A Case of Uterine Tumor Resembling Ovarian Sex Cord Tumor With Prominent Myxoid Features.

Uterine tumor resembling ovarian sex cord tumor (UTROSCT) is a rare tumor with low malignant potential that commonly occurs in middle age. Although more than 100 cases have been reported to date, myxoid morphology is not well documented. Here, we present a 75-yr-old woman with abnormal vaginal bleeding, with an 8-cm mass in the uterine corpus detected by irregular, high-intensity signaling on T2-weighted imaging. The uterine mass had a glistening mucinous appearance on gross examination. Microscopically, most of the tumor cells were floating in the myxoid stroma. The tumor cells formed clusters or nests with abundant cytoplasm, while some exhibited trabecular or rhabdoid appearances. Immunohistochemically, tumor cells were positive for pancytokeratin (AE1/AE3), α-smooth muscle actin, CD10, progesterone receptor, and some sex cord markers such as calretinin, inhibin, CD56, steroidogenic factor-1. Electron microscopy demonstrated epithelial and sex cord differentiation. This tumor was negative for JAZF1-JJAZ1 fusion gene that is frequently found in low-grade endometrial stromal sarcoma. Fusion genes related to UTROSCT, including NCOA2/3 , were not detected by reverse transcription polymerase chain reaction. The present case suggests that UTROSCT should be included in the differential diagnosis of myxoid uterine tumors.

Ultrastructure of spinal anterior horn cells in human Niemann-Pick type C (NPC) patient and mouse model of NPC with retroposon insertion in NPC1 genes.

Niemann-Pick disease type C (NPC) is a neurovisceral lipid-storage disease. Although NPC patients show lipid storage in anterior horn cells of the spinal cord, little information is available regarding the electron microscopic analyses of the morphologies of intra-endosomal lipid like-materials in the anterior horn cells of NPC patients. In this study, we elucidated the intra-endosomal ultrastructures in spinal anterior horn cells in an NPC patient, as well as in mutant BALB/c NPC1-/- mice with a retroposon insertion in the NPC1 gene. These morphologies were classified into four types: vesicle, multiple concentric sphere (MCS), membrane, and rose flower. The percentages of the composition in the NPC patient and NPC1-/- mice were: vesicle (55.5% and 14.9%), MCS (15.7% and 3.4%), membrane (23.6% and 57.1%), and rose flower (5.2% and 24.6%), respectively. Formation of the intra-endosomal structures could proceed as follows: (i) a vesicle or MCS buds off the endosome into the lumen; (ii) when a vesicle breaks down, a membrane is formed; and (iii) after an MCS breaks down, a rose flower structure is formed. Our new finding in this study is that ultrastructural morphology is the same between the NPC patient and NPC1-/- mice, although there are differences in the composition.

Autopsy report of a late delayed radiation injury after a period of 45 years.

For delayed radiation injury, image analysis has considerably advanced, but neuropathological findings are still required to establish diagnosis. A patient who had received radiation therapy for pineal germinoma at age 14 developed neurological and psychiatric abnormalities after 15 years as a late delayed radiation injury. Autopsy at age 59 revealed diffuse changes in the white matter consisting in order of severity of myelin pallor, demyelination, and necrosis which were characterized by a lack of glial reaction. The cerebral cortex was relatively well preserved. As delayed radiation injuries, hyalinous changes in the vascular wall, angiomatous lesions and, fresh and old petechial hemorrhages were found. Moreover, vascular changes associated with arteriosclerosis were also present. Furthermore, a focal glial nodule was detected which was considered to be a new radiation-induced neoplasia. These findings suggest that late delayed radiation injury may slowly develop over 30 years and may involve damage to neuroglial stem cell compensation. It is also evident that arteriosclerotic changes and newly induced neoplasia may develop in delayed radiation injury cases.

Autopsy findings in the early stage of amyotrophic lateral sclerosis with "dropped head" syndrome.

