Silencing of homeobox B9 is associated with down-regulation of CD56 and extrathyroidal extension of tumor in papillary thyroid carcinoma

Kim, J.H.,Kim, Y.H.,Han, J.H.,Lee, K.B.,Sheen, S.S.,Lee, J.,Soh, E.Y.,Park, T.J. W. B. Saunders Co ; Centrum Philadelphia 2012 Human pathology Vol.43 No.8

Papillary thyroid carcinoma is the most common type of thyroid malignancy, and CD56, a neural cell adhesion molecule, is typically down-regulated in almost all cases of papillary thyroid carcinoma. Homeobox B9 is a transcription factor, belongs to the products of the homeobox transcription factor gene family, and has been known to regulate transcription of CD56 and to promote tumorigenicity and metastasis in some malignancies. In this study, we investigated the expression and relation of homeobox B9 to reduced expression of CD56 in papillary thyroid carcinomas and also a relationship between their expression and clinicopathologic parameters. Therefore, we performed CD56 and homeobox B9 immunohistochemical staining on 72 papillary thyroid carcinomas and Western blotting on 31 papillary thyroid carcinomas. CD56 protein staining revealed that it was reduced or absent in 65 papillary thyroid carcinomas (90.3%) and was related to silencing of homeobox B9 (77.8%) (P = .003). The loss of homeobox B9 expression was associated with extrathyroidal extension (P = .002), pathologic stage of tumor (P = .01), and age older than 45 years (P = .032). However, the CD56 staining did not reveal any significant relationship with clinicopathologic features (P > .05). In conclusion, reduced expression of CD56 is associated with homeobox B9 in papillary thyroid carcinomas. Furthermore, silencing of homeobox B9 is more common in older age and is linked to extrathyroidal extension and advanced pathologic stage of papillary thyroid carcinoma.

Implications of infiltrating immune cells within bone marrow of patients with diffuse large B-cell lymphoma

Jeong, J.,Oh, E.J.,Yang, W.I.,Kim, S.J.,Yoon, S.O. W. B. Saunders Co ; Centrum Philadelphia 2017 Human pathology Vol.64 No.-

<P>The implications of infiltrating immune cells, especially T cells and macrophages, in the bone marrow (BM) microenvironment of patients with diffuse large B-cell lymphoma (DLBCL) have rarely been studied. We aimed to investigate the significance of infiltrating immune cells in the BM microenvironment as a prognostic factor for DLBCL patients. Using the initial pretreatment BM biopsy obtained from 198 DLBCL patients, we semiquantitatively evaluated CD3+ T cells, CD8+ T cells, and CD163+ macrophages that infiltrate into the paratrabecular and interstitial areas of BM by immunohistochemistry and analyzed their clinicopathological and prognostic implications. Levels of infiltrating CD3+ T cells, CD8+ T cells, and CD163+ macrophages were significantly higher in BM with DLBCL involvement (BMI-positive group) than in that without DLBCL involvement (BMI-negative group). Infiltration of CD8+ T cells significantly increased in cases with advanced Ann Arbor stage, elevated lactate dehydrogenase level, extranodal site involvement >= 2 sites, higher Eastern Cooperative Oncology Group performance status, and higher International Prognostic Index (IPI) risk. High levels of CD3+ T cells were significantly associated with age <= 60, and high levels of CD163+ macrophages were associated with advanced Ann Arbor stage and higher IPI risk. High infiltration of CD8+ T cells was significantly related to inferior overall and recurrence-free survival rate, even in the BMI-negative group. High infiltration of CD8+ T cells within the pretreatment BM was related to poor prognosis, and might be a useful prognostic factor of DLBCL patients. Therefore, evaluation of CD8+ T cells is helpful for predicting prognosis in initial pretreatment BM biopsy of DLBCL patients. (C) 2017 Elsevier Inc. All rights reserved.</P>

Frameshift mutations of chromosome cohesion-related genes SGOL1 and PDS5B in gastric and colorectal cancers with high microsatellite instability

Kim, M.S.,An, C.H.,Yoo, N.J.,Lee, S.H. W. B. Saunders Co ; Centrum Philadelphia 2013 Human pathology Vol.44 No.10

