Publications by authors named "Mikiko Aoki"

74 Publications

Eosinophilic Granulomatosis with Polyangiitis Presenting with Myocarditis as an Initial Symptom: A Case Report and Review of the Literature.

Case Rep Neurol 2021 May-Aug;13(2):329-333. Epub 2021 Jun 10.

Department of Neurology, Fukuoka University, Fukuoka, Japan.

A 66-year-old woman with a history of bronchial asthma had shortness of breath and fatigue upon mild exercise. She was diagnosed as congestive heart failure. A blood test showed eosinophilia without the presence of anti-neutrophil cytoplasmic antibody (ANCA), and a myocardial biopsy specimen revealed eosinophilic infiltration in the myocardium. Eosinophilia was improved when she was administered short-term methylprednisolone. After that, she had numbness and pain in her lower limbs with re-elevation of eosinophils. She had dysesthesia and hypalgesia in the distal part of the limbs. Sural nerve biopsy revealed axonal degeneration and thickness of the arterial wall, indicating a diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA). Two courses of steroid pulse therapy were performed, resulting in marked improvement of her sensory symptoms. ANCA-negative EGPA might be associated with myocarditis and peripheral neuropathy. A sufficient immunotherapy should have been considered to prevent rapid progression.
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http://dx.doi.org/10.1159/000516255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255704PMC
June 2021

Multicentric glioblastoma in a 4-year-old female patient: A case report.

Mol Clin Oncol 2021 May 5;14(5):90. Epub 2021 Mar 5.

Department of Pathology, Fukuoka University School of Medicine, Fukuoka 814-0180, Japan.

In the USA and Germany, pediatric glioblastoma (pGBM) makes up <3% of childhood brain tumors. Occasionally, GBM has multiple contrast lesions and is referred to as multicentric GBM. The current study present a case of a four-year-old female patient presented with headache, vomiting and consciousness disturbance. Radiologically, a neoplastic lesion of the right frontal lobe with hemorrhage, and bilateral thalamus, right temporal and left occipital neoplastic lesions were identified. The right frontal lesion was not continuous to other lesions. It was concluded that the tumor was a multicentric GBM with intra-tumoral hemorrhage. The tumor was pathologically GBM. Following surgery, the patient underwent chemotherapy and radiotherapy, but 11 months after surgery, the patient passed away. This case had features of childhood GBM and multicentric GBM and was difficult to treat.
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http://dx.doi.org/10.3892/mco.2021.2252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7976450PMC
May 2021

Ubiquitin-specific Peptidase 6 ()-associated Fibroblastic/Myofibroblastic Tumors: Evolving Concepts.

Cancer Genomics Proteomics 2021 Mar-Apr;18(2):93-101

Department of Orthopaedic Surgery, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.

Ubiquitin-specific peptidase 6 (USP6) is a hominoid-specific gene residing on chromosome 17p13 and serves as a deubiquitinating enzyme with a diverse set of functions including intracellular trafficking, inflammatory signaling, cell transformation and protein turnover. USP6 rearrangements were first identified in aneurysmal bone cysts, resulting in promoter swapping and over-expression of wild type USP6. Several morphologically overlapping fibroblastic/myofibroblastic tumors are known to harbor USP6 rearrangements, including nodular fasciitis, cellular fibroma of tendon sheath, myositis ossificans and fibro-osseous pseudotumor of digits. Over the past few years, fusions involving the USP6 gene and various partner genes have been described in these neoplasms. The current World Health Organization Classification of Tumors of Soft Tissue suggests that USP6-rearranged lesions are typically benign and usually self-limited in their growth. This review provides an updated overview of the clinical, histological and molecular genetic features of USP6-associated fibroblastic/myofibroblastic tumors and discusses how these lesions should be best classified.
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http://dx.doi.org/10.21873/cgp.20244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943209PMC
September 2021

Ependymoma-like tumor with mesenchymal differentiation harboring C11orf95-NCOA1/2 or -RELA fusion: A hitherto unclassified tumor related to ependymoma.

Brain Pathol 2021 05 12;31(3):e12943. Epub 2021 Feb 12.

Department of Human Pathology, Gunma University Graduate School of Medicine, Maebashi, Japan.

Recurrent fusion genes involving C11orf95, C11orf95-RELA, have been identified only in supratentorial ependymomas among primary CNS tumors. Here, we report hitherto histopathologically unclassifiable high-grade tumors, under the tentative label of "ependymoma-like tumors with mesenchymal differentiation (ELTMDs)," harboring C11orf95-NCOA1/2 or -RELA fusion. We examined the clinicopathological and molecular features in five cases of ELTMDs. Except for one adult case (50 years old), all cases were in children ranging from 1 to 2.5 years old. All patients presented with a mass lesion in the cerebral hemisphere. Histologically, all cases demonstrated a similar histology with a mixture of components. The major components were embryonal-appearing components forming well-delineated tumor cell nests composed of small uniform cells with high proliferative activity, and spindle-cell mesenchymal components with a low- to high-grade sarcoma-like appearance. The embryonal-appearing components exhibited minimal ependymal differentiation including a characteristic EMA positivity and tubular structures, but histologically did not fit with ependymoma because they lacked perivascular pseudorosettes, a histological hallmark of ependymoma, formed well-delineated nests, and had diffuse and strong staining for CAM5.2. Molecular analysis identified C11orf95-NCOA1, -NCOA2, and -RELA in two, one, and two cases, respectively. t-distributed stochastic neighbor embedding analysis of DNA methylation data from two cases with C11orf95-NCOA1 or -NCOA2 and a reference set of 380 CNS tumors revealed that these two cases were clustered together and were distinct from all subgroups of ependymomas. In conclusion, although ELTMDs exhibited morphological and genetic associations with supratentorial ependymoma with C11orf95-RELA, they cannot be regarded as ependymoma. Further analyses of more cases are needed to clarify their differences and similarities.
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http://dx.doi.org/10.1111/bpa.12943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8412126PMC
May 2021

An Update on Clinicopathological, Imaging and Genetic Features of Desmoplastic Fibroblastoma (Collagenous Fibroma).

