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ABSTRACT: Lymphangiomas are commonly regarded as vascular malformations during embryonic development rather than as true neoplasms. VEGF-C and VEGFR-3 are known to be active in the formation of lymphangiomas. However, the significance of the disorders seems to be obscured by confusing different entities. In 114 lymphangiomas, we investigated the clinicopathological features and the expression of VEGF-C and VEGFR-3. The age of patients with lymphangioma circumscriptum or intraabdominal lymphangioma was significantly higher than in patients with cavernous lymphangioma and in patients with cystic hygroma. In cavernous lymphangioma, the age of female patients was significantly higher than in male patients. Five adult cystic hygromas were identified. VEGF-C was detected in 21 of 58 (36%) cavernous lymphangiomas, ten of 28 (36%) cystic hygromas, 0 of 12 (0%) lymphangioma circumscriptum, and four of ten (40%) intraabdominal lymphangiomas. VEGFR-3 was detected in 43 of 58 (72%) cavernous lymphangiomas, 20 of 28 (71%) cystic hygromas, six of 12 (50%) lymphangiomas circumscriptum, and seven of ten (70%) intraabdominal lymphangiomas. VEGF-C was absent from superficial lymphangiomas associated with cavernous lymphangiomas. In typical cases of cavernous lymphangioma, VEGF-C was strongly expressed, suggesting that these cases possessed proliferative activity. In cystic hygroma and intraabdominal lymphangioma, VEGF-C was limited in its distribution. Superficial lymphangiomas more likely represent from peripheral lymphatic dilatation rather than due to growth factor.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 02/2009; 454(3):317-25. · 2.49 Impact Factor
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ABSTRACT: Various immunohistochemical studies have been performed regarding intrahepatic cholangiocarcinoma (ICC), including the cell cycle-related proteins (p27, cyclin D1, 14-3-3sigma, p53, cyclin B1 and Ki-67), the proto-oncogenes (c-erbB-2 and c-Met), the extracellular matrix proteins (tenascin and laminin) and others (beta-catenin, epidermal growth factor receptor, osteopontin, aquaporin 1, MUC5AC and fascin). Nevertheless, none of these have been proven to be a predictive power of the prognosis with high specificity and sensitivity for ICC.
Sixty-one patients with ICC were selected and ICC specimens were immunohistochemically stained with the above 16 markers, as previously reported. Results: The immunoreactivity of osteopontin, tenascin and Ki-67 divided the patients with ICC into 4 subgroups by the survival tree model. There was a significant relationship between the location of the tumor, TNM classification, histological differentiation, tumor size, lymphatic permeation, perineural invasion, lymph node metastasis, intrahepatic metastasis and viral infection among the 4 subgroups. In addition, there was a significant difference in survival among the 4 subgroups.
In this study, the subgrouping by the survival tree model might be helpful for predicting the patients' prognosis in ICC.
Oncology 02/2009; 76(4):293-300. · 2.27 Impact Factor
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Fukuoka igaku zasshi = Hukuoka acta medica 02/2009; 100(1):13-25.
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ABSTRACT: Metanephric adenoma is the most commonly occurring member of the metanephric tumor family, which also includes metanephric adenofibroma and metanephric stromal tumor. According to the World Health Organization classification, however, it is not commonly multifocal. Reported herein is the case of a 9-year-old boy with multifocal metanephric adenoma. Histologically, surgical sections showed multifocal proliferation of small rounded and uniform cells with smooth nuclear contours, scant pale-staining cytoplasm, dark-staining nuclei, and inconspicuous nucleoli: the cells were arranged in sheets and acinal, ductal, glomeruloid, and papillary structures. On immunohistochemistry the tumor cells were positive for vimentin, cytokeratins (CAM5.2, AE1/AE3, and CK18), and WT1, but negative for cytokeratin 7 (CK7) and epithelial membrane antigen (EMA). The Ki-67 labeling index was <1%. In addition, cytogenetic analysis indicated a normal karyotype (46XY). Other histologically similar tumors are papillary renal cell carcinoma and nephroblastoma, and it is necessary to distinguish metanephric adenoma from those tumors because of malignancy. In contrast to those tumors, metanephric adenoma has inconspicuous nucleoli, loss of CK7 and EMA expression, and no mitotic figures. Thus, the histological and immunohistochemical features of the present case were compatible with metanephric adenoma.