Cohesin is a protein complex that regulates chromatid cohesion and plays a role in preventing aneuploidy and maintaining chromosomal stability. SGOL1 encodes a cohesin protector, and PDS5B encodes a regulatory cohesion factor. Both SGOL1 and PDS5B are considered putative tumor suppressor genes. The aim of this study was to explore whether SGOL1 and PDS5B genes are mutated and expressionally altered in gastric and colorectal cancers. A genome database indicated that both genes possessed mononucleotide repeats in coding sequences, which could be mutation targets in cancers with microsatellite instability. We analyzed mutations in 91 gastric cancers and 100 colorectal cancers with high microsatellite instability or stable/low microsatellite instability by single-strand conformation polymorphism analysis and DNA sequencing. We also analyzed SGOL1 and PDS5B expression by immunohistochemistry. Overall, we found 21 SGOL1 frameshift mutations in 21 cases and 18 PDS5B frameshift mutations in 16 cases. SGOL1 and PDS5B frameshift mutations were detected in 26.6% and 20.3%, respectively, of high microsatellite instability but not in stable/low microsatellite instability (0/112). By immunohistochemistry, losses of SGOL1 and PDS5B were identified in 19% to 47% of the gastric and colorectal cancers irrespective of microsatellite instability status. The losses were more common in those with frameshift mutations or high microsatellite instability than those without mutations or high microsatellite instability. The data indicate that frameshift mutations of SGOL1 and PDS5B and the loss of their expression may be a feature of gastric and colorectal cancers with high microsatellite instability. In addition, the data suggest that these alterations might contribute to cancer pathogenesis by deregulating cohesin-related functions.

Synaptonemal complex protein 3 as a novel prognostic marker in early stage non-small cell lung cancer

Chung, J.Y.,Kitano, H.,Takikita, M.,Cho, H.,Noh, K.H.,Kim, T.W.,Ylaya, K.,Hanaoka, J.,Fukuoka, J.,Hewitt, S.M. W. B. Saunders Co ; Centrum Philadelphia 2013 Human pathology Vol.44 No.4

Synaptonemal complex protein 3 is a marker for cell transformation that has prognostic significance in various cancers. However, the prognostic significance of synaptonemal complex protein 3 has not been studied in non-small cell lung cancer. To investigate the potential correlation between synaptonemal complex protein 3 and various clinicopathologic parameters, we assessed the expression of synaptonemal complex protein 3 in archival tumor tissues from 258 patients with non-small cell lung cancer by immunohistochemical staining. By immunofluorescence, synaptonemal complex protein 3 was detected in both the cytoplasmic and nuclear fractions of NCI-H1299 cell. In tumor samples, synaptonemal complex protein 3 is detected as cytoplasmic expression pattern and observed in 50 clinical samples (19.4%) by immunohistochemical staining. Synaptonemal complex protein 3 expression was correlated with T status (P = .008), lymph node metastasis (P = .010), tumor types (P = .019), and pleural invasion (P = .005). In multivariate analysis of patients with early stage disease, increased synaptonemal complex protein 3 expression predicted worse overall survival in early stage (stage I and II) with pT1 status (P = .041). These results suggest that positive synaptonemal complex protein 3 expression is a portent of poor outcome and may be a potential biomarker in the early stages of the non-small cell lung cancer for survival and may provide clues in the identification of patients for adjuvant therapy.

PDGFB rearrangement in dermatofibrosarcoma protuberans: correlation with clinicopathologic characteristics and clinical implications

Ha, S.Y.,Lee, S.E.,Kwon, M.J.,Kim, Y.J.,Lee, E.H.,Seo, J.,Jang, K.T.,Lee, J.,Choi, Y.L. W. B. Saunders Co ; Centrum Philadelphia 2013 Human pathology Vol.44 No.7

Dermatofibrosarcoma protuberans (DFSP) is characterized genetically by the translocation t(17;22)(q22;q13), which creates a COL1A1/PDGFB fusion gene. The implications of this gene for the clinicopathologic features of the disease are not fully understood. Fifty-one cases of DFSP from 46 patients were reclassified as DFSP (n=29) and DFSP-fibrosarcomatous variant (DFSP-FS; n=22). Fluorescence in situ hybridization was performed using a dual-color break-apart probe to detect rearrangements involving PDGFB, and CD34 immunohistochemistry staining was done. The DFSP-FS was found in older patients, and the tumors were larger, with a smaller mean area of staining for CD34. PDGFB rearrangement was found in 45 cases (95.7%). The mean gene copy number was 3.82 (range 2.2-6.45) and was higher in DFSP-FS than in classic DFSP (4.54 vs. 3.47; P < .001). The PDGFB copy number showed a moderate positive correlation with the number of mitotic figures and tumor size. Patients undergoing wide excision or having no involvement of the resection margin had no relapses. These results suggest a role for COL1A1/PDGFB in sarcomatous change in DFSP over time. Detection of COL1A1/PDGFB rearrangement by fluorescence in situ hybridization is useful for confirmation of the diagnosis. Patients who present with metastatic DFSP-FS show less typical histologic findings and loss of CD34 staining, leaving PDGFB rearrangement as the preferred adjunctive method for diagnosis from small biopsies and for prediction of the value of imatinib therapy.