In Vivo 2021 Jan-Feb;35(1):69-73

Department of Orthopaedic Surgery, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.

Desmoplastic fibroblastoma (also known as collagenous fibroma) is an uncommon benign fibroblastic/myofibroblastic neoplasm that primarily arises in the subcutaneous tissue of upper extremity. Magnetic resonance imaging reveals a well-defined mass in intimate association with dense connective tissue and prominent low signal intensity on all pulse sequences. Peripheral and septal enhancement is usually seen after intravenous contrast. Histologically, the lesion is paucicellular and consists of spindle to stellate-shaped cells embedded in a collagenous or myxocollagenous stroma with low vascularity. Diffuse and strong nuclear immunoreactivity for FOS-like antigen 1 seems to be characteristic of desmoplastic fibroblastoma. Cytogenetic studies have demonstrated the presence of 11q12 rearrangements and an identical t(2;11)(q31;q12) translocation. This review provides an updated overview of the clinical, radiological, histological, cytogenetic and molecular genetic features of desmoplastic fibroblastoma and discusses the relationship to fibroma of tendon sheath.
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http://dx.doi.org/10.21873/invivo.12233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880796PMC
June 2021

Prevalence of Trichinella T9 in Japanese black bears (Ursus thibetanus japonicus) in Iwate prefecture, Japan.

Parasitol Int 2021 Feb 31;80:102217. Epub 2020 Oct 31.

Laboratory of Veterinary Parasitology, Faculty of Agriculture, Iwate University, 3-18-8 Ueda, Morioka 020-8550, Japan; Department of Pathogenetic Veterinary Science, The United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan. Electronic address:

Trichinellosis is a meat-borne zoonotic disease caused by nine Trichinella speices and three unclassified genotypes. In Japan, four domestic outbreaks of human trichinellosis are reported sporadically and were associated with the consumption of wild bear meat. This study examined Trichinella prevalence and its species in black bears, Ursus thibetanus japonicus in Iwate prefecture, Japan. Trichinella T9 larvae identified molecularly were first detected in 1.4% (2/144) of the masseters of black bears examined, and their densities were low (1 and 0.3 larvae /g muscle, respectively). Two cytochrome C oxidase I (COI) haplotypes (sequences) of Trichinella T9 were found in distinct bear populations, suggesting that Trichinella T9 populations isolated genetically by bear populations would occur in Japan.
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http://dx.doi.org/10.1016/j.parint.2020.102217DOI Listing
February 2021

Eicosapentaenoic acid ameliorates pulmonary hypertension via inhibition of tyrosine kinase Fyn.

J Mol Cell Cardiol 2020 11 2;148:50-62. Epub 2020 Sep 2.

Department of Cardiovascular Physiology, Faculty of Medicine, Kagawa University, Kita-gun, Miki-cho, Kagawa, Japan.

Pulmonary arterial hypertension (PAH) is a multifactorial disease characterized by pulmonary arterial vasoconstriction and remodeling. Src family tyrosine kinases, including Fyn, play critical roles in vascular remodeling via the inhibition of STAT3 signaling. EPA is known to inhibit Fyn kinase activity. This study investigated the therapeutic potential and underlying mechanisms of EPA and its metabolite, resolvin E1 (RvE1), to treat PAH using monocrotaline-induced PAH model rats (MCT-PAH), human pulmonary artery endothelial cells (HPAECs), and human pulmonary artery smooth muscle cells (HPASMCs). Administration of EPA 1 and 2 weeks after MCT injection both ameliorated right ventricular hypertrophy, remodeling and dysfunction, and medial wall thickening of the pulmonary arteries and prolonged survival in MCT-PAH rats. EPA attenuated the enhanced contractile response to 5-hydroxytryptamine in isolated pulmonary arteries of MCT-PAH rats. Mechanistically, the treatment with EPA and RvE1 or the introduction of dominant-negative Fyn prevented TGF-β2-induced endothelial-to-mesenchymal transition and IL-6-induced phosphorylation of STAT3 in cultured HPAECs. EPA and RvE1 suppressed Src family kinases' activity as evaluated by their phosphorylation status in cultured HPAECs and HPASMCs. EPA and RvE1 suppressed vasocontraction of rat and human PA. Furthermore, EPA and RvE1 inhibited the enhanced proliferation and activity of Src family kinases in HPASMCs derived from patients with idiopathic PAH. EPA ameliorated PAH's pathophysiology by mitigating vascular remodeling and vasoconstriction, probably inhibiting Src family kinases, especially Fyn. Thus, EPA is considered a potent therapeutic agent for the treatment of PAH.
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http://dx.doi.org/10.1016/j.yjmcc.2020.08.013DOI Listing
November 2020

Mutant Promotes NKG2D T Cell Infiltration and CD155 Dependent Immune Evasion.

Anticancer Res 2020 Aug;40(8):4663-4674

Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan

Background/aim: Roles for mutant (mt) KRAS in the innate immune microenvironment in colorectal cancer (CRC) were explored.

Materials And Methods: Human CRC HCT116-derived, mtKRAS-disrupted (HKe3) cells that express exogenous mtKRAS and allogenic cytokine-activated killer (CAK) cells were co-cultured in 3D floating (3DF) culture. The anti-CD155 antibody was used for function blocking and immuno histochemistry.

Results: Infiltration of CAK cells, including NKG2D T cells, into the deep layer of HKe3-mtKRAS spheroids, was observed. Surface expression of CD155 was found to be up-regulated by mtKRAS in 3DF culture and CRC tissues. Further, the number of CD3 tumor-infiltrating cells in the invasion front that show substantial CD155 expression was significantly larger than the number showing weak expression in CRC tissues with mtKRAS. CD155 blockade decreased the growth of spheroids directly and indirectly through the release of CAK cells.