Pathology International 01/2009; 59(1):49-52. · 1.62 Impact Factor
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ABSTRACT: In the present paper, recent advances in the molecular pathology of soft tissue sarcomas (STS) and the implications for their prognostic value are reviewed, and the potential targets of molecular therapy are discussed. According to the molecular genetic aspect, STS are divided into two groups: chromosome translocation-associated sarcomas and sarcomas without specific translocation. In the former group,specific fusion transcripts, such as SS18–SSX, EWS–FLI1, and PAX3–FKHR, could be detected in synovial sarcoma, Ewing's sarcoma and primitive neuroectodermal tumor, and alveolar rhabdomyosarcoma,respectively. The direct or indirect interactions between these fusion transcripts and cell cycle regulators have been elucidated by several investigators. Therefore, these fusion transcripts are promising candidates as molecular targets. As evaluated in carcinomas,alterations of several tumor-suppressor genes and adhesion molecules and overexpression of growth factors and their receptors have been extensively assessed in STS. In mixed-type STS, epidermal growth factor receptor overexpression was associated with decreased overall survival, suggesting the beneficial role of epidermal growth factor receptor inhibitors in STS. In malignant rhabdoid tumor and epithelioid sarcoma, frequent alteration of the SMARCB1/INI1 tumor-suppressor gene and the loss of its protein have been demonstrated, indicating that this molecule could be an effective target of these sarcomas. In sarcomas with epithelioid differentiation,such as synovial sarcoma and epithelioid sarcoma, overexpression of dysadherin, which downregulates E-cadherin expression, was a poor prognostic factor. In conclusion, further studies are necessary to search for effective and specific molecules for the inhibition of tumor growth in each type of STS, especially in sarcomas without specific translocation.
Cancer Science 01/2009; 100(2):200-8. · 3.33 Impact Factor
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ABSTRACT: Ovarian mature cystic teratomas (MCT) uncommonly undergo malignant transformation to squamous cell carcinoma (SCC). While alterations in the p53 tumor suppressor gene and protein have been shown, few studies have analyzed other molecular changes leading to this malignant conversion. The purpose of the present study was to investigate 21 samples of SCC arising in MCT for altered expression in known p53- and p16/Rb-dependent cell cycle regulatory proteins, and the association between their expression and cellular proliferation and histological features. Overexpression of the p53 protein was observed in 14 SCC (67%), while four (19%) had point mutations in the p53 gene. Reduced expression of the p16 protein was observed in 18 SCC (86%), while p16 gene alterations (hypermethylation (29%) and point mutation (33%)) were found in 11 (52%). Furthermore, a statistically significant correlation was observed between p53 and Rb overexpression (P=0.0010), and the overexpression of both p53 and Rb was respectively significantly correlated with increased cellular proliferation. The results indicate that alterations in both the p53 and p16-Rb pathways are associated with SCC arising in MCT.
Pathology International 01/2009; 58(12):757-64. · 1.62 Impact Factor
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ABSTRACT: Six cases of Bednaf tumor were analyzed clinicopatho-logically along with a review of 39 published cases. The findings were then compared with data on 44 cases of ordinary dermatofibrosarcoma protuberans (DFSP) obtained from our files. The clinical manifestations of the patients and the anatomic locations of the tumors were similar between the two categories, but the rate of recurrence was lower in cases of Bednar tumor. The histologic pattern of Bednar tumor was indistinguishable from ordinary DFSP except for scattered melanosome containing cells. Ultrastructural and immunohistochemical examinations showed no evidence of neuroectodermal differentiation of dominant spindle shaped cells in Bednaf tumor, supporting a fibroblastic line of differentiation. The origin and pathogenesis of the melanosome containing cells were considered. These cells failed to react with HNIB 45, a melanoma specific antibody, and the large majority of melanosomes present were mature or at Stage IV, plus a few immature ones at Stage II. These pigmented cells do not appear to be neoplastic, and cannot be used as proof to indicate that Bednar tumor is a neuroectodermal neoplasm. Acta Pathol Jpn 40: 744-754, 1990.