Dropped head syndrome (DHS) has been rarely observed in amyotrophic lateral sclerosis (ALS), and the neuropathological findings of this condition have almost never been described. The identification of transactivation response DNA-binding protein 43 kDa (TDP-43), which binds to RNA/DNA has provided a new method for studying ALS and frontotemporal lobar degeneration (FTLD). Post-mortem examination of an adult sudden death case of a 71-year-old patient who complained of DHS exhibited severe loss of anterior motor neurons in the cervical cord (C4-6). Loss of nerve fibers of the anterior roots was striking compared with posterior roots, together with marked neurogenic atrophy of posterior muscles semispinalis cervicis. Bunina bodies were found in large neurons of Betz giant cells, but not in the motor neurons of spinal cords, or neurons of bulbar regions. Phosphorylated TDP-43 (p-TDP-43)-positive structures were detected in the residual neurons of the cervical, thoracic and lumber cords, hypoglossal nucleus, cerebellar dentate nucleus and parahippocampal cortex, together with ubiquitin-positive inclusions. Phosphorylated Tau positive structures in neuronal cytoplasm were found in the amygdala, entorhinal cortex and parahippocampal cortex, some of which co-expressed p-TDP-43. The medial zone of cervical cords may be the first onset site, and that is the cause of head drop in the early stage of ALS. In spite of detailed examination, the direct cause of sudden death was not verified. This autopsy report revealed the relation of DHS which is a rare clinical manifestation of ALS, and neuropathological findings.

"Integrated diagnosis" of pilocytic astrocytoma: Molecular diagnostic procedure for an unusual case.

A 24 year-old female presented with a mass lesion in the right temporal lobe. This case was difficult to diagnose using histological and immunological methods and therefore molecular analyses were applied to provide a definitive diagnosis. The tumor was well-demarcated, partially cystic, and irregularly-enhanced on gadolinium-enhanced T1-weighted magnetic resonance images. Pathologically, a large part of the tumor consisted of cells with fine cytoplasmic processes on a myxoid and mucinous background. Cells formed a microcystic structure around the mucinous tissue. Numerous eosinophilic granular bodies, but not Rosenthal fibers, were present. The solid and compact regions of the tumor were composed of fasciculation of dense fibrous glial tissues and occasional multinucleated giant cells. Tumor cells and their fragmented cytoplasmic processes were positively stained with GFAP, while eosinophilic granular bodies were both positive and negative. Xanthomatous changes were not detected and the reticulin fibers were restricted to vascular tissues. The MIB1 index was scored as approximately 10%. In molecular analyses of BRAF, the KIAA1549-BRAF (K16-B9) fusion gene was detected in all tumor regions, whereas BRAF V600E mutation was not detected by either conventional Sanger sequencing or the Eprobe-PCR method. Based on the results of the molecular analyses, this case was diagnosed as pilocytic astrocytoma.

A case of giant cell-rich solitary fibrous tumor in the external auditory canal.

We present a rare case of giant cell-rich solitary fibrous tumor (SFT) arising at the left external auditory canal in a 31-year-old woman. The tumor was well-circumscribed and composed of spindle-shaped cells with abundant collagenous bands. Scattered multinucleate giant cells were observed, some of which lined pseudovascular spaces. Although a focal mild-hypercellular area was observed, mitoses were rare and necrosis was absent. Interstitial mast cells were scattered, especially in the hypercellular area. Immunohistochemically, CD34, vimentin, and Bcl-2 presented diffuse positivity. Moreover, both mononuclear spindle cells and multinucleate cells showed nuclear STAT6 positivity, while NAB2-STAT6 fusion gene could not be detected by reverse transcription polymerase chain reaction using formalin-fixed specimen. These findings suggest the pathological diagnosis of giant cell-rich SFT, previously known as giant cell angiofibroma, which is a rare variant of SFT with multinucleate giant cells and occurs predominantly in orbital region. Although giant cell-rich SFTs of extra-orbital sites have been reported, to our knowledge, this is the first case arising in the external auditory canal. Giant cell-rich SFT should be considered as a differential diagnosis of spindle cell lesion with multinucleate giant cells, and STAT6 immunohistochemistry should be performed to distinguish this rare tumor from other mesenchymal neoplasms.