Conclusion: CD155 blockade may be useful for therapies targeting tumors containing mtKRAS.
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http://dx.doi.org/10.21873/anticanres.14465DOI Listing
August 2020

A Case of Salivary Duct Carcinoma Intracranial Invasion due to Perineural Invasion Through the Facial Nerve.

World Neurosurg 2020 08 27;140:332-337. Epub 2020 May 27.

Department of Pathology, Faculty of Medicine Fukuoka University, Fukuoka, Japan.

Background: Salivary duct carcinoma (SDC) is a rare parotid tumor that often develops as a rapidly growing mass with a poor prognosis. It has a high rate of distant metastases, sometimes with infiltration along nerves. We describe a case of SDC that originated outside the cranium and extended into the cranium along the path of the facial nerve.

Case Description: A 74-year-old man underwent magnetic resonance imaging at a local hospital, which revealed a tumor in the left internal acoustic canal; the patient was referred to our department. A left facial schwannoma was suspected, and magnetic resonance imaging was performed again 6 months later. Rapid tumor growth was confirmed, and the tumor was resected. The tumor displayed atypical epithelial cells with comedo necrosis and cribriform structure and was diagnosed as SDC. All residual intracranial tumors were removed using the middle fossa approach. The tumor, which was considered to be a primary tumor, was found near the stylomastoid foramen, and it was removed with the parotid gland. Five months after the initial surgery, metastasis to the trigeminal nerve was observed, and this was removed using a retrosigmoid approach, followed by radiation therapy.

Conclusions: All 4 surgical specimens of this case were presented, and the path of tumor progression was examined in detail. Although the primary lesion was small, intracranial invasion along the facial nerve occurred. SDC should be considered as a tumor that can extend into the cranium, even with a small primary lesion.
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http://dx.doi.org/10.1016/j.wneu.2020.05.180DOI Listing
August 2020

Highly expressed tumoral emmprin and stromal CD73 predict a poor prognosis for external auditory canal carcinoma.

Cancer Sci 2020 Aug 22;111(8):3045-3056. Epub 2020 Jun 22.

Department of Pathology, Fukuoka University Hospital and School of Medicine, Fukuoka, Japan.

Squamous cell carcinoma of the external auditory canal (SCC-EAC) is rare and has a poor prognosis. The SCC-EAC cases with high-grade tumor budding (TB) or poorly differentiated clusters (PDCs) are associated with shorter survival than those with low-grade TB or PDCs. Extracellular matrix metalloproteinase inducer (emmprin) is a protein expressed in tumor cells that stimulates the production of MMP-2 by stromal fibroblasts to facilitate tumor invasion. Recently, we reported that emmprin forms a complex with CD73 to regulate MMP-2 production from fibroblasts in vitro. Here, we examined the association of emmprin and CD73 expression with TB or PDCs as well as with survival in 34 biopsy specimens of SCC-EAC patients. High tumoral emmprin expression was associated with high-grade TB, whereas high stromal CD73 expression was associated with high-grade PDCs. Furthermore, concurrent elevated expression of tumoral emmprin and stromal CD73 was determined to be an independent poor prognostic factor. In immunoprecipitation analyses, complex formation between emmprin and CD73 was demonstrated in vitro. Production of MMP-2 from fibroblasts was more abundant when cocultured with tumor cells than from fibroblasts cultured alone. Furthermore, MMP-2 production was reduced by the transfection of CD73 siRNA in fibroblasts cocultured with tumor cells. The colocalization of emmprin and CD73 was enhanced in not only the peripheral cells of the tumor cell clusters that interact with fibroblasts but also in the cells of intratumor clusters. Overall, this study provides novel insights into the roles of emmprin, CD73, and MMP-2 in tumor invasiveness.
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http://dx.doi.org/10.1111/cas.14508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419056PMC
August 2020

Midline Glioma in Adults: Clinicopathological, Genetic, and Epigenetic Analysis.

Neurol Med Chir (Tokyo) 2020 Mar 3;60(3):136-146. Epub 2020 Jan 3.

Department of Pathology, Fukuoka University School of Medicine.

The histone H3K27M-mutant diffuse midline glioma is often seen in children and has a very poor prognosis regardless of its histological grade. Although it can occur in adults, few studies on adult cases have been reported. We examined adult midline glioma cases for their histological grade, presence of H3K27M mutation, and expression of related factors-enhancer of zeste homolog 2 (EZH2), H3K27me3, p16, and methylthioadenosine phosphorylase. These tumor characteristics were also evaluated for their prognostic value in adult midline glioma. High histological grade, H3K27M-mutant, high EZH2 expression, and high H3K27me3 expression was detected in 12/23 (53%), 11/23 (48%), 9/23 (39%), and 12/23 (52%) cases, respectively. Histological grade and prognosis were significantly correlated (P <0.01). The high expression of EZH2 and the low expression of H3K27me3 correlated with histological malignancy (P = 0.019 and 0.009) and prognosis (P = 0.048 and 0.047). To broaden the scope of our analysis, a review of cases reported in the literature (2014-2019) was performed. In the 171 cases, H3K27M-mutant showed poor prognosis in the young adult group (P = 0.001), whereas H3K27 status had no effect on prognosis in the older age group (P = 0.141). Histological grade was correlated with prognosis in both young adults and older groups (P <0.001, P = 0.003, respectively). We demonstrate differences in prognostic factors for diffuse gliomas in the midline region for children and adults. Importantly, the H3K27M mutation significantly influences prognosis in children, but not necessarily in adults. Contrarily, histological grading and immunostaining are important prognostic tools in adults.
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http://dx.doi.org/10.2176/nmc.oa.2019-0168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073699PMC
March 2020

WHO Grade I Meningioma Metastasis to the Lung 26 Years after Initial Surgery: A Case Report and Literature Review.

NMC Case Rep J 2019 Oct 12;6(4):125-129. Epub 2019 Sep 12.

