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ABSTRACT: BACKGROUND: Ki67 is widely used in order to distinguish the "A" and "B" subtypes of luminal-type breast cancer. This study aimed to validate the prognostic value of adding p53 to Ki67 for characterizing luminal-type breast cancer. METHODS: Immunostaining for Ki67, p53, and the molecular markers HER2, CK5/6, CK14, EGFR, FOXA1, GATA3, and P-cadherin was examined hormone receptor (HR)-positive cancer tissues from 150 patients. The prognostic value of an immunohistochemical panel comprising Ki67 and p53 was compared with that of the single Ki67 labeling index (LI), and uni- and multivariate analyses were performed. RESULTS: Division of the patients based on the immunohistochemistry results into favorable- (low Ki67 LI, p53-negative) and unfavorable- (high Ki67 LI and/or p53-positive) phenotype groups yielded distinctly different Kaplan-Meier's curves of both disease-free (P<0.0001) and overall survival (P=0.0007). These differences were much more distinct than those between the corresponding low Ki67 LI vs. high Ki67LI curves. While the prognostic values of the other molecular markers were not significant, combined Ki67-p53 status was an independent prognostic factor by multivariate analysis. CONCLUSION: These data indicate that an immunohistochemical panel comprising Ki67 and p53 is a practical tool for management of patients with HR-positive breast cancer.
BMC Clinical Pathology 02/2013; 13(1):5.
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ABSTRACT: We examined the potential role of cell-cycle dysregulation in the development and histological progression of adult testicular germ cell tumors (TGCTs). Expressions of p27(Kip1) -interacting cell-cycle regulators (down-regulation of p27(Kip1) and overexpression of Skp2, Cks1, cyclin A, and cyclin E) and Ki-67 labeling index (LI) were immunohistochemically examined in histological components of 50 intratubular germ cell neoplasms, unclassified (IGCNUs); 74 seminomas; and 25 embryonal carcinomas, identified from 88 patients. Altered expression of p27(Kip1) , Skp2, Cks1, cyclin A, and cyclin E was observed in 20%, 12%, 16%, 10%, and 24% of IGCNUs; 26%, 36%, 27%, 89%, and 23% of seminomas; and 48%, 68%, 56%, 100%, and 60% of embryonal carcinomas, respectively. A significant difference in the frequency of Skp2 and cyclin A overexpression was observed between IGCNUs and seminomas. Significantly more frequent alterations of Skp2, Cks1, and cyclin E and p27(Kip1) were detected in embryonal carcinomas than in seminomas. Alterations of all cell-cycle regulators were significantly more frequent in embryonal carcinomas than in IGCNUs. The mean Ki-67 LI significantly increased from IGCNU (21.2%) through seminoma (34.7%) to embryonal carcinoma (54.2%). These results suggest that alterations of the p27(Kip1) -interacting cell-cycle regulators are common in TGCTs and may be involved in their histological progression.
Apmis 11/2012; 120(11):890-900. · 1.99 Impact Factor
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ABSTRACT: Recent studies indicate the clinical significance of the cellular localization of epidermal growth factor receptor (EGFR) in a variety of cancer types. Internalization of activated EGFR is reported to be closely associated with patient prognosis. This study investigated the clinical significance of the immunohistochemical localization of EGFR in patients with metastatic pancreatic cancers compared to those with surgically resected pancreatic cancers. Using 44 surgically resected primary pancreatic cancers and 40 primary or meta-static tumors from 20 autopsied patients with far advanced pancreatic cancers, the incidence of membranous and cytoplasmic EGFR overexpression was compared between primary tumors and far advanced tumors by immunohistochemistry using the Dako EGFR pharmDx™ kit, a global standard kit for EGFR assay. In the 44 surgically resected cancers, 13 (30%) exhibited membranous overexpression of EGFR, comprising 1 case (2%) with score 3+ and 12 cases (27%) with score 2+ and 10 (23%) exhibited cytoplasmic overexpression of EGFR. In the 40 tumors at a far advanced stage, the percentage of samples exhibiting positivity for membranous and cytoplasmic EGFR overexpression was 48% (19 of 40) comprising 7 (18%) with score 2+ and 12 (30%) with score 3+ and 33% (13 of 40), respectively. The far advanced tumors tended to show membranous and cytoplasmic EGFR overexpression more frequently than the surgically resected tumors, although the difference was not significant. These findings suggest that membranous and cytoplasmic overexpression of EGFR may be indicative of the potential aggressiveness of pancreatic cancers.
Experimental and therapeutic medicine 06/2012; 3(6):931-936.