Galectin 1 expression is associated with tumor invasion and metastasis in stage IB to IIA cervical cancer

Kim, H.J.,Do, I.G.,Jeon, H.K.,Cho, Y.J.,Park, Y.A.,Choi, J.J.,Sung, C.O.,Lee, Y.Y.,Choi, C.H.,Kim, T.J.,Kim, B.G.,Lee, J.W.,Bae, D.S. W. B. Saunders Co ; Centrum Philadelphia 2013 Human pathology Vol.44 No.1

Galectin 1 is a 14-kd laminin-binding lectin involved in important biologic mechanisms of tumors, including neoplastic transformation, cell survival, angiogenesis, cell proliferation, and metastasis. In this study, we investigated the role of galectin 1 in cell survival and metastasis in cervical cancer. The expression of galectin 1 was determined in 73 formalin-fixed, paraffin-embedded cervical cancer tissues using an immunohistochemical method and compared with clinicopathologic risk factors for recurrence after surgery. To evaluate the role of galectin 1 in cell proliferation and invasion, we performed proliferation and invasion assays with galectin 1 small interfering RNA (siRNA) using cervical cancer cell lines, including HeLa and SiHa cells. Immunohistochemical analysis revealed that galectin 1 expression was found in most peritumoral stroma samples (72/73; 98.6%). Galectin 1 expression was significantly correlated with the depth of invasion in the cervix (P=.015) and lymph node metastasis (P=.045) on univariate analysis. When progression-free survival of all of the patients studied was analyzed based upon galectin 1 expression, galectin 1 expression was not correlated with progression-free survival (P=.32). Down-regulation of galectin 1 using small interfering RNA resulted in the inhibition of cell growth and proliferation of HeLa and SiHa cells. Moreover, the ability of cells to invade was significantly reduced by galectin 1 small interfering RNA. Our results revealed that high galectin 1 expression in peritumoral stroma was significantly correlated with depth of invasion in cervical lesions and lymph node metastasis of cervical cancer and that galectin 1 may be functionally involved in cell proliferation and invasion.

Overexpression of annexin A4 is associated with chemoresistance in papillary serous adenocarcinoma of the ovary

Choi, C.H.,Sung, C.O.,Kim, H.J.,Lee, Y.Y.,Song, S.Y.,Song, T.,Kim, J.,Kim, T.J.,Lee, J.W.,Bae, D.S.,Kim, B.G. W. B. Saunders Co ; Centrum Philadelphia 2013 Human pathology Vol.44 No.6

Annexin A4 study in ovarian cancer has been primarily focused on clear cell carcinoma, which exhibits strong resistance to chemotherapy. The aim of this study was to examine the expression and cellular localization of annexin A4 in serous ovarian carcinomas. We evaluated the expression of annexin A4 with real-time polymerase chain reaction in 40 ovarian serous carcinoma tissues. Furthermore, the distribution of the protein within the tumor was studied by immunohistochemistry in 70 epithelial ovarian carcinoma tissues. The levels of annexin A4 transcripts were higher in 14 chemoresistant tumors than those in 26 chemosensitive tumors (P = .013). Immunohistochemical expressions showed that nuclear expression was detected in 14 (20.0%) of 70 samples, and cytoplasmic expression was detected in 17 (24.3%) of 70 samples. The results showed that 35.7% of women with nuclear expression were resistant to platinum-based chemotherapy, whereas only 14.3% of women without expression were chemoresistant (P = .065). In addition, patients with nuclear staining had significantly shorter disease-free survival than did patients who showed negative staining. Multivariate proportional hazards model revealed that the stage and nuclear annexin A4 expression were independent prognostic factors (hazard ratios, 6.34 [P = .001] and 2.85 [P = .011], respectively). This study showed that overexpression and nuclear localization of annexin A4 are related to chemoresistance and poor survival in patients with serous papillary ovarian carcinomas. Future studies are required to develop new therapies targeting annexin A4 in patients with ovarian epithelial adenocarcinoma.

