Michiko Takahashi

Juntendo University, Edo, Tōkyō, Japan

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Publications (10)18.63 Total impact

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    ABSTRACT: Background Low-grade fibromyxoid sarcoma (LGFMS) is a rare soft tissue tumor typically affecting young to middle-aged adults. Despite its otherwise benign histologic appearance and indolent nature, it can have fully malignant behavior, and recurrence and metastasis may occur even decades later.Case historyWe report a case of LGFMS in the left lower leg of a 5-year-old Japanese boy. A magnetic resonance imaging (MRI) uncovered a well-demarcated intra-gastrocnemial tumor measuring 27¿×¿20 mm with a slightly high intensity on T1WI and heterogeneously high intensity on T2WI. Histologically, the tumor was composed of bland spindle-shaped cells with a whorled growth pattern. The tumor stroma was variably hyalinized and fibromyxoid with arcades of curvilinear capillaries and arterioles with associated perivascular fibrosis. Although LGFMS is known to affect children under 18 years of age, it is extremely rare in infants and children under 5 years of age. Despite the young age, this patient was accurately diagnosed by the typical histology and the detection of a FUS-CREB3L2 gene fusion.Conclusion Although LGFMS in children tends to be located superficially, this case presented with an intramuscular tumor in the region of the gastrocnemius. To the best of our knowledge, this is the first case of deep LGFMS arising in a child younger than 5 years of age. The patient is still alive with no evidence of the disease 4 months after diagnosis.Virtual SlidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_163.
    Diagnostic pathology. 09/2014; 9(1):163.
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    ABSTRACT: Solitary fibrous tumors (SFTs), initially observed in the pleura, were later found to develop in almost any extrapleural site. Dedifferentiation within SFTs was characterized only recently. We report a case of dedifferentiated SFT arising within the pelvis of a 70-year-old Japanese woman. Macroscopically, the resected tumor measured 17 × 17 × 13 cm. Histologically, the tumor displayed distinct heterologous osteosarcomatous and chondrosarcomatous components on a background of conventional SFT. Immunohistochemistry uncovered a loss of CD34 expression in the dedifferentiated area, whereas the nuclear expression of signal transducer and activator of transcription-6 (STAT6) and NGFI-A-binding protein 2 (NAB2) was maintained in both components. The p53 mutation 158 CGC > CAC (A158H) was found only in the dedifferentiated component. Furthermore, a fusion gene of NAB2(exon6)-STAT6(exon18) was detected in both the conventional and dedifferentiated components. The patient died of the disease 4 months after surgery. This case identifies a possible role of p53 dysfunction in the dedifferentiation process of SFT as reported in other sarcomas.
    Virchows Archiv : an international journal of pathology. 07/2014;
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    ABSTRACT: A 70-year-old Japanese woman was referred to our hospital due to hyperhidrosis and rapid weight loss of 10 kg in a month. A lump measuring 26 mm in diameter was detected in the left adrenal gland by computed tomography. Biochemical tests showed high levels of serum and urinary norepinephrine and epinephrine. However, a 123 I-MIBG scintigram failed to detect any accumulation in the left adrenal tumor. A left adrenalectomy was per-formed post clinical diagnosis of 123 I-MIBG negative pheochromocytoma. Microscopically, the tumor exhibited pheo-chromocytoma compatible features. Immunohistochemical analysis revealed low expression of VMAT1 in the tumor compared to the normal, surrounding tissue. To test for a possible genetic alteration of the monoamine transporter genes, we performed whole-exome sequencing of the VMAT1, VMAT2, and NET genes in the tumor. No significant base sequence substitution or deletion/insertion was found in any transporter. This suggests that MIBG negativ-ity is caused by a change that is independent of the base sequence abnormalities, such as an epigenetic change. Furthermore, a retrospective literature review of 123 I-MIBG negative-scintigraphy cases indicates that a negative finding in the 123 I-MIBG scintigram is frequently associated with metastatic pheochromocytomas or SDHB muta-tions. However, a SDHB/D gene mutation has not been identified in the reported case. Although the patient needs careful monitoring following the surgery, to date she has been disease free for 12 months. This study could not find clear reasons for negative conversion, however, investigations of the negative conversion mechanism might reveal significant insights towards the improvement of patient survival.