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ABSTRACT: Ovarian clear-cell adenocarcinoma (CCA) is known to be a type of cancer in humans with a high frequency of expression of the mammalian target of rapamycin (mTOR), hypoxia-inducible factor-1 (HIF-1), and glucose transporter 1 (Glut1). In this study, we aimed to determine how these alterations contribute to tumor development of CCAs. Immunohistochemical expressions of phosphorylated-mTOR (p-mTOR), HIF-1α, and Glut1 were analyzed in 36 CCAs and 60 coexistent putative precursor lesions: 19 nonatypical and 16 atypical endometriotic lesions, and 11 benign and 14 borderline clear-cell adenofibroma (CCAF) components. Twenty-one cases with solitary endometriosis were also examined. The frequencies of immunopositivity for p-mTOR (in cytoplasm or nucleus), HIF-1α (in nucleus), and Glut1 increased in accordance with higher cytological atypia in the putative precursors: 58%, 5%, and 16% in the nonatypical endometriosis; 63%, 37%, and 50% in the atypical endometriosis; 77%, 95%, and 95% in the endometriosis-associated CCAs; 27%, 0%, and 0% in the benign-CCAF components; 64%, 79%, and 43% in the borderline CCAF components; and 71%, 100%, and 93% in the CCAF-associated CCAs, respectively. p-mTOR, HIF-1α (in the nucleus), and Glut1 were positive in 10%, 5%, and 19% of the solitary endometriosis, respectively. In the putative precursor lesions coexisting with CCA, a strong correlation in the expression between p-mTOR and HIF-1α and between HIF-1α and Glut1 was identified. Expressions of p-mTOR, HIF-1α, and Glut1 have already been evident in the putative precursor lesions of CCA, and these alterations cumulatively occur in the development of ovarian CCA.
International journal of gynecological pathology: official journal of the International Society of Gynecological Pathologists 04/2012; 31(3):254-63. · 2.07 Impact Factor
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ABSTRACT: Femoral artery aneurysms (FAAs) are very rare, and their natural history is not well understood. In this study, we sought to analyze the pathogenesis of inflammatory FAAs in interleukin-1 receptor antagonist-deficient (IL-1Ra(-/-)) B6 mice. Systolic arterial pressures and plasma lipid levels of IL-1Ra(-/-) mice and wild-type (WT) mice did not differ significantly. However, IL-1Ra(-/-) mice spontaneously developed fusiform FAAs. Real-time PCR of 9-month-old IL-1Ra(-/-) mice revealed significantly increased mRNA levels of IL-1β (6.6-fold), tumor necrosis factor-α (TNF-α) (12.4-fold), and matrix metalloproteinase-9 (6.0-fold) compared with WT mice. Histological analysis revealed numerous inflammatory cells around the FAAs in IL-1Ra(-/-) mice, and elastin staining showed destruction of both the internal and external elastic lamina in IL-1Ra(-/-) mice. Afterward, macrophage function was studied. After lipopolysaccharide (1 μg/mL) stimulation, IL-1Ra-deficient macrophages produced much higher levels of TNF-α than those from WT mice. Finally, we performed bone marrow cell transplantation. FAAs with many inflammatory cells in the adventitia were detected in several WT mice that received bone marrow cells from IL-1Ra(-/-) mice (44%), but not from WT mice (0%). Our study is the first to demonstrate that IL-1Ra deficiency in inflammatory cells disrupts immune system homeostasis and induces inflammatory FAAs in IL-1Ra(-/-) B6 mice. We believe that these mice will provide much information about the natural history and management of FAAs.
