epithelial-Mesenchymal Transition in Lung Cancer Cells.

Epithelial-mesenchymal transition (EMT) plays a role in not only cancer metastasis, but also drug resistance, which is associated with increased levels of efflux transporters such as P-glycoprotein (P-gp). Here, we examined whether P-gp activation during Snail-induced EMT of lung cancer cells is mediated by ezrin, radixin, and moesin (ERM), which regulate transporter localization. HCC827 lung cancer cells overexpressing the transcription factor Snail showed increased Rhodamine123 efflux and increased paclitaxel resistance, reflecting increased P-gp activity. Concomitantly, the expression level of moesin, but not ezrin or radixin, was significantly increased. The increase of P-gp activity was suppressed by knockdown of moesin. Thus, the increase of P-gp activity associated with Snail-induced EMT may be mediated mainly by moesin in HCC827 cells. On the other hand, the Snail mRNA expression level was correlated with the expression level of each ERM in 4 non-small-cell lung cancer cell lines (HCC827, A549, H441, H1975) and in tumor tissues, but not normal tissues, of patients with lung cancer. These results suggest that P-gp activation during EMT is at least partially due to increased expression of moesin. Coadministration of moesin inhibitors with anticancer drugs might block P-gp-mediated drug efflux organ-specifically, improving treatment efficacy and minimizing side effects on other organs.

Intramucosal adenocarcinoma of the ileum originated 40 years after ileosigmoidostomy.

BACKGROUND: Small bowel adenocarcinomas (SBAs) are rare carcinomas. They are asymptomatic and usually neither endoscopy nor contrast studies are performed for screening CASE PRESENTATION: A 72-year-old Japanese male had a positive fecal occult blood test at a regular check-up in 2006. He suffered appendicitis and received an ileosigmoidostomy in 1966. A colonoscopy revealed an irregular mucosal lesion with an unclear margin at the ileum side of the anastomosis. A mucosal biopsy specimen showed adenocarcinoma histopathologically. Excision of the anastomosis was performed for this patient. The resected specimen showed a flat mucosal lesion with a slight depression at the ileum adjacent to the anastomosis. Histological examination revealed a well differentiated intramucosal adenocarcinoma (adenocarcinoma in situ). Immunohistological staining demonstrated the overexpression of p53 protein in the adenocarcinoma. CONCLUSION: Adenocarcinoma of the ileum at such an early stage is a very rare event. In this case, there is a possibility that the ileosigmoidostomy resulted in a back flow of colonic stool to the ileum that caused the carcinogenesis of the small intestine.

Renal primitive neuroectodermal tumor with elevated plasma adrenocorticotropic hormone levels: A case report.

INTRODUCTION: Primitive neuroectodermal tumors are small round-cell tumors - Ewing sarcoma family, frequently occurring in the extremities, but rarely in the kidney. CASE PRESENTATION: A 58-year-old woman presented with whole-body edema and weakness of lower limb muscles. Computed tomography revealed a left renal tumor, and the plasma adrenocorticotropic hormone level was elevated. The tumor was surgically removed without complications, her plasma adrenocorticotropic hormone reverted to normal levels, and symptoms disappeared after surgery. Histopathological examination revealed a primitive neuroectodermal tumor arising in her kidney. The patient was alive without metastasis 3 years after the surgery. CONCLUSION: We report the first case of renal primitive neuroectodermal tumor accompanying elevated plasma adrenocorticotropic hormone levels which are thought to be produced and secreted in an ectopic fashion.

[USEFULNESS OF VIVID (VISUALIZATION OF VARIOUS INTEGRATION WITH DIFFUSION) ON COGNITIVE FUSION PROSTATE BIOPSY].