Department of Pathology, Faculty of Medicine, Fukuoka University, Fukuoka, Fukuoka, Japan.

Metastases from meningioma grade I are especially rare. We describe a case of a 65-year-old male with meningioma WHO grade I with a history of local recurrence and distant metastasis to the lung 26 years after the initial surgery. The original tumor was localized at the occipital low convex and invaded into the venous sinus and posterior cranial fossa; it was resected. About 15 years later, the tumor recurred in the posterior cranial fossa and -knife radiosurgery was performed. About 4 years later, the recurred tumor was resected at our hospital. Another 7 years later, the tumor recurred in the same area and right middle cranial fossa. All tumors except that inside the venous sinus were excised. All specimens obtained were classified as meningioma WHO grade I. Preoperative examination of the third operation revealed a nodule in the lower lobe of the right lung. The nodule grew gradually. Four months after the third surgery, partial resection of the right lung was performed. Histology indicated meningioma WHO grade I. The two lesions in the cranium and lung lesions were subjected to fluorescence hybridization of the NF2 gene, and the three specimens had similar findings, genetically confirming them to be metastases of the intracranial meningioma. A literature review of past cases of meningioma progression revealed that the mean duration to metastasis is 12.5, 6.8, 3.7 years for grades I, II, and III, respectively. The current case therefore has an extended time frame.
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http://dx.doi.org/10.2176/nmccrj.cr.2019-0020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6776748PMC
October 2019

[A Case of Meningeal Solitary Fibrous Tumour/Haemangiopericytoma WHO Grade III Metastasized to the Spleen Shortly After Tumor Resection].

No Shinkei Geka 2019 Mar;47(3):329-334

Department of Pathology, Faculty of Medicine, Fukuoka University.

Revision of WHO guidelines in 2016 led to the classification of solitary fibrous tumours(SFTs)and haemangiopericytomas(HPCs)as a single tumor entity characterized by NAB2-STAT6 fusion. Standard-of-care treatment involves surgery, but local recurrence and distant metastasis sometimes occur. The average latency to metastasis after surgery is 99 months. A 38-year-old female patient presented with a complaint of headache. An 8×5×2cm lesion showing Gd-T1 enhancement was detected near the superior sagittal sinus. Pathological assessment following resection revealed proliferating, polymorphic, atypical tumor cells with distinct nucleoli in a "patternless pattern." Cellularity was moderate to high, and mitotic figures were observed in 15/10 high power fields. Immunohistochemically, tumor cells tested positive for STAT6, and RT-PCR revealed a NAB2-STAT6 fusion gene(exons 6 and 17, respectively), supporting a diagnosis of SFT/HPC WHO grade III. Despite postoperative radiotherapy, multiple metastases to the spleen were detected 8 months after surgery, and distal pancreatectomy with splenectomy was performed. The pathology of the splenic tumor was similar to that of the intracranial tumor. Recurrent disease in a lymph node was detected 1 month later, and local radiation therapy was administered. The patient died of cancerous peritonitis 5 months later. In this case, exceedingly rapid metastasis to the spleen occurred, despite the administration of vigorous treatment. Here, we review SFT/HPC incidence, treatment, and outcomes to better understand this rare malignancy.
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http://dx.doi.org/10.11477/mf.1436203938DOI Listing
March 2019

Adenoid cystic carcinoma with high-grade transformation forming spindle cell component of the submandibular gland.

Auris Nasus Larynx 2019 Dec 16;46(6):934-939. Epub 2019 Feb 16.

Department of Pathology, Fukuoka University, School of Medicine, Japan.

Adenoid cystic carcinoma (AdCC) with high-grade transformation (AdCC-HGT) is rare, and AdCC-HGT with spindle cell component is particularly rare. The patient was a 65-year-old man with a 5 cm sized swelling of the right submandibular gland. Submandibular sialoadenectomy was performed. Histopathological findings mainly showed conventional AdCC, and minorly showed two other components: (1) the pleomorphic component, a proliferation of atypical pleomorphic epithelial cells forming solid or small clusters and accompanied by necrosis; (2) the spindle cell component, containing atypical spindle cells invading the stroma. Postoperative chemoradiotherapy was performed. Multiple right lung nodular lesions were found on the contrast-enhanced chest CT one month after the surgery. Thoracoscopic pulmonary resection was performed. The lung tumors exhibited a proliferation of atypical spindle cells, accompanied by necrosis. We considered that the spindle cell component of the AdCC-HGT of the submandibular gland developed lung metastases. The patient died seven months after submandibular sialoadenectomy due to respiratory failure. Although rare, our case highlights the importance of recognising spindle cell components in conventional AdCC; even if the area is small, these high-grade transformation areas can metastasise and become prognostic factors.
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http://dx.doi.org/10.1016/j.anl.2019.01.014DOI Listing
December 2019

Activated EphA2 Processing by MT1-MMP Is Involved in Malignant Transformation of Ovarian Tumours .

Anticancer Res 2018 Jul;38(7):4257-4266

Department of Pathology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan

Background/aim: Erythropoietin-producing hepatocellular receptor-2 (EphA2) is overexpressed in ovarian cancer. The N-terminals of EphA2 are processed by membrane-type 1 matrix metalloproteinase (MT1-MMP) and can subsequently induce ligand-independent signal activation to promote motility, invasion, and metastasis. The aim of this study was to investigate whether EphA2 processing occurs in benign, borderline, and malignant ovarian tumours.

Materials And Methods: Overall 107 ovarian epithelial carcinomas (OECs; 47 serous, 24 endometrioid, 16 mucinous, and 20 clear cell), 54 ovarian borderline tumours (OBTs; 12 serous, 42 mucinous), and 45 adenomas (15 serous, 17 mucinous, and 13 endometriotic cysts) were evaluated. Expression and processing of EphA2 were semi-quantitatively analyzed. EphA2 processing was also investigated by immunoblotting.