American Journal Of Pathology 03/2012; 180(3):1254-63. · 4.89 Impact Factor
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Sohei Yamamoto,
Hitoshi Tsuda,
Hideyuki Shimazaki,
Masashi Takano,
Tomoyuki Yoshikawa,
Kazuo Kuzuya,
Hiroshi Tsuda,
Hirohisa Kurachi,
Junzo Kigawa,
Yoshihiro Kikuchi,
Toru Sugiyama, Osamu Matsubara
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ABSTRACT: In this study, we aimed to develop a histological grading system for ovarian clear cell adenocarcinoma (CCA), based on the tumor growth architectures. Cases were defined as Group A if ≥90% of a tumor examined was composed of well-differentiated tubulocystic and/or papillary architectures; Group C if at least 10% of the tumor was composed of very poorly differentiated histology (i.e. solid masses or individual infiltrating tumor cells with no or little glandular/papillary differentiation); and tumors not corresponding to the first 2 descriptions were defined as Group B. The interobserver reproducibility and prognostic value of the assigned groups were analyzed for 159 CCAs from 5 institutions. The level of agreement in assigning the groups between 2 pathologists was 88.7% (=0.82). After consensus was reached, 46 (29%), 79 (50%), and 34 (21%) tumors were classified in Groups A, B, and C, respectively. In early-stage cases [International Federation of Gynecology and Obstetrics (FIGO) stage I-II], Group A tumors had significantly better outcomes (100% 5-yr survival) than Group B tumors (82% 5-yr survival, P=0.024 by log-rank test) or Group C tumors (56% 5-yr survival, P=0.00054 by log-rank test). Moreover, early-stage Group B tumors had significantly better outcomes than Group C tumors (P<0.001 by a generalized Wilcoxon test). In advanced cases (FIGO stage III-IV), Group A tumors had significantly better outcomes than Group C tumors (52% vs. 16% 5-yr survival, respectively, P=0.043). Group A and C tumors defined with our system were identified to have favorable and unfavorable prognostic factors, respectively, independent of the clinical stage of the disease and presence of residual tumors after the initial surgery. The proposed grouping system could divide patients with CCA into 3 subgroups with distinct prognostic indications, providing a 3-tier histological grading system for ovarian CCA.
International journal of gynecological pathology: official journal of the International Society of Gynecological Pathologists 03/2012; 31(2):116-24. · 2.07 Impact Factor
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ABSTRACT: Actinin-4, encoded by the ACTN4 gene located on chromosome 19q13.2, enhances cell motility by bundling the actin cytoskeleton. We assessed how ACTN4/actinin-4 alterations contribute to the tumorigenesis of ovarian clear-cell adenocarcinomas (CCAs).
Fluorescence in-situ hybridization analysis demonstrated that ACTN4 amplification (≥4 ACTN4 copies in ≥40% of cells) occurred in 27 (33%) of 81 CCAs and genomic gains of ACTN4 were associated strongly with immunohistochemical actinin-4 overexpression, poorly differentiated tumour histology and shorter patient survival (all P < 0.05). From the 27 ACTN4-amplified CCAs, 23 tumours with adjacent putative precursor lesions were selected and examined for ACTN4/actinin-4 alterations with respect to their intratumoral heterogeneity. In this selected cohort, none of the precursors lacking cytological atypia exhibited gains of ACTN4 or actinin-4 overexpression; 50% of the atypical endometrioses and 75% of the borderline CCAFs showed low-level gains of ACTN4 and actinin-4 overexpression, respectively. In 12 of 23 ACTN4-amplified CCAs, intratumoral heterogeneity for ACTN4 alterations was documented in carcinomatous components; the better differentiated carcinoma components exhibited fewer alterations than those with poorly differentiated histology.
Accumulative genomic gains of ACTN4, causing actinin-4 protein overexpression, drive the development and progression of ovarian CCAs with high-grade histology.
Histopathology 02/2012; 60(7):1073-83. · 3.08 Impact Factor
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ABSTRACT: Our previous study demonstrated that, among ovarian carcinomas, amplification of the MET gene and overexpression of MET specifically and commonly occur in clear-cell adenocarcinoma histology. This study was conducted to address how these alterations contribute to development and progression of this highly chemoresistant form of ovarian cancer. We histologically reviewed 21 previously described MET amplification-positive clear-cell adenocarcinoma cases, and selected 11 tumors with synchronous endometriosis and 2 tumors with adjacent clear-cell adenofibroma (CCAF) components. Using double in situ hybridization and immunohistochemistry, copy number alterations of the MET gene and levels of MET protein expression were analyzed in these putative precursor lesions and the corresponding invasive carcinoma components in this selected cohort. All of the non-atypical precursor lesions analyzed (ie, non-atypical endometrioses and the benign CCAFs) were negative for MET gain. However, low-level (≥3 MET copies in ≥10% and ≥4 MET copies in 10-40% of tumor cells) gain of MET was detected in 4 (40%) of the 10 atypical endometrioses and 1 of the 2 borderline CCAFs. Moreover, high-level (≥4 MET copies in ≥40% of tumor cells) gain of MET were detected in five (50%) of the atypical endometrioses. In 4 (31%) of the 13 cases enrolled, intratumoral heterogeneity for MET gain was documented in invasive carcinoma components, wherein all the relatively differentiated carcinoma components showed low-level gain of MET and all the corresponding poorly differentiated carcinomas showed high-level gain. The overall incidence of MET overexpression gradually increased from the precursors of non-atypical form (0%), through those of atypical form (67%) and the relatively differentiated carcinoma components (92%), to the poorly differentiated carcinoma components (100%). These results suggest that accumulative MET gene copy number alterations causing MET overexpression are associated with higher tumor grade and might drive the development and progression of the MET amplification-positive ovarian clear-cell adenocarcinoma.