Tyr724 phosphorylation of ELMO1 by Src is involved in cell spreading and migration via Rac1 activation.

BACKGROUND: The complex of Dock180/ELMO1 that functions as a bipartite guanine nucleotide exchange factor for Rac is essential for diverse physiological and pathological processes of cells such as cell migration, phagocytosis, and invasion of cancer cells. Among the Src-family tyrosine kinases (SFKs), it has been reported that Hck directly phosphorylates ELMO1, regulating phagocytosis by promoting activation of Rac1; however, the involvement of other SFKs in ELMO1 phosphorylation has remained unknown. Here, we identified novel tyrosine (Y) residues of ELMO1 phosphorylated by SFKs, and examined the effects on Rac1 activity, cell adhesion, spreading, and cell motility on extracellular matrix (ECM). RESULTS: In this study, we unveiled that Src and Fyn can induce tyrosine phosphorylation of ELMO1 in in vivo and in vitro phosphorylation assays. Mutational analyses identified both Y720 and Y724 residues of ELMO1 as Src-mediated phosphorylation sites, preferentially on Y724. Single substitution of Y724 to Phe abrogated Rac1 activation triggered by Src. To elucidate the biological function of pY724, we established NIH3T3 cells stably expressing wild-type ELMO1 or its Y724F mutant together with Dock180. Among them, Y724-deficient cells exhibited a depletion of Rac1 activity with diminished phosphorylation of ELMO1 even upon the ECM-stimulation. It is noteworthy that NIH3T3 cells with ELMO1 Y724F were strikingly defective to promote cell spreading on fibronectin-coated dish, concomitantly exhibiting immature assemblies of actin stress fibers and focal adhesions. Eventually, ELMO1 Y724F significantly impaired cell migration. CONCLUSION: These results define that Src-mediated Y724 phosphorylation in ELMO1 plays a critical role for cell spreading via activation of Rac1, leading to promotion of cell migration. As the overexpression and/or hyperactivation of Src have been shown in a wide variety of human cancers, Src-mediated phosphorylation of Y724 in ELMO1 may regulate cancer cell adhesion to the ECM, invasion into surrounding tissues, and subsequent distant metastasis.

[Clinicopathological Study of Pilomyxoid-Spectrum Astrocytomas:An Analysis of the BRAF Gene. Report of Two Cases].

In contrast to pilocytic astrocytomas(PAs), pilomyxoid astrocytomas(PMAs)demonstrate monophasic piloid cells with angiocentric distribution and a more aggressive clinical course. Recently, several reports have described combined histological features of both subtypes;accordingly, these were termed intermediate pilomyxoid tumors(IPTs). The KIAA1549-BRAF fusion gene has been found in approximately 70% of PAs, but is reportedly rare in PMAs. We describe a clinicopathological study of two patients with pilomyxoid-spectrum astrocytoma(PMSA). Case 1 was of a 29-year-old man who presented with a generalized seizure. Gadolinium-magnetic resonance imaging(Gd-MRI)demonstrated a less enhanced tumor in the left temporal lobe. Case 2 was of a 9-year-old boy who presented with headache. Gd-MRI revealed an irregularly enhanced tumor in the left cerebellum. In Case 1, the tumor showed monomorphous bipolar cells in a myxoid background and angiocentric arrangement;therefore, the diagnosis was PMA. In Case 2, part of the tumor had a myxoid, angiocentric pattern characteristic of PMA;the other part had a biphasic pattern characteristic of PA. PMA and PA were mixed in a 7:3 ratio;therefore, IPT was diagnosed. No BRAF V600E mutations were found by immunohistochemistry and sequencing in either case. Three major KIAA1549-BRAF fusion subtypes were analyzed by quantitative reverse transcription polymerase chain reaction(RT-PCR)and sequencing. No fusions were found in Case 1. However, K16-B9 fusion was identified in Case 2, and this fusion was more prevalent in the PA component than in the PMA component. In summary, no BRAF V600E mutations were found in PMSAs, but KIAA1549-BRAF fusion was identified in IPT, particularly in the PA component.