(Purpose) We created an image reconstructing multiparametric MRI system called VIVID (Visualization of Various Integration with Diffusion) and examined the efficacy of VIVID in detecting prostate cancer. (Methods and materials) The subjects were 80 patients who underwent one target biopsy with reference to MRI images in addition to 8-20 biopsies. (Results) The significant cancer detection rate was 61%, the significant cancer detection rate of PI-RADS 4 or 5 was 55%, and the significant cancer detection rate of VIVID score 4 or 5 was 55%. Three cases with PI-RADS 4 at TZ lesion with positive T2WI only were evaluated as having VIVID scores 1 or 2. Cancer was not detected with target biopsy from the site. (Conclusion) Our finding suggest that VIVID correctly excludes TZ lesions with only T2WI positively in multiparametric MRI.

Localized lymphoid hyperplasia of the rectum representing progressive transformation of the germinal center. A report of two cases.

Histologically, benign lymphoid hyperplasia (BLH) of the rectum is usually characterized by large lymphoid follicles with active germinal centers, and a narrow surrounding mantle zone and marginal zone. We present two cases of BLH of the rectum demonstrating progressive transformation of the germinal center (PTGC). The patients were 50- and 71-year-old Japanese women. Colonoscopy demonstrated small sessile polyps in both cases. The resected specimen contained numerous lymphoid follicles with active germinal centers and a portion of the lymphoid follicles exhibited PTGC. The area showing PTGC contained a few large lymphoid cells resembling lymphocytic and histiocytic Reed-Sternberg cells of nodular lymphocyte-predominant Hodgkin lymphoma. These PTGC contained small- to-medium clusters of epithelioid cells in both cases. In situ hybridization studies demonstrated scattered Epstein-Barr virus (EBV)-encoded small RNA-positive medium and large lymphoid cells and crypt epithelium in both lesions. EBV may be involved in the etiology of a subset of BLH of the rectum. However, reactivity of lymphoid cells for EBV has been reported in lymphoid tissues in a high percentage of "normal" individuals. The etiology of BLH of the rectum remains unclear.

Florid monocytoid B-cell hyperplasia resembling nodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue type. A histological and immunohistochemical study of four cases.

A pale ring of medium-to-large cells surrounding the follicles, namely a marginal zone distribution pattern, is the key criterion for diagnosing nodal marginal zone B-cell lymphoma (NMZBL). The tumor cells of NMZBL occasionally exhibit the morphology of monocytoid B-cells (MBC). However, this condition can be difficult to distinguish from MBC hyperplasia in reactive conditions. We describe the histopathological and immunohistochemical findings of four cases exhibiting florid MBC hyperplasia and resembling NMZBLs. The patients consisted of three males and one female (age range 48-64 years) who had asymptomatic lymphadenopathy in the head and neck area. Histologically, a pale ring surrounding more than 75% of the lymphoid follicles characterizes the lesion. The lymphoid follicles usually had hyperplastic germinal centers, and progressive transformation of germinal center was noted in two cases. The pale ring was composed of medium-to-large cells with indented or round nuclei and relatively abundant pale clear cytoplasm. Numerous plasma cells were observed in one case. The overall histomorphological findings in these four cases were similar to those of NMZBLs. However, immunohistochemical investigations demonstrated that MBCs were CD43- and bcl-2-. Moreover, immunohistochemistry, polymerase chain reaction, and flow cytometry studies demonstrated the polytypic nature of B-lymphocytes. Recognition of this unusual MBC hyperplasia in reactive lymph node lesions is important to avoid confusion with NMZBLs.

Tuberculosis-like peritonitis due to an atypical Mycobacterium infection in a Japanese woman.

It is not known whether atypical Mycobacterium (AM) causes peritonitis in humans. We described a case of tuberculosis-like peritonitis caused by an AM. Genetic analysis of the biopsy specimens suggested an AM infection. Thus, we concluded that peritonitis in humans can be caused by some AM species as well as by Mycobacterium tuberculosis complex.

Decreasing expression of glucose-regulated protein GRP78/BiP as a significant prognostic predictor in patients with advanced laryngeal squamous cell carcinoma.