Modern Pathology 01/2012; 25(1):122-30. · 4.79 Impact Factor
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ABSTRACT: ARID1A is a recently identified tumor suppressor gene that is mutated in ∼50% of ovarian clear-cell carcinomas. This mutation is associated with loss of ARID1A protein expression as assessed by immunohistochemistry. The present study aimed at determining the timing of the loss of ARID1A protein expression during the development of ovarian clear-cell carcinoma and assessing its relevance in correlation to PIK3CA gene mutations. A total of 42 clear-cell carcinoma cases with adjacent putative precursor lesions (endometriosis-associated carcinoma cases (n=28) and (clear-cell) adenofibroma-associated carcinoma cases (n=14)) were selected and subjected to immunohistochemical analysis for ARID1A protein expression and direct genomic DNA sequencing of exons 9 and 20 of the PIK3CA gene. ARID1A immunoreactivity was deficient in 17 (61%) of the 28 endometriosis-associated carcinomas and 6 (43%) of the 14 adenofibroma-associated carcinomas. Among the precursor lesions adjacent to the 23 ARID1A-deficient carcinomas, 86% of the non-atypical endometriosis (12 of 14) and 100% of the atypical endometriosis (14 of 14), benign (3 of 3), and borderline (6 of 6) clear-cell adenofibroma components were found to be ARID1A deficient. In contrast, in the 19 patients with ARID1A-intact carcinomas, all of the adjacent precursor lesions retained ARID1A expression regardless of their types and cytological atypia. Analysis of 22 solitary endometrioses and 10 endometrioses distant from ARID1A-deficient carcinomas showed that all of these lesions were diffusely immunoreactive for ARID1A. Among the 42 clear-cell carcinomas, somatic mutations of PIK3CA were detected in 17 (40%) tumors and majority (71%) of these were ARID1A-deficient carcinomas. These results suggest that loss of ARID1A protein expression occurs as a very early event in ovarian clear-cell carcinoma development, similar to the pattern of PIK3CA mutation recently reported by our group, and frequently coexists (not mutually exclusive) with PIK3CA mutations.
Modern Pathology 12/2011; 25(4):615-24. · 4.79 Impact Factor
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Manabu Kitagaki,
Kikuo Isoda,
Haruhiko Kamada,
Takayuki Kobayashi,
Shinichi Tsunoda,
Yasuo Tsutsumi,
Tomiharu Niida,
Takehiko Kujiraoka,
Norio Ishigami,
Miya Ishihara, Osamu Matsubara,
Fumitaka Ohsuzu,
Makoto Kikuchi
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ABSTRACT: Tumor necrosis factor receptor 1 (TNFR1) participates importantly in arterial inflammation in genetically altered mice; however it remains undetermined whether a selective TNFR1 antagonist inhibits arterial inflammation and intimal hyperplasia. This study aimed to determine the effect and mechanism of a novel TNFR1 antagonist in the suppression of arterial inflammation.
We investigated intimal hyperplasia in IL-1 receptor antagonist-deficient mice two weeks after inducing femoral artery injury in an external vascular cuff model. All mice received intraperitoneal injections of TNFR1 antagonist (PEG-R1antTNF) or normal saline twice daily for 14 days.
PEG-R1antTNF treatment yielded no adverse systemic effects, and we observed no significant differences in serum cholesterol or blood pressure in either group; however, selective PEG-R1antTNF treatment significantly reduced intimal hyperplasia (19,671±4,274 vs. 11,440±3,292 µm(2); p=0.001) and the intima/media ratio (1.86±0.43 vs. 1.34±0.36; p=0.029), compared with saline injection. Immunostaining revealed that PEG-R1antTNF inhibits Nuclear factor-κB (NF-κB), suppressing smooth muscle cell (SMC) proliferation and decreasing chemokine and adhesion molecule expression, and thus decreasing intimal hyperplasia and inflammation.
Our data suggest that PEG-R1antTNF suppresses SMC proliferation and inflammation by inhibiting NF-κB. This study highlights the potential therapeutic benefit of selective TNFR1 antagonist therapy in preventing intimal hyperplasia and arterial inflammation.
Journal of atherosclerosis and thrombosis 12/2011; 19(1):36-46. · 2.69 Impact Factor
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ABSTRACT: IκBNS regulates a subset of Toll-like receptor (TLR)-dependent genes including interleukin-6 (IL-6) by inhibiting nuclear factor-κB (NF-κB). IL-6 is an inflammatory biomarker for cardiovascular diseases. The aim of this study was to determine whether IκBNS changes arterial inflammation and intimal hyperplasia after vascular injury.