    International journal of clinical and experimental pathology 07/2014; 2014(7):4438-4447. · 2.24 Impact Factor
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    ABSTRACT: Sessile serrated adenoma/polyp (SSA/P) is considered as an early precursor in the serrated neoplasia pathway leading to colorectal cancer development. The conventional adenoma-carcinoma sequence is associated with activation of the WNT signaling pathway, although its role in serrated lesions is still controversial. To clarify differences in WNT signaling activation in association with MLH1 methylation or BRAF/KRAS mutations between serrated and conventional routes, we performed β-catenin immunostaining, methylation-specific PCR for MLH1 and WNT signaling associated genes such as AXIN2, APC, and MCC and secreted frizzled-related proteins (SFRPs), and direct sequencing of BRAF/KRAS in 27 SSA/Ps, 14 SSA/Ps with high-grade dysplasia and 9 SSA/Ps with submucosal carcinoma, as well as 19 conventional adenomas, 26 adenomas with high-grade dysplasia and 25 adenomas with submucosal carcinoma. Nuclear β-catenin labelings were significantly lower in the serrated series than in their adenoma counterparts, and a significant increment in those labelings was found from SSA/Ps to those with high-grade dysplasia or submucosal carcinoma. The frequency of MLH1 and SFRP4 methylation was significantly higher in SSA/P series, as compared with corresponding adenoma series. AXIN2 and MCC were more frequently methylated in SSA/Ps with high-grade dysplasia and those with submucosal carcinoma than in adenoma counterparts. Stepwise increment of AXIN2 and MCC methylation was identified from SSA/Ps through those with high-grade dysplasia to those with submucosal carcinoma. A significant correlation was seen between nuclear β-catenin expression and methylation of AXIN2 or MCC in the SSA/P series. BRAF mutation was more frequent, whereas KRAS mutation was less frequent in the SSA/P series as compared with the adenoma series. There was an inverse association of BRAF mutation with AXIN2 methylation in SSA/P series. In conclusion, WNT/β-catenin signal activation mediated by the methylation of SFRP4, MCC, and AXIN2 may make different contributions to colorectal neoplasia between the serrated and conventional routes.Modern Pathology advance online publication, 13 June 2014; doi:10.1038/modpathol.2014.41.
    Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 06/2014;
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    ABSTRACT: Basaloid squamous cell carcinoma (BSCC) of the esophagus is a rare variant of typical squamous cell carcinoma (SCC) associated with poor survival. A characteristic feature is nuclear accumulation of β-catenin, without a mutation of the gene. We studied the methylation status of Wnt antagonist genes, such as secreted frizzled-related protein (sFRP) gene family members, Wnt inhibitory factor-1 (WIF-1), Dickkopf-1 (Dkk-1), and human Dapper protein-1 (HDPR-1), and alterations of the APC, Axin1, and Axin2 genes in 30 cases of esophageal BSCC. β-catenin and sFRP (sFRP-1, sFRP-2, sFRP-4, sFRP-5) protein expression was examined by immunohistochemistry. APC, Axin1, and Axin2 gene mutations were detected in 3, 2, and 2 cases, respectively, and 6 cases (20 %) harbored at least 1 alteration in these genes. Methylation of the sFRP-2 promoter region was observed in all cases, and methylation was frequent in sFRP-1 and sFRP-5, but infrequent in Dkk-1, WIF-1, sFRP-4, and HDPR-1. sFRP-2 expression was almost completely absent in 25 cases (83 %), consistent with the methylation status. Nuclear accumulation of β-catenin was observed in all cases. sFRP-5 expression was associated with a low nuclear β-catenin labeling index. These results show that sFRP-2 is a target gene of hypermethylation in esophageal BSCC and suggest that sFRP-2 might contribute to BSCC tumorigenesis through the Wnt/β-catenin signaling pathway.
    Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 01/2014; · 2.68 Impact Factor
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    ABSTRACT: Gastric neoplasia of chief cell-predominant type (GN-CCP) has been reported as a new, rare variant of gastric tumor. GN-CCPs were defined as tumors consisting of irregular anastomosing glands of columnar cells mimicking chief cells of fundic gland with nuclear atypia and prolapse-type submucosal involvement. We comparatively evaluated clinicopathologic features between 31 GN-CCPs and 130 cases of conventional gastric adenocarcinoma invading into submucosa (CGA-SM) in additon to nuclear β-catenin immunolabeling and direct sequencing of members of the Wnt/β-catenin pathway, CTNNB1, APC, and AXIN, in a subset of these tumors. GN-CCP presented as small protruded lesions located in the upper third of the stomach, with minimal involvement into the submucosa and rare lymphovascular invasion. None of the lesions have demonstrated a recurrence of disease or metastasis on follow-up. Nuclear β-catenin immunolabeling was higher in GN-CCP (labeling index [LI]: median, 19.3%; high expresser [LI >30%], 7/27 cases [26%]) than CGA-SM (median LI, 14.7%; high expresser, 1/19 cases [6%]). Missense mutation of APC was observed in 1 GN-CCP but not CGA-SM. Missense or nonsense mutations of CTNNB1 and AXIN1 were higher in GN-CCPs (14.8%, both) than CGA-SMs (5.3%, both). Missense mutations of AXIN2 were higher in GN-CCPs (25.9%) than in CGA-SMs (10.5%). Overall, 14 (51.9%) of 27 GN-CCPs and 5 (26.3%) of 19 CGA-SM cases harbored at least 1 of these gene mutations. In conclusion, GN-CCPs as a unique variant of nonaggressive tumor are characterized by nuclear β-catenin accumulation and mutation of CTNNB1 or AXIN gene, suggesting activation of the Wnt/β-catenin pathway.
    Human pathology 09/2013; · 3.03 Impact Factor
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    ABSTRACT: Basal-like breast cancer (BLBC) is characterized by aggressive behaviour; its genesis is the perturbation of DNA repair as a consequence of BRCA1 methylation or mutation. We comparatively evaluated alterations of DNA repair proteins and p53 between BLBC and non-BLBC cases. Tumour sections from 104 BLBC and 89 non-BLBC patients were immunostained for hMLH1, hMSH2, MGMT, BRCA1 and p53. Methylation status of DNA repair genes was analysed by methylation-specific PCR, and p53 mutation was examined by direct sequencing. Immunoreactive levels of hMLH1 and MGMT were lower in BLBC, whereas the levels of hMSH2 and p53 were higher, compared to non-BLBC (P ≤ 0.014). Reduced expression of hMLH1 [hazard ratio (HR) 5.26, P = 0.001] and preserved expression of MGMT (HR 2.58, P = 0.039) proved to be independent predictors of poor survival in BLBC patients. DNA repair genes were methylated in approximately 20-40% of BLBCs without a significant relationship between their methylation and p53 mutation. BRCA1 methylation was associated with the loss of its protein expression (P = 0.004). MGMT methylation was linked to larger tumour size (P < 0.001). Perturbations of the DNA repair system might be different between BLBC and non-BLBC. Alterations of hMLH1 and MGMT appear important for tumour progression and survival in BLBC patients.
    Histopathology 07/2013; · 2.86 Impact Factor
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    ABSTRACT: Renal carcinomas associated with Xp11.2 translocations/transcription factor 3 (TFE3) gene fusion (Xp11 translocation RCC) are a rare subtype of renal cell carcinoma. A middle-aged Japanese man, who had a medical history of dialysis for more than 12 years, had bilateral renal cancers with a background of acquired cystic disease of the kidney and remarkable deposition of calcium oxalate in the tumorous area. The right renal tumor showed papillary architecture of clear cells with diffuse and strong immunoreactivity for TFE3 and focal and weak positivity for cathepsin K, suggesting a possibility of Xp11 translocation RCC. However, RT-PCR failed to detect any type of the reported fusion genes involving TFE3. Thus, the sample was sent for a TFE3 break-apart FISH assay in a renal tumor consultation service, which reported no evidence of TFE3 gene rearrangement. The right renal tumor was finally diagnosed as papillary renal cell carcinoma with cystic change. We report here a case of bilateral renal cell carcinoma in a patient undergoing long-term dialysis, which showed false-positive immunoreactivity for TFE3 immunostaining. Titration of TFE3 immunohistochemical staining (IHC) should be performed and cross-referenced wcith the FISH or RT-PCR results to avoid the misinterpretation of TFE3 IHC results.