Pathology International 12/2008; 40(10):744 - 754. · 1.62 Impact Factor
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ABSTRACT: This clinicopathologic study concerns 21 patients with myositis ossificans, whose ages ranged from 7 to 81 years (average, 40.3 years). The lesions were located in the thigh (10 cases), upper arm (6 cases), and other sites (5 cases). In all patients the lesion was solitary, and in all but one, it was seen within the muscle. Histologically, the lesions exhibited a wide range of histologic features with different amounts of immature fibroblastic cells, osteoid, cartilage, and young or mature bone accompanied by fibrous connective tissue. They could be classified into three types according to the predominant or most striking histologic features. Type I (6 cases) was characterized by highly cellular areas with islands of osteoid, having occasionally been confused with extraskeletal osteogenic sarcoma. Type II lesions (8 cases) consisted mainly of osteoid and young bone rimmed by osteoblasts, in the occasional presence of cellular areas. Type III lesions (7 cases) were made up almost wholly of mature bone and cartilage surrounded invariably by dense fibrous connective tissue. Prognosis was excellent in 17 patients for whom follow-up information was available. Difference between Type I myositis ossificans and extraskeletal osteogenic sarcoma was briefly described, following an additional review of three cases of the latter.
Pathology International 12/2008; 35(5):1109 - 1122. · 1.62 Impact Factor
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ABSTRACT: A clinicopathologic study of 18 cases of fibroma of tendon sheath included an immunohistochemical survey of 7 cases and an electron-microscopic examination of one. The age of the patients ranged from 1 to 77 years, with a median of 34 years. The most common site of the tumors was the finger (7 cases), followed by the knee (3), the hand (2), and the foot (2). The median greatest diameter of the tumor was 2 cm. The tumors were attached or closely related to the tendon or tendon sheath, and usually well circumscribed, and multinodular or tabulated. Microscopically, spindle or stellate tumor cells with fuchsinophilic cytoplasm were embedded in a dense fibrous stroma with scattered small blood vessels. Most tumor cells have immunoreaction products for actin in the cytoplasm with accentuation along the cell membrane. Ultrastructurally, many of the tumor cells proved to be myofibroblasts.
Pathology International 12/2008; 35(5):1099 - 1107. · 1.62 Impact Factor
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ABSTRACT: This clinicopathologic study concerns 42 cases of synovial sarcoma (13 biphasic and 29 monophasic), including electron-microscopic examination of five cases, among 753 cases of soft tissue sarcomas. The age of the patients ranged from 9 to 70 years, with a median of 35 years. Tumors occurred most commonly on the extremities with 31 on the lower extremities. Histologically the monophasic type on this occasion included tumors with focal or minimal biphasic differentiation (9 cases) in addition to totally monophasic tumor (20 cases). A comparative light microscopy revealed otherwise inappreciable differences in histologic characteristics between the monophasic synovial sarcoma and certain other spindle cell sarcomas. Ultrastructurally, the cells composing the spindle-cell area of the synovial sarcoma contained basically the same elements as did the cells forming epithelioid or gland-like structures, and as the cells in the areas of gradual transitions of the two. One exception was that the cells lining the gland-like lumina had microvillar projections. Characteristic secretory-like granules, similar to those seen in the synovial type B cell of the normal human synovium, were evident in all five cases studied electron microscopically. In contrast to the findings of others, patients with monophasic tumors had a better prognosis, 58% surviving 5 years compared to 36% for those with biphasic tumors.