We investigated neointimal formation in IκBNS-deficient (IκBNS(-/-); C57BL/6 background) and wild-type (IκBNS(+/+)) mice 2 weeks after cuff injury. The mean intimal area and the intima/media ratio of IκBNS(-/-) mice increased 89% (8066 ± 1141 vs. 4267 ± 1095 μm(2); P = 0.027) and 100% (0.72 ± 0.13 vs. 0.36 ± 0.09; P = 0.032) compared with IκBNS(+/+) mice. We observed significant up-regulation of TLR4 in injured arteries of IκBNS(-/-) mice. NF-κB activity in the intima of IκBNS(-/-) mice was 5.1-fold higher (P = 0.008) compared with IκBNS(+/+) mice at 7 days post-injury. IL-6 mRNA levels in injured arteries of IκBNS(-/-) mice were 1.8-fold higher (P = 0.002) compared with those of IκBNS(+/+) mice at 3 days post-injury. Vascular smooth muscle cells from IκBNS(-/-) mice showed a significant increase in cell migration compared with those from IκBNS(+/+) mice after IL-6 stimulation in the scratch-wound healing assay. Furthermore, anti-mouse IL-6 receptor antibody (MR16-1) significantly reduced intimal hyperplasia compared with control IgG injection in IκBNS(-/-) mice. These findings suggest that IL-6 participates in the development of neointimal hyperplasia after vascular injury in IκBNS(-/-) mice.
IκBNS down-regulates TLR4 expression, NF-κB activity, and IL-6 production after vascular injury. IκBNS might suppress intimal hyperplasia caused by vascular inflammation such as atherosclerosis, and restenosis after angioplasty.
Cardiovascular research 12/2011; 93(2):371-9. · 5.80 Impact Factor
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ABSTRACT: Somatic mutations of PIK3CA and ARID1A are the most common genetic alterations observed in ovarian clear cell adenocarcinomas (CCA). In a previous report, we showed that PIK3CA gene mutations and loss of ARID1A expression occur early during the development of CCA. In the present study, using direct genomic DNA sequencing for exons 9 and 20 of PIK3CA and immunohistochemistry for ARID1A protein expression, we analyzed the association of these molecular alterations with various clinicopathological parameters in a total of 90 cases of primary ovarian CCA, including 42 previously examined cases. The presence of PIK3CA mutations, identified in 34 (39%) of the 88 informative cases, was significantly associated with a grossly cystic tumor, the presence of adjacent endometriosis, prominent papillary architecture of tumor growth, the presence of hyalinized and mucoid stroma, and the absence of clear cell adenofibroma components (P < 0.05, each). There was no significant association of PIK3CA mutations with other clinical variables, such as age, clinical stage, or clinical outcome of the patients. The intensity of immunoreactivity for ARID1A was assigned as negative, weakly positive, and strongly positive in 44%, 22%, and 33% of tumors, respectively. Compared to tumors immunoreactive for ARID1A, ARID1A-negative tumors were significantly associated with the presence of adjacent endometriosis (P = 0.025), but there was no statistically supported association with other examined clinicopathological parameters. Compared with CCAs strongly positive for ARID1A, CCAs negative for ARID1A more frequently harbor PIK3CA mutations (P = 0.013). PIK3CA gene mutations and ARID1A immunohistochemistry lacked prognostic significance. These data further support the idea that these molecular alterations occur as very early events during tumor development of ovarian CCA.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 11/2011; 460(1):77-87. · 2.49 Impact Factor
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Takashi Takeshita,
Hitoshi Tsuda,
Tomoyuki Moriya,
Tamio Yamasaki,
Hideki Asakawa,
Shigeto Ueda,
Kazuhiko Sato,
Shinsuke Aida,
Seiichi Tamai, Osamu Matsubara,
Kazuo Hase,
Junji Yamamoto
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ABSTRACT: This study was designed to clarify retrospectively the clinical significance of occult metastases in both sentinel lymph nodes (SLNs) and non-SLNs in patients with early breast cancer.
A total of 109 (80.1%) of 136 women with breast cancer who had consecutively undergone SLN biopsy (176 lymph nodes) were intraoperatively diagnosed as being free of SLN involvement. SLNs were routinely examined by hematoxylin-eosin (HE) staining of one to four frozen sections per node. Sixty-four (58.7%) of these patients also underwent backup axillary dissection. For the 109 patients, all formalin-fixed, paraffin-embedded tissues of SLNs and non-SLNs were entirely cut into 5-μm-thick sections. All serial step sections at 85-μm intervals were stained with HE and immunohistochemistry with pancytokeratin.