BACKGROUND: The immunoglobulin heavy chain binding protein (BiP)/glucose-regulated protein 78 (GRP78) is important in the endoplasmic reticulum stress, and is highly expressed in various human cancers. The clinical and pathological features of GRP78/BiP are unclear in patients with advanced laryngeal squamous cell carcinoma (SCC). The purpose of this study was to investigate the clinicopathological significance of GRP78/BiP as a prognostic marker for laryngeal SCC. METHODS: A total of 59 patients with advanced laryngeal SCC (stage III/IV) were analyzed, and tumor specimens were stained by immunohistochemistry for GRP78/BiP and Ki-67. Microvessel density was determined by immunohistochemical staining for CD34 and p53. RESULTS: Expression of GRP78/BiP was confirmed in 87% of cases. Decreased expression of GRP78/BiP was highly associated with positive expression of p53. Decreased GRP78/BiP expression was identified on multivariate analysis as an independent factor of decreased progression-free survival (PFS). CONCLUSION: GRP78/BiP was found to be commonly expressed in laryngeal SCC, whereas its downregulation was found to serve a significant prognostic role for predicting poor survival in patients with laryngeal SCC with advanced disease. GRP78/BiP may be a potentially attractive target for the treatment of various human neoplasms. © 2016 Wiley Periodicals, Inc. Head Neck 38: First-1544, 2016.

Tumor-infiltrating CD45RO(+) memory cells are associated with a favorable prognosis breast cancer.

BACKGROUND: CD45RO is a marker for memory lymphocytes. Whether CD45RO(+) tumor-infiltrating lymphocytes (TILs) prevent breast cancer recurrence is unclear. METHODS: In the present study, we evaluated CD45RO expression in TILs as a predictor of prognosis in 98 patients with breast cancer who underwent radical surgery without neoadjuvant chemotherapy. Patients were classified as CD45RO(+)/TILs(High) or CD45RO(+)/TILs(Low) based on median immunohistochemistry levels. RESULTS: CD45RO(+)/TILs(High) were associated with smaller tumor size. The CD45RO(+)/TILs(High) group also had significantly fewer metastatic lymph nodes (P = 0.0082) and fewer peritumoral lymphatic invasions (P = 0.0284). The CD45RO(+)/TILs(High) group enjoyed longer recurrence-free survival (P = 0.0453) but not cancer-specific survival (P = 0.0640) in univariate analysis. CONCLUSIONS: These results suggested that CD45RO(+) effector cells may both help eradicate local tumors and prevent metastases to the lymphatic systems in breast cancer patients. High ratio of CD45RO expressing TILs was associated with recurrence-free survival improvement and a trend toward cancer-specific survival improvement in breast cancer patients.

Lymphoid variant of hyaline vascular Castleman's disease containing numerous mantle zone lymphocytes with clear cytoplasm.

We report two unusual cases of hyaline vascular type Castleman's disease showing a pale clear cuff of mantle zone lymphocytes presenting a marginal zone distribution pattern. These cells had medium-sized round or slightly indented nuclei and a moderate amount of clear cytoplasm. The histopathologic findings in our cases were similar to those of nodal marginal zone B-cell lymphoma. However, immunohistochemistry demonstrated that both the mantle zone lymphocytes and the pale cuff of the lymphoid cells were CD20+, CD79a+, sIgM+, sIgD+, CD5-, CD10-, CD43-, CD45RO-, Bcl-2+, Bcl-6- and cyclin D1-. The polytypic nature of these cells was demonstrated by immunohistochemistry and polymerase chain reaction. Reactive lymph node lesions only rarely show mantle cell hyperplasia with clear cytoplasm. This unusual mantle cell hyperplasia with clear cytoplasm associated with a hyaline vascular type of Castleman's disease should be differentiated from nodal marginal zone B-cell lymphoma, mantle cell lymphoma and follicular lymphoma. To avoid overdiagnosis and overtreatment, it is suggested that immunophenotypic and genotypic studies might be required, and furthermore careful attention should be paid to the morphologic examination.