Pathology International 12/2008; 33(1):23 - 36. · 1.62 Impact Factor
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ABSTRACT: This clinicopathologic study concerns 8 cases of extraskeletal Ewing's sarcoma, including electron-microscopic examination of one case. In three patients, autopsy was done. The age of the patients ranged from 12 to 31 years with a median of 16 years. The tumors mainly arose in the soft tissues of the trunk (4 cases) and the lower extremity (3 cases). Histologically, they were made up of closely packed uniform, small cells, arranged in sheets separated by strands of fibrovascular stroma. The tumor cells had round to oval nuclei with finely dispersed chromatin and scanty ill-defined cytoplasm almost invariably containing a fair amount of diastase-digested PAS-positive material. Ultra-structurally, the tumor cells were composed principally of undifferentiated mesenchymal cells, and contained prominent pools of glycogen in the cytoplasm. Aggregates of intermediate filaments were seen in a perinuclear location. These light- and electron-microscopic findings are indistinguishable from those of Ewing's sarcoma of the bone. Differential points from other soft-tissue small round cell sarcomas such as malignant neuroepithelioma (peripheral neuroblastoma), embryonal or alveolar rhabdomyosarcoma were briefly discussed.
Pathology International 12/2008; 35(5):1087 - 1098. · 1.62 Impact Factor
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ABSTRACT: Multiple gastrointestinal stromal tumors (GISTs) rarely occur in patients with neurofibromatosis type 1 (NF-1). In contrast to sporadic GISTs characterized by frequent allelic losses of 1p, 14q and 22q and mutations of KIT or PDGFRA gene with the activation of the downstream RAS-MAPK pathway, the molecular pathogenetic mechanisms of NF-1-related GISTs (NF-1 GISTs) remain unclear.
Thirty-one GISTs and two foci of Cajal cell hyperplasia (CCH) were obtained from five patients with NF-1. Phospho-MAPK p44/42 expression was examined by immunohistochemical stain. KIT and PDGFRA mutations were analyzed by PCR and direct sequencing methods. Loss of heterozygosity (LOH) was analyzed by PCR-based method with microsatellite markers on 14q and 22q.
Immunohistochemical expression of phospho-MAPK p44/42 was frequently found in NF-1 GISTs (23/25 cases, 92%). Neither the KIT nor PDGFRA mutation was detected in 25 NF-1 GISTs and 2 CCH. Among the informative cases, LOH was seen at 14q and 22q in 7/8 (87.5%) and 5/12 (41.7%) NF-1 GISTs, respectively. Such LOH was not detected in CCH, whereas it was detected in small GIST less than 1 cm in diameter.
Our results support that KIT and PDGFRA mutations are very rare events in NF-1 GIST. Rather, activation of the Ras-MAPK pathway associated with the inactivation of the NF1 gene may play an important role in the cell proliferation of NF-1 GIST. Additionally, LOH at 14q and 22q may contribute to the relatively early phase of tumor development of NF-1 GIST.
Journal of Cancer Research and Clinical Oncology 12/2008; 135(6):791-8. · 2.56 Impact Factor
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ABSTRACT: Melanoma is commonly associated with multi-organ metastasis, and bone is a frequent metastatic site for melanoma. However, the mechanism responsible for such melanoma-induced bone metastasis is still poorly understood. In the present study, the intracardiac inoculation of leukemia inhibitory factor (LIF)-producing human melanoma-derived cells (SEKI) developed osteolytic bone destruction in male BALB/cA-nu/nu nude mice. To elucidate the role of LIF in melanoma-induced osteolysis, cells were prepared in which the expression of LIF was reduced using a siRNA technique from the parent SEKI cells. Osteoclastogenesis was induced in the co-culture of LIF and/or SEKI cells with osteoblastic stromal cells in vitro, whereas the LIF-reduced SEKI cells did not induce osteoclastogenesis. The intracardiac inoculation of LIF-reduced SEKI cells resulted in a significant reduction in the incidence and number of bone metastasis in comparison to those in the mice inoculated with the parent SEKI cells. The expression of LIF was found in seven of nine human melanoma-derived cell lines, suggesting that LIF expression is a universal event in melanoma. These findings suggest that a potential role for LIF in the melanoma-induced bone metastasis possibly through the stimulation of osteoclastogenesis. LIF might therefore be a potentially effective drug target in the treatment of bone metastasis in melanoma.