Occult metastases in SLNs and non-SLNs were detected in 25 (23%) and 10 (16%) patients, respectively. The presence of occult SLN metastasis was marginally correlated with T-factor (P=0.06), and predictive factors for occult non-SLN metastases were tumor nuclear grade (P=0.039). With a median follow-up of 86 months, disease-free survival (P=0.3) or overall survival (P=0.8) did not differ between the patients with and without occult SLN metastases, regardless of backup axillary lymph node dissection.
SLN or non-SLN occult metastases detected by serial step sections at 85-μm intervals did not have significant prognostic implications.
Annals of Surgical Oncology 10/2011; 19(4):1160-6. · 4.17 Impact Factor
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Sohei Yamamoto,
Hitoshi Tsuda,
Hideyuki Shimazaki,
Masashi Takano,
Tomoyuki Yoshikawa,
Kazuo Kuzuya,
Hiroshi Tsuda,
Hirohisa Kurachi,
Junzo Kigawa,
Yoshihiro Kikuchi,
Toru Sugiyama, Osamu Matsubara
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ABSTRACT: In this study, we aimed to determine whether the presence of poorly differentiated histologic components in ovarian clear cell adenocarcinoma (CCA) affects patient prognosis. Pathologic slides from 159 patients with CCA were studied, and the tumors were classified as Por(+) in the event of poorly differentiated histology; that is, if solid masses or cords, or individual infiltrating tumor cells with little or no glandular/papillary differentiation were present in >5% of the tumor area examined. All other tumors were classified as Por(-). The prognostic value and interobserver reproducibility of this assignment were analyzed. The agreement level in the assignment between 2 pathologists was 93.7% (κ=0.86). After a consensus was reached, 53 (33%) and 106 (67%) tumors were classified as Por(+) and Por(-), respectively. Patients with Por(+) tumors showed a significantly worse outcome than those with Por(-) tumors, both in the early stages (stages I/II, 5-year survival rate 53.9% vs. 96.3%, P<0.0001 by log-rank test) and advanced stages (stages III/IV, 5-year survival rate 26.5% vs. 49.2%, P<0.001 by generalized Wilcoxon test). Por(-) tumors showed an effective response to postoperative platinum-based first-line chemotherapy more frequently compared with Por(+) tumors (48% vs. 14%, P=0.042). The Por(+) tumor was found to be an independent prognostic factor for survival irrespective of the clinical stage or presence of residual tumor after the initial surgery. These results suggest that the tumor with a poorly differentiated histology is an adverse prognostic subgroup in ovarian CCA. On the basis of the prognostic impact and interobserver reproducibility, the present binary classification system for CCAs was deemed to be highly superior to the compared conventional histologic grading system.
International journal of gynecological pathology: official journal of the International Society of Gynecological Pathologists 09/2011; 30(5):431-41. · 2.07 Impact Factor
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ABSTRACT: Clear cell adenocarcinoma (CCA), a highly lethal histological subtype of ovarian carcinoma, is a type of human cancer with a high frequency of activating mutations in the PIK3CA gene. In this study, we aimed to determine how these mutations contribute to tumour development of CCAs. Exons 9 and 20 of the PIK3CA gene were analysed by direct genomic DNA sequencing of 23 CCAs with synchronous putative precursor lesions (ie endometriosis adjacent to carcinoma, with or without cytological atypia) and their mutational statuses were compared. Somatic mutations of the PIK3CA gene were detected in 10/23 (43%) carcinomas and in all cases the type of mutation was H1047R in the kinase domain. The identical H1047R mutation was also detected in the coexisting endometriotic epithelium, adjacent to the CCAs, in nine of ten (90%) cases. Moreover, in six of the nine lesions, the H1047R mutation was identified even in the endometrioses lacking cytological atypia. These findings provide evidence that mutations of the PIK3CA gene occur in the putative precursor lesions of CCA, strongly suggesting that they are very early events in tumourigenesis, probably initiating the malignant transformation of endometriosis. A specific kinase inhibitor to mutated PIK3CA may potentially be an effective therapeutic reagent against these carcinomas.