Results: EphA2 and MT1-MMP co-expression were detected. N-terminal EphA2 levels were significantly lower than those of C-terminal EphA2 in OECs and OBTs, but not in adenomas. Immunoblotting revealed processed fragments in OEC and OBTs.

Conclusion: EphA2 processing by MT1-MMP is associated with malignant transformation in ovarian tumours.
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http://dx.doi.org/10.21873/anticanres.12722DOI Listing
July 2018

Poorly Differentiated Clusters Predict a Poor Prognosis for External Auditory Canal Carcinoma.

Head Neck Pathol 2019 Jun 30;13(2):198-207. Epub 2018 May 30.

Department of Pathology, Fukuoka University Hospital and School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan.

Squamous cell carcinoma (SCC) of the external auditory canal (EAC) is rare and offers a poor prognosis; more accurate prognostic biomarkers are required. Our laboratory recently demonstrated that tumor budding, characterized by tumor cell clusters (< 5 cells), and laminin 5-γ2 staining of SCC of the EAC are associated with shorter survival. However, clusters composed of ≥ 5 tumor cells are also found in the stroma. Previous reports of colorectal cancer suggest that poorly differentiated clusters (PDCs) are a negative prognostic indicator. Here, we report on the association between PDCs and prognosis in SCC of the EAC. PDCs and tumor budding were histopathologically and immunohistochemically (cytokeratin AE1/AE3) analyzed in 31 cases of pre-treatment biopsy SCC of the EAC. Clusters in the stroma composed of < or ≥ 5 cancer cells were defined as tumor budding or PDCs, respectively. Entire tumors were initially scanned to identify greatest PDC density. Tumors with low or high PDC density were classified as low- and high-grade, respectively. Patients with high-grade PDCs had a significantly poorer outcome than those with low-grade. Even in cases of low-grade tumor budding, those with high-grade PDCs had a poor prognosis. Multivariate analysis results indicated that high-grade PDCs were associated with poor prognosis. PDC grade can provide a more accurate prognosis than tumor budding in SCC of the EAC.
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http://dx.doi.org/10.1007/s12105-018-0939-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513932PMC
June 2019

Multiple Thrombi in the Heart in Trousseau Syndrome Caused by Pancreatic Carcinoma.

J Stroke Cerebrovasc Dis 2018 May 2;27(5):e75-e77. Epub 2018 Mar 2.

Department of Neurology, Fukuoka University School of Medicine, Fukuoka, Japan. Electronic address:

A 65-year-old woman presented to our emergency room because of sudden onset of right hemiparesis with severe fatigue. Neurological examination revealed right hemiparesis with right facial numbness and an extensor planter response on the right side.Magnetic resonance imaging with diffusion-weighted imaging revealed multiple highintensity areas in both cerebral hemispheres and the right cerebellum. A diagnosis of acute stage of multiple brain infarctions caused by emboli was made. An abdominal computed tomography showed a pancreatic tumor with multiple liver metastases. High D-dimer and serum carbohydrate antigen 19-9 concentration strongly suggested Trousseau syndrome associated with pancreatic cancer. The patient had another large embolic stroke and died on day 47. Autopsy was performed. There were large thrombi in the left ventricular apex and in the left atrial appendage There was also a papillary-shaped vegetation on the aortic valve that consisted mainly of fibrin without any inflammatory cells or destruction of the valve, these findings being characteristic of NBTE. This case is remarkable in that the patient had 3 different types of cardiac thrombi in her heart associated with Trousseau syndrome.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2017.12.005DOI Listing
May 2018

A rare case of dedifferentiated liposarcoma of the sinonasal cavity: A case report.

Mol Clin Oncol 2017 Oct 18;7(4):539-542. Epub 2017 Aug 18.

Department of Pathology, Fukuoka University School of Medicine, Fukuoka 814-0180, Japan.

Sarcoma is an uncommon histopathological presentation of sinonasal tumors, comprising ~15% of all cases; liposarcoma is particularly uncommon. An analysis of the available medical literature revealed no prior reports of dedifferentiated liposarcoma (DDLPS) of the sinonasal cavity. This case report presents a rare case of DDLPS of the sinonasal cavity. A 40-year old six-week pregnant female was admitted with a left nasal obstruction. Endoscopic evaluation of the left nasal cavity revealed a polypoid lesion. A computed tomography scan indicated a mass invading the left nasal cavity, maxillary sinus and anterior ethmoid sinus with focal destruction of the surrounding bone. A biopsy of the tumor was performed and hematoxylin and eosin staining of the tissue sections revealed proliferation of atypical and pleomorphic spindle cells with enlarged or elongated hyperchromatic nuclei and occasional vacuolated cytoplasm arranged in short interlacing fascicles or storiform structures, accompanied by tumor necrosis. These findings were consistent with undifferentiated pleomorphic sarcoma. Immunohistochemically, the tumor cells were positive for cyclin dependent kinase 4, mouse double minute 2 homolog (MDM2) and adipophilin. Fluorescence hybridization (FISH) analysis revealed amplification of the MDM2 gene. Recently, undifferentiated pleomorphic sarcoma without areas of well-differentiated liposarcoma but with MDM2 amplification is regarded as conventional DDLPS. In the present case, the tumor was diagnosed as a DDLPS due to the results of histopathological, immunohistochemical and FISH analysis.
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http://dx.doi.org/10.3892/mco.2017.1379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5639279PMC
October 2017

Intra-articular angiofibroma of soft tissue of the knee: A case report.

Mol Clin Oncol 2017 Aug 21;7(2):229-232. Epub 2017 Jun 21.

Department of Orthopaedic Surgery, Faculty of Medicine, Fukuoka University, Fukuoka 814-0180, Japan.