Clinical and Experimental Metastasis 11/2008; 26(2):133-41. · 3.52 Impact Factor
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ABSTRACT: The expression of chemokine receptor CXCR4 has been associated with poor prognosis and VEGF expression in several kinds of human malignancy. We measured CXCR4 expression levels in soft-tissue sarcoma and compared them with VEGF expression or microvessel density (MVD). We used real-time quantitative PCR to examine the CXCR4 and VEGF expression levels in a total 176 tumors, including 24 intermediate tumors, 24 malignant round-cell tumors (MRCTs) and 128 malignant non-round-cell tumors (MNRCTs). We also assessed their immunohistochemical expression of CXCR4 and VEGF, MVD and proliferative activities, as measured by the MIB-1-labeling index (LI). Furthermore, we evaluated their significance with respect to patient survival rates in MNRCTs, using the Cox regression model. Within the different types of tumor tissue, the expression levels of CXCR4 (p < 0.0001) and VEGF (p < 0.0001) in MNRCTs were significantly higher than those in intermediate tumors or MRCTs. Immunohistochemical expression levels of CXCR4 and VEGF were significantly correlated with their mRNA expression levels (p < 0.0001). Significant positive correlation was found between CXCR4 and VEGF expression in 112 primary MNRCTs (r = 0.434, p < 0.0001). Moreover, both univariate (p < 0.0001) and Cox multivariate analysis (p = 0.0001) revealed that overexpression of CXCR4 was an independent adverse prognostic factor, in addition to high stage according to the American Joint Committee on Cancer and a high MIB-1-LI. Determination of the CXCR4 expression level as a novel marker can provide useful prognostic information for patients and it could be a candidate for molecular targeting therapy in MNRCTs of soft-tissue sarcomas.
International Journal of Cancer 11/2008; 124(8):1852-9. · 5.44 Impact Factor
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ABSTRACT: Loss of SMARCB1/INI1 protein expression is considered useful for confirming a histologic diagnosis of malignant rhabdoid tumor. However, loss of SMARCB1/INI1 protein expression has recently been reported in other tumors as well, including a few cases of epithelioid sarcoma. In addition, the histopathologic differences between proximal-type epithelioid sarcoma and malignant rhabdoid tumor have not been conclusively defined. We analyzed SMARCB1/INI1 protein expression in 54 epithelioid sarcoma (proximal-type, 25; distal-type, 29) and examined alterations of the SMARCB1/INI1 gene in the cases lacking protein expression. We found that 19 (76.0%) proximal-type epithelioid sarcoma and 27 (93.1%) distal-type epithelioid sarcoma showed loss of SMARCB1/INI1 protein expression. Analysis of 39 cases with loss of protein expression revealed 4 cases (10.3%) with SMARCB1/INI1 gene alterations at the DNA level (homozygous deletion, 2; 1- or 2-bp deletion, 2) that could have induced the loss of gene products, and all 4 of these were proximal-type epithelioid sarcoma. Epithelioid sarcoma was thus associated with a high frequency of loss of SMARCB1/INI1 protein expression similar to that in malignant rhabdoid tumor. However, the frequency of SMARCB1/INI1 gene alteration at the DNA level in proximal-type epithelioid sarcoma was significantly lower than that in malignant rhabdoid tumor. In addition, the prognosis of patients with malignant rhabdoid tumor is significantly worse than that of patients with proximal-type epithelioid sarcoma (P = .001). Therefore, proximal-type epithelioid sarcoma and malignant rhabdoid tumor are suggested to be distinctive tumors with respect to the mechanism of the loss of SMARCB1/INI1 protein expression. Analysis of alterations in the SMARCB1/INI1 gene may thus be a useful diagnostic tool to distinguish proximal-type epithelioid sarcoma from malignant rhabdoid tumor.