[A Case of Acute Lymphoblastic Leukemia with Adult-Onset Still's Disease-Like Erythema].

A 62-year-old woman developed B lymphoblastic leukemia (B-ALL) in April 2010, and achieved complete remission after hyper-CVAD/high-dose-MA therapy combined with rituximab. ALL recurred in December 2011, and remission was again achieved with the Japan Adult Leukemia Study Group (JALSG) ALL202 protocol combined with rituximab. Owing to a fever and rash that persisted from July 2012, the patient was examined again. On examination, redness was observed in the pharynx, and poorly defined oval erythemas were seen on the cheeks, posterior region of the neck, and upper arms. Blood test results showed high levels of ferritin, tumor necrosis factor (TNF)-α, an d C-reactive protein (CRP), and mild hepatosplenomegaly was identified on abdominal computed tomography (CT), indicative of an adult-onset Still's disease-like condition. Prednisolone therapy was initiated in August 2012, and remission was achieved. A second recurrence of ALL developed in September 2012, and although remission was again achieved using the JALSG ALL202 protocol, a third recurrence of ALL occurred in April 2013, and the patient could not be saved. In this case, adult-onset Still's disease-like erythema developed during the remission phase of ALL.

[Subcutaneous myeloid sarcoma in a patient with essential thrombocythemia that transformed into acute myeloid leukemia].

Since November 2008, an 80-year-old man had been administered hydroxyurea and aspirin for the treatment of essential thrombocythemia (ET). In January 2012, his white blood cell count was markedly elevated, and he was treated with busulfan and cytarabine. In October 2012, he was hospitalized because of fever and general malaise, and a central venous port was placed in the right anterior chest owing to difficulty obtaining peripheral vascular access. Approximately 2 weeks after port placement, a subcutaneous mass was observed near the port. The patient died in November 2012 owing to exacerbation of the original disease. Autopsy revealed transformation to acute myeloid leukemia( AML; M2 subtype) and myeloid sarcoma (MS) in lymph nodes and the right anterior chest. The incidence of transformation of ET to AML is low, and MS as a comorbidity is rare. However, the risk of MS complications should be considered in patients with hematological malignancies due to recent increases in the use of central venous ports in such cases.

Successful treatment of an essential thrombocythemia patient complicated by Sweet's syndrome with combination of chemotherapy and lenalidomide.

A 79-year-old man had been followed up since July 2003 based on a diagnosis of essential thrombocythemia (ET). The patient visited our hospital after developing a high fever and rash in August 2010, and Sweet's syndrome was diagnosed based on skin biopsy results. The bone marrow aspirate showed features like those of myelodysplastic/myeloproliferative neoplasm (MDS/MPN, unclassifiable). Administration of metenolone and azacitidine was initiated in March and May 2011, respectively, but the rash associated with Sweet's syndrome showed exacerbation. Ranimustine was therefore administered starting in July 2011 to control the blood cell count, but the rash associated with Sweet's syndrome persisted. Combination therapy with lenalidomide was initiated in September 2012, and resulted in control of the blood cell count and marked improvement of Sweet's syndrome.

[Aortic root replacement with a freestyle stentless valve for prosthetic valve detachment caused by aortitis syndrome; report of a case].

A surgical case of a 65-year-old man with aortitis syndrome is presented. The patient had undergone aortic valve replacement for aortic valve regurgitation with a mechanical prosthesis, followed by a re-do operation (valve fixation) for prosthetic valve detachment 6 months after the 1st operation. Three months after the 2nd operation, perivalvular leakage due to valve detachment was detected again. Aorticroot replacement with a Freestyle stentless valve( full root technique) was performed. Prednisolone was given postoperatively, and no valve detachment nor pseudoaneurysm formation has been noted for 8 years.