Angiofibroma of soft tissue (AFST) is an extremely rare soft tissue neoplasm that typically presents as a slow-growing, painless mass in the extremities. The present study reports an unusual case of an intra-articular AFST occurring in the left knee of a 23-year-old female. Physical examination revealed a 3-cm, relatively mobile, elastic-hard, non-tender mass. Magnetic resonance imaging detected an intra-articular soft tissue mass with iso-signal intensity relative to skeletal muscle on T1-weighted sequences and heterogeneous high signal intensity on T2-weighted sequences. Contrast-enhanced fat-suppressed T1-weighted sequences demonstrated strong peripheral enhancement of the mass. An arthroscopic excision of the mass was performed. Histologically, the tumor was composed of spindle- or oval-shaped cells in a fibromyxoid stroma with a prominent vascular pattern. Immunohistochemically, the tumor cells were diffusely positive for vimentin and CD163 and focally positive for CD68, desmin and estrogen receptor. Based on these findings, the tumor was diagnosed as an AFST. The patient had no evidence of local recurrence within 9 months of follow-up. To the best of our knowledge, this is the first case of intra-articular AFST managed successfully with arthroscopic excision.
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http://dx.doi.org/10.3892/mco.2017.1298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5532633PMC
August 2017

Emmprin, released as a microvesicle in epithelioid sarcoma, interacts with fibroblasts.

Int J Oncol 2017 Jun 8;50(6):2229-2235. Epub 2017 May 8.

Department of Pathology, Fukuoka University Hospital and School of Medicine, Fukuoka, Japan.

Emmprin (extracellular matrix metalloproteinase inducer, CD147) is a glycosylated transmembrane protein, consisting of two immunoglobulin domains, that stimulates the production of matrix metalloproteinases (MMPs) by tumor-associated fibroblasts. These effects play important roles in tumor invasion and metastasis. However, the precise mechanisms by which emmprin acts on fibroblasts have not been fully elucidated, especially in sarcoma cells. Previously, we demonstrated that emmprin, expressed in conditioned medium collected from the epithelioid sarcoma cell line (FU-EPS-1), stimulates MMP-2 production via interactions with fibroblasts. In this study, we used microvesicles derived from sarcoma cells, and determined whether emmprin exists in the microvesicles, which enhance the production of MMP-2 via fibroblasts. Microvesicles released from FU-EPS-1 cells were shown to contain full-length emmprin, identified as a 45-kDa protein characterized by polylactosamine glycosylation. Microvesicles collected from FU-EPS-1 cells transfected with emmprin-specific siRNA or transduced with shRNA displayed significantly reduced MMP-2 production by fibroblasts compared with those from control-transfected cells. Our findings show that emmprin is released through microvesicle shedding in sarcoma cells, and emmprin in microvesicles regulates MMP-2 production by influencing the activity of fibroblasts located at sites distant from the tumor cells.
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http://dx.doi.org/10.3892/ijo.2017.3986DOI Listing
June 2017

Acyclovir resistant acute herpes simplex encephalitis associated with acute retinal necrosis: A case report and review of the literature.

Rinsho Shinkeigaku 2017 05 28;57(5):230-233. Epub 2017 Apr 28.

Departments of Neurology, Fukuoka University.

A 55-year-old man was admitted to our hospital for investigation of high fever, decreased consciousness and bilateral visual impairment. His cerebrospinal fluid analysis revealed pleocytosis of mononuclear cells and an increased protein concentration. FLAIR images revealed multiple high-intensity lesions in the frontal lobe, part of which was enhanced with gadolinium. Despite initiating treatment with acyclovir and corticosteroids, his consciousness and visual acuity deteriorated. Immunopathological examination of brain biopsies showed numerous herpes simplex virus type 2-positive neurons and macrophages, leading to a diagnosis of herpes simplex encephalitis (HSE). Fundoscopic examination revealed multiple foci of retinitis with vasculopathies, and inflammation in the anterior chamber and vitreous, indicating acute retinal necrosis (ARN). Foscarnet treatment was initiated in place of acyclovir and his consciousness improved, with a slight improvement in visual acuity. ARN is typically caused by a herpes virus infection limited to the eyeball, and rarely in combination with HSE. In such cases, there is a latency of approximately 2-4 weeks between ARN and the onset of encephalitis. Our case is unique in that HSE and ARN developed simultaneously, and it highlights that there may not always be a latency between the onsets of the two disorders. Finally, foscarnet should be considered in cases of HSE and ARN with acyclovir resistance.
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http://dx.doi.org/10.5692/clinicalneurol.cn-000959DOI Listing
May 2017

Immunohistochemical demonstration of EphA2 processing by MT1-MMP in invasive cutaneous squamous cell carcinoma.

Virchows Arch 2016 Jul 7;469(1):25-34. Epub 2016 Apr 7.

Department of Pathology, Fukuoka University Hospital and School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan.

Erythropoietin-producing hepatocellular receptor-2 (EphA2) overexpression is prevalent in many types of human cancers, and it has been reported that high EphA2 expression is correlated with malignancy. Recent studies revealed that processing of EphA2 by cleaving off the N-terminal portion by membrane-type 1 matrix metalloproteinase (MT1-MMP) promotes invasion via stimulation of Ras in cancer cells in vitro. The objectives of this study were to investigate the presence and role of EphA2 processing in cutaneous squamous cell carcinoma (SCC) tissues. EphA2 (C-terminal and N-terminal) and MT1-MMP expression patterns and levels were analyzed immunohistochemically in SCC (n = 70) and Bowen disease (BD; n = 20). Levels of MT1-MMP and EphA2 expression were evaluated using digital image analysis. Proximity between MT1-MMP and EphA2 in cancer cells and its effect on EphA2 processing were investigated using a combination of in situ proximity ligation assay (PLA) and Western blotting. Immunohistochemical analyses showed that levels of EphA2 N-terminal expression were significantly lower than those of EphA2 C-terminal expression in SCC, whereas levels of EphA2 C- and N-terminal expression were similar in BD. Western blotting showed processed EphA2 fragments in human SCC tissues. Expression levels of MT1-MMP, EphA2, and processed EphA2 fragments were higher in SCC than BD. Proximity between MT1-MMP and EphA2 in SCC was demonstrated by in situ PLA. Our results suggest possible involvement of MT1-MMP processing of EphA2 in invasiveness of cutaneous SCC.
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http://dx.doi.org/10.1007/s00428-016-1934-9DOI Listing
July 2016

Tumor budding and laminin5-γ2 in squamous cell carcinoma of the external auditory canal are associated with shorter survival.