Follicular lymphoid hyperplasia of the oral cavity representing progressive transformation of germinal center.

Follicular lymphoid hyperplasia (FLH) of the oral cavity is a rare and poorly understood lymphoproliferative disorder. We present a case of FLH of the oral cavity presenting with progressive transformation of germinal center (PTGC). The patient was a 49-year-old Japanese woman presenting with a hard mass in the right cheek. The resected specimen contained numerous lymphoid follicles with active germinal centers and a portion of the lymphoid follicles exhibited PTGC. The PTGCs contained a few large lymphoid cells resembling lymphocytic and histiocytic Reed-Sternberg cells of nodular lymphocyte-predominant Hodgkin lymphoma. The PTGC was surrounded by groups of epithelioid cells. In situ hybridization studies demonstrated strong expression of Epstein-Barr virus (EBV)-encoded small RNA in scattered large lymphoid cells in the PTGC. Although the etiology of FLH of the oral cavity remains unclear, the present case suggests that a subset of FLH of the oral cavity appears to be an EBV-associated lymphoproliferative disorder.

Usefulness of immunohistochemistry for recognizing metastatic colorectal adenocarcinoma in infarcted lymph nodes.

Lymph node infarction is a spontaneous coagulative necrosis of the affected lymph node and is frequently associated with concurrent and subsequent malignant lymphoma. However, this phenomenon appears to be rarely associated with metastatic carcinomas. Here, we report on the histopathologic and immunohistologic findings of three cases showing lymph node infarction in the regional lymph node associated with metastatic colorectal adenocarcinoma. Histologically, coagulative necrosis of metastatic carcinoma was surrounded by a thick rim of granuloma consisting of histiocytes with or without epithelioid features, foamy cells, and a small number of lymphocytes. The immunohistochemical study of the coagulative necrosis demonstrated that cytokeratins (AEI/AE3 and CAM5.2) and carcinoembryonic antigen (CEA) were well preserved in all three cases. However, compared with viable tumor tissues, only a few tumor cells were positive for epithelial membrane antigen. Using formalin-fixed and paraffin-embedded tissues, immunostaining for cytokeratins and CEA of the lymph node containing necrotic carcinoma may provide clinically valuable information.

Atypical lymphoplasmacytic and immunoblastic proliferation from systemic lupus erythematosus. A case report.

A case of atypical lymphoplasmacytic and immunoblastic proliferation (ALPIBP) in the lymph nodes associated with well-documented systemic lupus erythematosus (SLE) is presented. A 30-year-old Japanese female with an 18-year history of SLE presented with right neck lymphadenopathy of 3 months duration. A biopsy specimen showed a diffuse effaced lymph node architecture without follicles and minimal sinuses. At high power field, a polymorphous population of small- to medium-sized lymphocytes, plasma cells, plasmacytoid cells, as well as large, basophilic transformed lymphocytes and immunoblasts diffusely infiltrated the paracortical area. Interestingly, the immunohistochemical study demonstrated large, irregularly shaped accumulations of follicular dendritic cells (FDCs) surrounding the small vessels, which is an immunohistochemical finding characteristic of angioimmunoblastic T-cell lymphoma (AILT). However, the present lesion showed the following differences to AILT: (a) absence of CD3+, CD4+ and CD10+ clear cells, which are tumor cells of AILT; (b) absence of pronounced arborizing vascular proliferation; (c) on molecular analysis, the present case demonstrated a polyclonal pattern converse to the monoclonal T-cell receptor gamma chain gene rearrangement in most AILTs (d) absence of EBV infected lymphoid cells, which are frequently detected AILT. As previously suggested, the present case indicates that a clinical correlation as well as immunohistologic and genotypic studies may be necessary to discriminate between ALPIBPs and AILT.