[Combined modality therapy for a patient with primary adrenal lymphoma].

A 71-year-old man with malaise, anorexia, and weight loss was referred to our hospital from a clinic. Abdominal computed tomography(CT)revealed bilateral adrenal masses. An ultrasound-guided percutaneous needle biopsy of the adrenal grand indicated diffuse large B-cell lymphoma. A rapid adrenocorticotropic hormone(ACTH)test revealed primary adrenal failure. Rituximab-cyclophosphamide/doxorubicin/vincristine/prednisolone(common name, R-CHOP)therapy accompanied by intrathecal treatment was initiated along with steroid replacement therapy. After the fourth courses, a CT scan showed a reduction of the adrenal masses, and there was no[18F]-fluorodeoxyglucose(FDG)uptake in the adrenal masses. The patient has remained in metabolic complete remission. Subsequently, both adrenal lymphomas were irradiated. The patient has been disease-free for 6 months after the diagnosis of primary adrenal lymphoma. The combined modality of chemoradiation therapy plus intrathecal treatment could be effective for primary adrenal lymphoma with a poor prognosis.

Thymus-derived leukemia-lymphoma in mice transgenic for the Tax gene of human T-lymphotropic virus type I.

Adult T-cell leukemia-lymphoma (ATLL) is a group of T-cell malignancies caused by infection with human T-lymphotropic virus type I (HTLV-I). Although the pathogenesis of ATLL remains incompletely understood, the viral regulatory protein Tax is centrally involved in cellular transformation. Here we describe the generation of HTLV-I Tax transgenic mice using the Lck proximal promoter to restrict transgene expression to developing thymocytes. After prolonged latency periods, transgenic mice developed diffuse large-cell lymphomas and leukemia with clinical, pathological and immunological features characteristic of acute ATLL. Transgenic mice were functionally immunocompromised and they developed opportunistic infections. Fulminant disease also developed rapidly in SCID mice after engraftment of lymphomatous cells from transgenic mice. Flow cytometry showed that the cells were CD4(-) and CD8(-), but CD44(+), CD25(+) and cytoplasmic CD3(+). This phenotype is indicative of a thymus-derived pre-T-cell phenotype, and disease development was associated with the constitutive activation of NF-kappaB. Our model accurately reproduces human disease and will provide a tool for analysis of the molecular events in transformation and for the development of new therapeutics.

[Primary myelofibrosis complicated by acquired hemophilia A and subsequent development of acute myeloid leukemia].

A 77-year-old man diagnosed with primary myelofibrosis (PMF), successfully controlled by thalidomide and prednisolone, was referred to us for massive subcutaneous bleeding involving the face, body, and all four limbs. Hemostatic studies showed prolonged activated partial thromboplastin time, decreased factor VIII coagulation, and a high factor VIII inhibitor titer, resulting in a diagnosis of acquired hemophilia A (AHA) for which he was treated with prednisolone and cyclophosphamide on admission. He developed right femoral intramuscular hemorrhage soon after immunosuppressive therapy and was treated with rituximab combined with activated prothrombin complex concentrates. Furthermore, he suffered complications of respiratory failure with increasing throat hemorrhaging. Recombinant activated factor VII (rFVIIa) was administered combined with methylprednisolone pulse therapy. Bleeding, including respiratory failure, was ameliorated with rFVIIa. Immunosuppressive rituximab therapy resolved AHA with marked efficacy. He died of Pneumocystis jiroveci pneumonitis. Autopsy showed transformation from PMF to acute myeloid leukemia.

[Hematologic improvement with deferasirox following tandem antithymocyte globulin treatment in a transfusion-dependent patient with severe aplastic anemia].