Springerplus 2015 24;4:814. Epub 2015 Dec 24.

Department of Pathology, Fukuoka University School of Medicine and Hospital, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180 Japan.

Squamous cell carcinoma (SCC) of the external auditory canal (EAC) is rare, usually presents at an advanced stage, and is a more aggressive tumor with poor prognosis. The University of Pittsburgh TNM staging system commonly used in prognostication is not perfect, and more accurate biomarkers predicting prognosis are needed. Tumor budding is an established negative prognostic factor at the invasive front in colorectal cancer. Moreover, immunohistochemical studies showed that laminin 5-γ2 (Ln5-γ2) is expressed at the invasive front in tumor or tumor budding cells. We assessed the prognostic significance of tumor budding and Ln5-γ2 expression by performing Ln5-γ2 immunohistochemistry and evaluated the degree of tumor budding in pre-treatment biopsy specimens, and investigated their correlations to clinicopathological parameters in patients with SCC of the EAC. Patients whose tumors had high budding grade and Ln5-γ2 expression had significantly shorter survival times. Budding grade was significantly correlated with Ln5-γ2 expression. Multivariate analysis revealed that high budding grade predicted poorer prognosis regardless of disease stage. Our results suggested that budding grade and Ln5-γ2 expression can be used as indicators of poor prognosis in patients with SCC of the EAC.
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http://dx.doi.org/10.1186/s40064-015-1620-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4690822PMC
January 2016

Prolactin-producing pituitary adenoma with atypical spindle cell morphology: a case report.

World J Surg Oncol 2015 Jul 31;13:229. Epub 2015 Jul 31.

Department of Pathology, School of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan.

Reported herein is a 25-year-old woman who was treated for a large and highly atypical prolactin-producing pituitary adenoma. On presentation, she exhibited right hemiparesis and left-sided visual loss, associated with amenorrhea. A massive (>5 cm) intra- and suprasellar lesion was seen on imaging, and her serum prolactin level was 4408 ng/ml. The patient received dopamine agonist treatment preoperatively for 4 weeks. To resect the tumor, a two-stage excision was required. Histologically, the specimen was composed of polygonal or spindle cells showing marked nuclear pleomorphism and/or multinucleation. Fibrosis was also focally conspicuous. Differential diagnoses included pituitary adenoma, pituitary carcinoma, pituicytoma, paraganglioma, spindle cell oncocytoma, and meningioma. Immunohistochemically, the tumor cells were positive for prolactin, chromogranin-A, and synaptophysin, but were negative for glial fibrillary acidic protein, S-100 protein, epithelial membrane antigen, and vimentin. No apparent cerebrospinal or systemic metastases are found. Ultimately, prolactin-producing pituitary adenoma was diagnosed. Our case highlights the difficulty in definitively diagnosing an unusual prolactin-producing adenoma based on histopathology alone and the importance of referring to clinical information and immunohistochemical findings when deriving the diagnosis.
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http://dx.doi.org/10.1186/s12957-015-0655-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521347PMC
July 2015

Proteolysis of EphA2 Converts It from a Tumor Suppressor to an Oncoprotein.

Cancer Res 2015 Aug 30;75(16):3327-39. Epub 2015 Jun 30.

Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Tokyo, Japan. Integrated Center for Advanced Medical Technologies, Kochi Medical School, Kochi, Japan.

Eph receptor tyrosine kinases are considered candidate therapeutic targets in cancer, but they can exert opposing effects on cell growth. In the presence of its ligands, Eph receptor EphA2 suppresses signaling by other growth factor receptors, including ErbB, whereas ligand-independent activation of EphA2 augments ErbB signaling. To deploy EphA2-targeting drugs effectively in tumors, the anti-oncogenic ligand-dependent activation state of EphA2 must be discriminated from its oncogenic ligand-independent state. Because the molecular basis for the latter is little understood, we investigated how the activation state of EphA2 can be switched in tumor tissue. We found that ligand-binding domain of EphA2 is cleaved frequently by the membrane metalloproteinase MT1-MMP, a powerful modulator of the pericellular environment in tumor cells. EphA2 immunostaining revealed a significant loss of the N-terminal portion of EphA2 in areas of tumor tissue that expressed MT1-MMP. Moreover, EphA2 phosphorylation patterns that signify ligand-independent activation were observed specifically in these areas of tumor tissue. Mechanistic experiments revealed that processing of EphA2 by MT1-MMP promoted ErbB signaling, anchorage-independent growth, and cell migration. Conversely, expression of a proteolysis-resistant mutant of EphA2 prevented tumorigenesis and metastasis of human tumor xenografts in mice. Overall, our results showed how the proteolytic state of EphA2 in tumors determines its effector function and influences its status as a candidate biomarker for targeted therapy.
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http://dx.doi.org/10.1158/0008-5472.CAN-14-2798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4682662PMC
August 2015

[A case of ganglioglioma extended to the lateral ventricle and associated with neurofibromatosis type 1].

No Shinkei Geka 2015 Feb;43(2):147-52

Department of Neurosurgery, Fukuoka City Hospital.