    International journal of clinical and experimental pathology 01/2013; 6(11):2585-90. · 2.24 Impact Factor
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    ABSTRACT: To clarify differences in mucin phenotype, proliferative activity and oncogenetic alteration among subtypes of colorectal laterally spreading tumor (LST). LSTs, defined as superficial elevated lesions greater than 10 mm in diameter with a low vertical axis, were macroscopically classified into two subtypes: (1) a granular type (Gr-LST) composed of superficially spreading aggregates of nodules forming a flat-based lesion with a granulonodular and uneven surface; and (2) a non-granular type (NGr-LST) with a flat smooth surface and an absence of granulonodular formation. A total of 69 LSTs, comprising 36 Gr-LSTs and 33 NGr-LSTs, were immunohistochemically stained with MUC2, MUC5AC, MUC6, CD10 (markers of gastrointestinal cell lineage), p53, β-catenin and Ki-67 antibodies, and examined for alteration in exon 1 of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and exon 15 of v-raf murine sarcoma viral oncogene homologue B1 (BRAF) by polymerase chain reaction followed by direct sequencing. Histologically, 15 Gr-LST samples were adenomas with low-grade dysplasia (LGD), 12 were high-grade dysplasia (HGD) and 9 were adenocarcinomas invading the submucosa (INV), while 12 NGr-LSTs demonstrated LGD, 14 HGD and 7 INV. In the proximal colon, MUC5AC expression was significantly higher in the Gr-type than the NGr-type. MUC6 was expressed only in NGr-LST. MUC2 or CD10 did not differ. P53 expression demonstrated a significant stepwise increment in progression through LGD-HGD-INV with both types of LST. Nuclear β-catenin expression was significantly higher in the NGr-type. Ki-67 expression was significantly higher in the Gr-type in the lower one third zone of the tumor. In proximal, but not distal colon tumors, the incidence of KRAS provided mutation was significantly higher in the Gr-type harboring a specific mutational pattern (G12V). BRAF mutations (V600E) were detected only in two Gr-LSTs. The two subtypes of LST, especially in the proximal colon, have differing phenotypes of gastrointestinal cell lineage, proliferation and activation of Wnt/β-catenin or RAS/RAF/extracellular signal-regulated kinase signaling.
    World Journal of Gastroenterology 10/2012; 18(39):5551-9. · 2.55 Impact Factor
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    ABSTRACT: Basaloid squamous cell carcinoma of the esophagus is a rare variant of squamous cell carcinoma. We reviewed 878 cases of esophageal squamous cell carcinoma and detected 22 cases (3%) of basaloid squamous cell carcinoma. These tumors and stage-matched paired conventional squamous cell carcinomas were investigated for clinicopathologic features and immunoreactivity of cytokeratin subtypes, p53, B-cell lymphoma 2 (bcl-2), β-catenin, and epidermal growth factor receptor. Molecular aberrations in p53, CTNNB1 (the gene encoding β-catenin), and epidermal growth factor receptor (EGFR) were also determined. Patients with basaloid squamous cell carcinomas demonstrated a 5-year survival rate of 42%, significantly worse than those with well-differentiated squamous cell carcinoma (P < .01). Histologically, solid nests with central necrosis and a cribriform pattern were identified in almost all (≥95%) cases, and ductal differentiation was less frequent (45%) but associated with significantly better survival (P < .05). Compared with conventional squamous cell carcinomas, the basaloid squamous cell carcinomas were less immunoreactive for cytokeratin 14, cytokeratin 903, and membranous β-catenin (P < .01-.001) but more reactive for bcl-2, nuclear β-catenin, epidermal growth factor receptor, and Ki-67 (P < .05-.001). Direct sequencing showed mutations of p53 (36%), EGFR (14%), but not CTNNB1; fluorescent in situ hybridization detected amplification of the epidermal growth factor receptor gene (22%). In basaloid squamous cell carcinomas, low-level expression of cytokeratin 14/cytokeratin 903 and mutations of p53 and EGFR had a significant influence on worse survival (P < .05-.001). We conclude that the esophageal basaloid squamous cell carcinoma, a neoplasm with particularly aggressive biologic behavior, should be differentiated from conventional squamous cell carcinomas. In this context, immunohistochemical assessment of several markers might provide a useful adjunct diagnostic tool. Aberrations of p53 and epidermal growth factor receptor genes are possibly involved in progression of esophageal basaloid squamous cell carcinoma.
    Human pathology 05/2012; 43(11):2012-23. · 3.03 Impact Factor