A 62-year-old man with transfusion-dependent severe aplastic anemia received immunosuppressive therapy (IST) with rabbit antithymocyte globulin and cyclosporine A in April 2010. However, his transfusion dependency did not improve. As more than 100 red blood cell (RBC) transfusions had been performed, he was administered iron chelation therapy (ICT) with deferasirox (DFX) to improve iron overload starting in July 2011. Consequently, both RBC and platelet transfusion dependency gradually improved concomitant with a decrease in serum ferritin. The bone marrow (BM) biopsy findings before administration of DFX showed severe iron accumulation and strong positive immunostaining for 8-OHdG, a marker of oxidative stress due to free iron. One year after ICT, the number of BM hematopoietic cells was increased and both iron deposition and oxidative stress were decreased. These findings suggest that DFX may contribute to hematological improvement in patients with IST-refractory aplastic anemia.

[Follicular lymphoma complicated with myelofibrosis and macroglobulinemia at initial presentation].

A 49-year-old woman presented with pharyngeal and cervical lymph node swelling in December 2010. Biopsy of the pharynx demonstrated follicular lymphoma which secreted large volumes of immunoglobulin M (IgM) and transforming growth factor-ß (TGF-ß). Bone marrow aspiration yielded a dry tap, and bone marrow biopsy demonstrated myelofibrosis associated with lymphoma cells on admission. The plasma concentration of TGF-ß was elevated and monoclonal IgM gammopathy was detected. After only one course of chemotherapy with CHOP plus rituximab, remission of both lymphoma and myelofibrosis was achieved. Bone marrow aspiration became possible, and TGF-ß and IgM levels normalized. Thus, the myelofibrosis was reversible.

[An elderly patient with large cell neuroendocrine carcinoma(LCNEC)for whom chemotherapy with irinotecan and split-dose cisplatin(CDDP)proved very effective].

Large cell neuroendocrine carcinoma(LCNEC)is a rare malignant disease with a poor and the clinical outcome. Although no standard chemotherapy regimen has been developed, LCNEC should be treated in a manner similar to that used for small cell lung cancer because of their similar chemosensitivity and aggressive characteristics, even though LCNEC is classified as non-small cell lung cancer. A 78-year-old man was admitted with the complaint of convulsions on the left side of his body. A chest computed tomographic(CT)scan on admission demonstrated a 4 cm mass in a left lung S9. Brain magnetic resonance imaging(MRI)revealed enhanced tumors in the left occipital lobe. The brain tumor was surgically resected and histological findings were diagnosed as LCNEC. After induction of 4 courses with irinotecan and split-dose cisplatin chemotherapy, a partial response was obtained. After 4 courses, the tumor size was increased, and the chemotherapy was changed to amrubicin. The patient is alive and with no relapse.

[Bendamustine-rituximab therapy is effective for transformed follicular lymphoma with significant expression of p53].

We describe a patient with transformed follicular lymphoma(FL), expressing p53 but remaining in complete remission(CR) due to bendamustine-rituximab(BR)therapy. She was a 64-year-old female diagnosed with stage IV FL(grade 3A)in July 2007 when she was admitted with right lower abdominal pain and body weight loss. Colonoscopy revealed Bauhin' valve lymphoma of the terminal ileum, and computed tomography(CT)scan showed lymphadenopathy, involving the cervical, mediastinal para-aortic lymph nodes and right tonsil. She received chemotherapy with eight courses of CHOP therapy with rituximab and achieved CR. Two and a half years later, mediastinal lymph node swelling relapsed, and ibritumomab tiuxetan therapy induced the second CR. After ten months, however, a third relapse occurred as a submucosal tumor(SMT)of the stomach. Gastric SMT biopsy showed diffuse large B cell lymphoma(DLBCL)transformation with immunohistochemical expression of p53. Although gastric SMT disappeared after radiotherapy, which achieved the third CR, lymph node swelling was detected again in the para-aortic and-iliac artery lymph nodes in September 2011. Subsequently, she was treated with five courses of BR therapy, because bendamustine had been reported to be effective for p53 gene-deficient B cell neoplasms. The therapy was successful and achieved the fourth CR, demonstrating that BR therapy was effective for p53-expressing DLBCL.