The Journal of Pathology 05/2011; 225(2):189-94. · 6.32 Impact Factor
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ABSTRACT: The aim of this study was to assess protein overexpression and gene copy number alterations of MET in ovarian clear-cell adenocarcinoma, and to assess its potential as a novel therapeutic target. Ninety cases of clear-cell adenocarcinoma were analyzed for MET protein overexpression and copy number alterations of the MET gene by immunohistochemistry and brightfield double in situ hybridization, respectively. In addition, 101 cases of the non-clear-cell type ovarian carcinomas at advanced stages were also evaluated for comparison. MET overexpression was assigned when complete membrane staining with moderate or strong intensity was observed in at least 10% of the tumor cells examined. Double in situ hybridization was determined as positive when the tumor exhibited high-level polysomy (≥4 copies in ≥40% of tumor cells) or MET gene amplification. MET overexpression was detected in 20 of 90 clear-cell adenocarcinomas (22%) and none of 111 non-clear-cell type ovarian carcinomas. Double in situ hybridization was positive in 21 of 89 informative clear-cell adenocarcinomas (24%) and only 3 non-clear-cell type ovarian carcinomas (3%). In the whole population, true amplification of the MET gene was detected only in the clear-cell adenocarcinoma histology (five cases, 6%). In clear-cell adenocarcinomas, double in situ hybridization positivity was highly correlated with the presence of MET overexpression and a poorly differentiated histology of tumors (P=0.0105 and 0.00038, respectively). For the patients with clear-cell adenocarcinomas, MET overexpression, as well as advanced clinical stage and the poorly differentiated histology of tumors, was identified as an independent unfavorable prognostic factor for overall survival. In conclusion, among ovarian carcinomas, the amplification of the MET proto-oncogene is highly selective and commonly occurs in clear-cell adenocarcinoma. MET could serve as a biomarker for the prognostication of patients with clear-cell adenocarcinoma and tumor progression, and has potential as a novel therapeutic target for this carcinoma.
Modern Pathology 04/2011; 24(8):1146-55. · 4.79 Impact Factor
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ABSTRACT: Little is known about the pathologic significance of epidermal growth factor receptor (EGFR) expression in malignant testicular germ cell tumors (TGCTs) in adults. From the primary tumor sites of a cohort of 110 TGCT cases, we obtained 209 histologically distinct components: 53 intratubular germ cell neoplasia unclassified (IGCNU) lesions, 83 seminomas (66 pure-form seminomas and 17 seminoma components in the mixed-form with nonseminomatous TGCTs), 27 embryonal carcinomas, eight choriocarcinomas, 18 yolk sac tumors, and 20 immature teratomas. Samples were analyzed for expression of EGFR protein and EGFR gene amplification by immunohistochemistry and fluorescence in situ hybridization (FISH), respectively. Overexpression of the EGFR protein was detected in 28% of seminomas (27% in the pure-form and 29% in the mixed-form), 11% of embryonal carcinomas, 88% of choriocarcinomas, 44% of yolk sac tumors, and none of the IGCNU lesions or immature teratomas. A higher copy number (≥4 copies per cell) and amplification of the EGFR gene were detected in 20% and 10% of seminomas, 13% and 0% of embryonal carcinomas, 71% and 60% of choriocarcinomas, 15% and 8% of yolk sac tumors, and none of the IGCNU lesions or immature teratomas, respectively. Both higher copy number and amplification of the EGFR gene were positively correlated with immunohistochemical overexpression of EGFR protein (each P < 0.0001). These results suggest that overexpression of EGFR protein and increased copy number or amplification of the EGFR gene occur relatively frequently in primary TGCTs, and may play roles in the formation of invasive cancer and in the progression, especially morphological evolution, of tumors.
Cancer Science 09/2010; 101(9):1970-6. · 3.33 Impact Factor
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ABSTRACT: We report a case of massive intra-abdominal undifferentiated carcinoma derived from a tiny well-differentiated endometrioid adenocarcinoma of the ovary. The patient, a 56-year-old woman, who presented with a large intra-abdominal mass, underwent cytoreductive surgery with hysterectomy and bilateral salpingo-oophorectomy. Macroscopically, the intra-abdominal mass was composed of fragile and solid tumor components with extensive necro-hemorrhagic areas, mimicking a primary peritoneal tumor. Both ovaries were apparently normal in size, but a cut section of the right ovary revealed a 2-cm solid and cystic tumor showing focal rupture to the peritoneal surface. The intra-abdominal tumor consisted of pleomorphic cells without specific differentiation, showing diffuse sheet-like proliferation. The right ovarian tumor was a histologically well-differentiated endometrioid adenocarcinoma. Both the intra-abdominal undifferentiated tumor and the ovarian adenocarcinoma cells were immunohistochemically positive for keratin AE1/3, Ber-EP4, and CD10. Epithelial membrane antigen was positive only in the ovarian adenocarcinoma component, and vimentin was diffusely positive only in the intra-abdominal undifferentiated tumor component. Calretinin was negative in both tumor components. Allelotype analysis using 24 polymorphic markers located on 12 chromosomal arms showed that the intra-abdominal undifferentiated carcinoma and ovarian adenocarcinoma components had a high concordance rate (88%) of allelic patterns including identical allelic loss patterns at 7 chromosomal loci, suggesting a common genetic lineage. These data suggest that ovarian endometrioid adenocarcinoma, even when small in size, can give rise to a massive undifferentiated carcinoma filling the peritoneal cavity.