In situ analysis of HER2 mRNA in gastric carcinoma: comparison with fluorescence in situ hybridization, dual-color silver in situ hybridization, and immunohistochemistry

Kim, M.A.,Jung, J.E.,Lee, H.E.,Yang, H.K.,Kim, W.H. W. B. Saunders Co ; Centrum Philadelphia 2013 Human pathology Vol.44 No.4

The importance of anti-HER2 therapy has focused attention on the ability of clinical assays to correctly assign HER2 amplification status. In the present study, we evaluated HER2 mRNA expression using a new mRNA in situ detection technique called RNAscope in 211 cases of formalin-fixed, paraffin-embedded gastric carcinoma. In addition, we compared the results with the conventional methods of immunohistochemistry, fluorescence in situ hybridization, and dual-color silver in situ hybridization. RNA in situ hybridization (in situ hybridization) showed that 162 cases (76.8%) were score 0, 5 cases (2.4%) were score 1, 10 cases (4.7%) were score 2, 13 cases (6.2%) were score 3, and 21 cases (10.0%) were score 4. HER2 transcription levels were found to be significantly related to pT class, pN class, and tumor recurrence. mRNA expression was well correlated with protein overexpression and gene amplification; 20 cases out of 23 with DNA amplification showed a score of 4 in RNA in situ hybridization (P < .001). Three cases showed false negative and one case showed false positive results by in situ hybridization. More studies are needed to determine whether the in situ hybridization method can identify additional patients that may benefit from anti-HER2 therapy or exclude those who may be resistant to anti-HER2 therapy.

Lymph node metastasis in early gastric cancer: evaluation of a novel method for measuring submucosal invasion and development of a nodal predicting index

Kim, J.Y.,Kim, W.G.,Jeon, T.Y.,Kim, G.H.,Jeong, E.H.,Kim, D.H.,Park, D.Y.,Lauwers, G.Y. W. B. Saunders Co ; Centrum Philadelphia 2013 Human pathology Vol.44 No.12

After endoscopic resection of early gastric cancer (EGC), it is imperative to accurately determine whether follow-up surgery is indicated, since this technique is used as a first line of treatment. Herein, we developed a scoring system to indicate the risk of lymph node metastasis in submucosal EGC (smEGC), and present a novel method to measure depth of submucosal invasion. In our series, 15.9% of the smEGC presented with lymph node metastasis. A nodal prediction index, based on the variables extracted from the univariate analysis and defined as nodal prediction index = (2.128 x lymphovascular tumor emboli) + (1.083 x submucosal invasion width ≥0.75 cm) + (0.507 x submucosal invasion depth ≥1000 μm) + (0.515 x infiltrative growth pattern), yielded an area under the receiver operating characteristic curve of 0.809 (P =.000, 95% CI = 0.713-0.096) in a training group, and showed comparable result in validation group (0.886, P =.000, 95% CI = 0.796-0.977). Depth of invasion was statistically higher in the metastatic group when measured from the lowest point of an imaginary line in continuity with the adjacent muscularis mucosa to the point of deepest tumor penetration, but not when using the classic measurement method. The area under the receiver operating characteristic curve of the alternative measurement method was 0.652 (P =.013, 95% CI = 0.550-0.754) compared to 0.620 for the classic measurement method (P =.0480, 95% CI = 0.509-0.731). In deciding whether surgery is indicated after endoscopic submucosal dissection for smEGCs, we recommend to test our alternative method of measuring submucosal invasion and to evaluate our nodal prediction index as an adjunct tool.

P-cadherin expression in gastric carcinoma: its regulation mechanism and prognostic significance

Kim, M.A.,Jung, E.J.,Lee, H.S.,Lee, H.E.,Yang, H.K.,Oh, D.Y.,Bang, Y.J.,Kim, W.H. W. B. Saunders Co ; Centrum Philadelphia 2010 Human pathology Vol.41 No.6

P-cadherin is a member of the cadherin family and is expressed in several solid tumors. This molecule was recently highlighted with the development of a new targeted compound being studied in a clinical trial on solid tumors. In the present study, we examined the protein and messenger RNA (mRNA) expression status of P-cadherin and its promoter methylation in gastric carcinoma cell lines and tissues. Of the 10 cell lines, 4 were found to express P-cadherin protein and mRNA, and the P-cadherin gene was found to be hypomethylated in its promoter region in these cell lines. Nonneoplastic gastric mucosal tissues from gastric carcinoma patients were negative for P-cadherin protein evaluated by immunohistochemistry and Western blotting and had a methylated P-cadherin promoter region. In carcinoma tissues, 70.8% (749/1058) of cases showed P-cadherin protein expression, and P-cadherin positive cases had a well or moderately differentiated histology according to the World Health Organization classification, intestinal-type histology by Lauren classification, and an earlier pT class. Furthermore, patients with P-cadherin expressing tumors had a favorable prognosis by univariate and multivariate survival analyses. In addition, P-cadherin protein expression was found to be significantly correlated with promoter hypomethylation. In summary, P-cadherin is silenced in nonneoplastic gastric mucosa, and P-cadherin expressing tumors constitute a subset of gastric carcinoma with intestinal-type histology and a favorable prognosis. In addition, our findings suggest that P-cadherin promoter methylation underlies the regulation of its expression. These findings may aid patient selection and the interpretation of P-cadherin targeted therapy and clinical trial results.