Human pathology 11/2008; 40(3):349-55. · 3.03 Impact Factor
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Hayato Fujita,
Kenoki Ohuchida,
Kazuhiro Mizumoto,
Takuya Egami,
Yoshihiro Miyasaka,
Hiroshi Yamaguchi,
Jun Yu,
Lin Cui,
Manabu Onimaru,
Shunichi Takahata, Masazumi Tsuneyoshi,
Masao Tanaka
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ABSTRACT: Clinicians frequently require cytopathological assessment of tumor samples for preoperative diagnosis, but in some specimens, diagnosis remains inconclusive after cytological examination. To date, several molecular markers, including human telomerase reverse transcriptase (hTERT), have been assessed for the ability to detect malignancy. However, analyses using whole cytological specimens are generally affected by contamination of untargeted cells. The present study investigated the feasibility of more sensitive examination by quantitative mRNA analysis of target cells microdissected from cytological specimens. Laser capture microdissection (LCM) was used to obtain target cells from cytological specimens. hTERT mRNA levels were then measured in target cells by quantitative real-time RT-PCR (qRT-PCR). The effect of RNA fragmentation on qRT-PCR was also assessed. Total RNA from cytological specimens was sometimes fragmented to a large degree. To avoid the effect of RNA fragmentation, gene specific priming and PCR primers generating short PCR products were used and no difference in delta Ct values between fragmented and non-fragmented RNA were found. hTERT mRNA levels were measured in cells microdissected from 33 cytological specimens. The levels of hTERT mRNA were significantly higher in malignant cases compared to those in non-malignant cases (P = 0.0003). The sensitivity was 96.2%, even when the specificities were 100%. High levels of hTERT mRNA were also found in three cases that were not diagnosed as malignant by cytological examination. Quantitative assessment of hTERT mRNA levels in cells microdissected from cytological specimens is a potential diagnostic tool to potentiate cytological examination in diagnosing malignancy.
Cancer Science 10/2008; 99(11):2244-51. · 3.33 Impact Factor
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ABSTRACT: Transcatheter arterial chemoembolization (TACE) is now the mainstay of treatment for non-curative hepatocellular carcinoma (HCC), and hoped to have chemotherapeutic and ischemic effects; however, the histopathological changes of HCC caused by TACE have not been sufficiently discussed so far. We aimed to assess the morphological and immunohistochemical features of HCC treated with TACE by immunostaining cytokeratin (CK) 7, CK14, CK19 and vimentin, and to correlate these data with observed clinicopathological characteristics.
Eighty cases of surgically resected HCC with preoperative TACE and 146 cases of HCC resected without TACE as a control were analyzed.
The incidences of intrahepatic metastasis, poorly differentiated histology, multinucleated giant cells, mitotic figures and cytoplasmic inclusion bodies in the TACE group were significantly higher than those in the non-TACE group. The TACE group showed reactivity for CK7 in 56.3% (45/80) of patients, CK14 in 12.5% (10/80), CK19 in 23.8% (19/80) and vimentin in 6.3% (5/80) of patients. CK19 expression in the TACE group was significantly higher than in the non-TACE group (P = 0.0423). There was no correlation between immunoreactivity and the number of times TACE was carried out, but the expression of CK19 and vimentin in the massive necrotic group was higher than that in the mild necrotic group (P = 0.0197, P = 0.0229, respectively). Only TACE was an independent determinant of CK19 expression in all cases by multivariate analysis.
These results suggest that preoperative TACE may have an impact on the biliary phenotype of HCC. Some post-therapeutic HCC patients might develop HCC with a biliary phenotype indicating more aggressive malignancies.
Journal of Gastroenterology and Hepatology 10/2008; 23(12):1860-8. · 2.87 Impact Factor
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ABSTRACT: Fascin is an actin-bundling protein that induces membrane protrusions and cell motility after the formation of lamellipodia or filopodia. Fascin expression has been associated with progression or prognosis in various neoplasms; however, its role in intrahepatic cholangiocarcinoma is unknown. Tumor sections from 84 patients with intrahepatic cholangiocarcinoma and 16 patients with intrahepatic biliary dysplasia were stained with antifascin antibody. Fascin mRNA expression, measured by real-time reverse transcription-polymerase chain reaction in 20 frozen samples, was compared with the immunohistochemical results. Furthermore, the expression of cyclin D1 was compared with that of fascin. Immunohistochemically, fascin expression was absent or sporadic in normal biliary epithelium, whereas high expression (>70% of tumor cells) was found in 2 (12.5%) dysplasias and 30 (35.7%) intrahepatic cholangiocarcinomas. The difference between the fascin mRNA concentrations in the high-expression and low-expression groups was significant (P = .0082). Tumors showing high expression were poorly differentiated (P = .0019), and among poorly differentiated intrahepatic cholangiocarcinoma, larger tumors (>5 cm) were more likely than smaller lesions to have high fascin expression (P = .0205). A significant correlation was observed between fascin and cyclin D1 immunoreactivity (P = .0289). Patients whose tumors expressed fascin abundantly had a poorer outcome (P = .0085), and fascin overexpression was an independent prognostic factor (P = .0477). Fascin is expressed early in biliary carcinogenesis and might contribute to poor differentiation and to growth of intrahepatic cholangiocarcinoma. It is a significant indicator of a poor prognosis for patients with intrahepatic cholangiocarcinoma.