International journal of gynecological pathology: official journal of the International Society of Gynecological Pathologists 07/2010; 29(4):321-7. · 2.07 Impact Factor
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ABSTRACT: To identify the key cell-cycle dysregulations in the development of endometriosis-associated ovarian clear cell adenocarcinoma (CCA).
Expression of p27(Kip1)-interacting cell-cycle regulators, such as p27(Kip1) itself, Skp2, cyclin-dependent kinase subunit 1 (Cks1), cyclin A and cyclin E, and Ki67 labelling index (LI), were analysed by immunohistochemistry in 23 CCAs with 36 endometriotic or atypical endometriotic lesions adjacent to CCA from a cohort of 23 patients, and in 31 cases of solitary endometriosis. The cell-cycle regulators examined were overexpressed (Skp2, Cks1, cyclin A and cyclin E; P < 0.01, each) or down-regulated (p27(Kip1), P = 0.044) significantly more frequently in the CCAs than in the adjacent endometriosis. The frequency of Skp2 overexpression was significantly higher in atypical endometriosis than in endometriosis, and the frequency of Skp2 and cyclin A overexpression was significantly higher in CCA than in atypical endometriosis (P < 0.01, each). Mean Ki67 LI increased from endometriosis (8.4%) through atypical endometriosis (21.4%) to CCA (46.9%), with statistical significance between each component (P < 0.01, each). The frequency of cell-cycle regulator expression and mean Ki67 LIs were not significantly different between solitary endometriosis and endometriosis adjacent to CCA.
Alteration of the p27(Kip1)-interacting cell-cycle regulators appeared strongly involved in the progression of endometriosis-associated ovarian clear cell carcinogenesis through increasing cell proliferative activity.
Histopathology 05/2010; 56(6):740-9. · 3.08 Impact Factor
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ABSTRACT: Chemokine receptor CXCR4 is known to be crucially involved in tumor progression, but the role of its ligand, stromal cell-derived factor-1 (SDF-1), remains unclear. The present study was conducted to clarify the clinicopathological and prognostic impact of SDF-1 expression in invasive breast cancers. Expression of SDF-1 mRNA and protein was examined in five breast cancer cell lines with or without estradiol treatment. In 52 surgically resected breast cancers, the level of SDF-1 mRNA in frozen samples and the pattern of SDF-1 protein immunoreactivity in formalin-fixed paraffin-embedded tissue sections were compared. In another cohort of 223 breast cancers, the correlation between SDF-1 immunoreactivity and clinicopathological parameters was examined using a tissue microarray. Estradiol treatment markedly increased the expression of SDF-1 mRNA and protein in the estrogen receptor (ER)-positive cell lines, MCF-7 and T47D. Among the 52 resected breast cancers, those with a cytoplasmic-dominant pattern of SDF-1 expression showed higher SDF-1 mRNA levels (median 27.4) than those with a membrane-dominant or negative pattern (median 13.6, P = 0.0017). Accordingly, the cytoplasmic-dominant pattern was defined as "high SDF-1 expression," and other patterns were defined as "low SDF-1 expression." Among the cohort of 223 tumors, "high SDF-1 expression" was detected in 158 (70.9%) and was significantly correlated with ER positivity (P < 0.0001), HER2 negativity (P = 0.021), and lower grade (P < 0.0001). Univariate analysis demonstrated that "high SDF-1 expression" was a significant indicator of better clinical outcome in both the entire patient cohort (P = 0.017) and the 133 patients with ER-positive tumors (P = 0.036), but not in the 90 patients with ER-negative tumors. Multivariate analysis showed that SDF-1 status was an independent factor related to overall survival in patients with ER-positive tumors (P = 0.046). SDF-1 status is a significant prognostic factor and may be clinically useful for assigning adjuvant therapy to patients with ER-positive invasive breast cancers.
Breast Cancer Research and Treatment 12/2009; 123(3):733-45. · 4.43 Impact Factor