We encountered a rare case of intraventricular ganglioglioma associated with neurofibromatosis type 1. A 42-year-old woman presented with a feeling of heaviness of the head and dizziness. She was diagnosed with neurofibromatosis type 1 because she had multiple subcutaneous neurofibromas and café au lait spots. On admission, she deteriorated slightly(Japan Coma Scale 1)and suffered from cognitive dysfunction and right hemiparesis. A computed tomography(CT)scan showed that she had an obstructed hydrocephalus with a long and circular mass lesion, 2cm in diameter, in the anterior horn of the left lateral ventricle. The mass showed low signal intensity(SI)on the T1-weighted image(WI), heterogeneous high SI on the T2-WI, and dense enhancement on a Gd-DTPA contrast MRI, extending from the head of the left caudate nucleus to the lateral ventricle. The patient underwent an urgent operation via an anterior transcallosal approach because of an obstructed hydrocephalus. The tumor was removed in its entirety, including its origin at the caudate head. The pathological diagnosis was a ganglioglioma grade 1 according with the classification of the World Health Organization. Here we describe this case and discuss the rare association between gangliogliomas and neurofibromatosis type 1.
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http://dx.doi.org/10.11477/mf.1436202972DOI Listing
February 2015

FDG PET/CT and MR imaging of CD34-negative soft-tissue solitary fibrous tumor with NAB2-STAT6 fusion gene.

Anticancer Res 2015 Feb;35(2):967-71

Department of Orthopaedic Surgery, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.

Extrapleural solitary fibrous tumor (SFT) is an uncommon mesenchymal neoplasm of intermediate biological potential. Herein, we describe the radiological, histological, immunohistochemical and molecular genetic features of an SFT arising in the left thigh of a 55-year-old woman. Magnetic resonance imaging exhibited a well-defined mass with intermediate signal intensity on T1-weighted sequences and heterogeneous high signal intensity on T2-weighted sequences. Contrast-enhanced T1-weighted sequences showed strong homogeneous enhancement of the mass. A prominent vascular pedicle was visible. Integrated positron-emission tomography (PET)/computed tomographic (CT) scan demonstrated a moderate 18F-fluorodeoxyglucose (FDG) uptake (maximum standardized uptake value, 4.45) in the mass. Following an open biopsy, wide excision of the tumor was performed. Histologically, the tumor was composed of a proliferation of spindle cells in a fibrous stroma with focal hyalinization. Thin-walled branching hemangiopericytoma-like vessels were observed. Immunohistochemically, the tumor cells were diffusely positive for signal transducer and activator of transcription 6 (STAT6) but negative for CD34. The MIB-1 labeling index was less than 5%. Subsequent reverse transcriptase-polymerase chain reaction analysis identified a nerve growth factor inducible-A binding protein 2-STAT6 gene fusion. Our case supports the utility of STAT6 immunohistochemistry as an adjunct in the diagnosis of soft-tissue SFT with loss of CD34 positivity. To the best of our knowledge, this is the first report showing the FDG PET/CT findings of soft-tissue SFT.
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February 2015

Extensive lipoma-like changes of myxoid liposarcoma: morphologic, immunohistochemical, and molecular cytogenetic analyses.

Virchows Arch 2015 Apr 4;466(4):453-64. Epub 2015 Feb 4.

Department of Pathology, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan,

Myxoid liposarcomas (MLSs) with extensive lipoma-like changes (MLSLC) are rare, and it is often difficult to distinguish them from well-differentiated liposarcoma (LS)/dedifferentiated LS (WDLS/DDLS) with myxoid changes. For the characterization of these neoplasms, we studied 8 MLSLCs, 11 ordinary MLSs, 4 WDLSs, and 6 DDLSs. Cytogenetically, MLSLC and ordinary MLS were characterized by t(12;16)(q13;p11) and FUS-DDIT3 fusion gene, whereas WDLS/DDLS lacked the fusion gene but possessed giant marker/ring chromosomes. Both lipoma-like and myxoid components of the same MLSLC exhibited the identical FUS-DDIT3, as confirmed by fluorescence in situ hybridization (FISH) and reverse transcription polymerase chain reaction (RT-PCR). Immunohistochemically, MDM2 and CDK4 were positive in WDLS/DDLS but negative in MLSLC and ordinary MLS. PPARγ, C/EBPα, adipophilin, and perilipin were found in each type of LS. Adipophilin was expressed chiefly in tiny fat droplets of immature lipoblasts, whereas perilipin showed a strong positive staining in large fat vacuoles of signet ring and multivacuolated lipoblasts. The Ki-67 labeling index was lower in the lipoma-like component of MLSLC when compared with the myxoid component of the same tumors as well as ordinary MLS (p < 0.001). When compared with ordinary MLS, MLSLC may be less aggressive in clinical behavior (rare recurrences or metastases) after a wide surgical excision. In conclusion, the distinction between MLSLC and WDLS/DDLS is important, because of the differences of molecular cytogenetic features as well as clinical behaviors between these distinct sarcomas presenting similar morphologic features. In addition, the combined immunohistochemical detection of adipophilin and perilipin may provide a useful ancillary tool for identification of lipoblastic cells in soft tissue sarcomas.
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http://dx.doi.org/10.1007/s00428-015-1721-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4392166PMC
April 2015

Giant cell tumor of the patella: An uncommon cause of anterior knee pain.

Mol Clin Oncol 2015 Jan 1;3(1):207-211. Epub 2014 Oct 1.

Departments of Orthopaedic Surgery and Fukuoka University, Fukuoka 814-0180, Japan.

The patella is a rare site for the development of primary tumors. This is the case report of a giant cell tumor (GCT) occurring in the patella in a 25-year-old woman. The patient presented with a 1-year history of occasional right anterior knee pain. The radiological characteristics suggested a benign condition. The intraoperative pathological diagnosis was GCT of the bone. The lesion was treated by radical curettage with adjuvant therapy comprising phenol and ethanol and injection of calcium phosphate cement. Histologically, the tumor consisted of round or spindle-shaped mononuclear cells admixed with numerous osteoclastic giant cells. The patient was asymptomatic and there was no evidence of local recurrence or distant metastasis 16 months after surgery. Although rare, patellar GCT may be included in the differential diagnosis of anterior knee pain and/or swelling, particularly in young adults.
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http://dx.doi.org/10.3892/mco.2014.433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4251109PMC
January 2015
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