Human pathology 10/2008; 40(2):174-80. · 3.03 Impact Factor
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ABSTRACT: Recently, determining the MYCN status in neuroblastoma (NB) using the quantitative PCR (Q-PCR) and FISH instead of the Southern blotting (SB) has been recommended. In order to assess the implications of the gene dosage of MYCN in NB, the MYCN status was evaluated using Q-PCR on DNA extracted from small areas of NB specimens obtained using laser capture microdissection (LCM).
MYCN gene dosages (MYCN/NAGK) were determined in 63 primary NB block samples, as well as in 243 microdissected tissues from 63 samples using Q-PCR. In 23 of 63 cases, the MYCN gene status was evaluated using FISH.
Nine block samples with the amplification of MYCN based on SB showed a remarkable increase of the MYCN gene dosage using Q-PCR. Twelve of 54 block samples with no amplification of MYCN based on SB showed a slight increase of the MYCN gene dosage (3.56 > or == MYCN/NAGK > 1.84), and 8 of these 12 cases were in the advanced stage. Among these 12 cases, 1 case had several LCM areas with a high copy number of MYCN and several LCM areas which showed no increase of MYCN gene. Another case showed a slight increase in the MYCN gene dosage (3.65 < or == MYCN/NAGK < or == 4.82) in all LCM areas. In addition, a large number of cells with the MYCN gain were found using FISH in the block sample. In 2 other cases of 12 cases, although no LCM areas showed an increased gene dosage of MYCN, a small number of cells with MYCN amplification were found using FISH were found in the block sample.
A slight increase in the gene dosage of MYCN detected by Q-PCR may indicate that the NB tissue contains a small number of cells with the MYCN amplification or a large number of cells with the MYCN gain, which are associated with the aggressive progression of NB.
Pediatric Surgery International 09/2008; 24(10):1095-100. · 1.25 Impact Factor
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ABSTRACT: Desmoid tumors (desmoid-type fibromatoses) are locally aggressive soft tissue tumors associated with the Wnt/beta-catenin signaling pathway (APC-beta-catenin-Tcf pathway). Matrix metalloproteinase-7, which is one of the target genes of the Wnt/beta-catenin signaling pathway, has been reported to play an important role in tumor progression. We examined the immunohistochemical expression of beta-catenin and matrix metalloproteinase-7 in 72 samples (63 primary and 9 recurrent samples, 63 patients) of sporadic desmoid tumors without familial adenomatous polyposis, and the genetic alteration of the beta-catenin gene in 33 frozen materials (22 primary and 11 recurrent samples, 22 patients). We further examined messenger RNA expression of matrix metalloproteinase 7 by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and compared the results with those of normal skeletal muscles. Immunohistochemically, there was a statistically significant correlation between widespread nuclear expression of beta-catenin and overexpression of matrix metalloproteinase-7 (P < .01 in extra-abdominal desmoid, Fisher test). There were 7 missense point mutations in the 22 primary frozen samples (32%). In the beta-catenin mutated group, matrix metalloproteinase-7 messenger RNA expression was significantly higher than that of the beta-catenin wild-type group (P = .0018, Mann-Whitney U test). Our results suggest that the matrix metalloproteinase-7 gene may be up-regulated by mutated or continuously elevated beta-catenin protein and that the matrix metalloproteinase-7 gene may also be targeted in the Wnt/beta-catenin signaling pathway in sporadic desmoid tumors.
Human pathology 09/2008; 39(12):1802-8. · 3.03 Impact Factor
