[A Case of a Metastatic Liver Tumor from a Thymic Carcinoma Detected During a Cesarean Section].

A 40-year-old pregnant woman who had previously been diagnosed with uterine myoma underwent cesarean section. During the operation, a tumor thought to be uterine myoma was found to be an extrauterine tumor arising from the upper abdomen. After the delivery of the fetus, a staging CT scan was performed, which revealed a huge, 18 cm, hepatic tumor in the left lateral segment, a mediastinal tumor with calcification, and multiple lung nodules. She underwent a left hepatic lobectomy and a wedge resection 8 days after the delivery. The initial pathological diagnosis was moderately differentiated neuroendocrine tumor (NET). However, as a primary hepatic NET is extremely rare, further immunohistochemical staining was performed. The tumor was positive for p63, CD5, c-kit, and bcl-2, indicating a diagnosis of thymic carcinoma with liver and lung metastases.

Vaccination-induced systemic autoimmunity in farmed Atlantic salmon.

Over half of the salmon consumed globally are farm-raised. The introduction of oil-adjuvanted vaccines into salmon aquaculture made large-scale production feasible by preventing infections. The vaccines that are given i.p. contain oil adjuvant such as mineral oil. However, in rodents, a single i.p. injection of adjuvant hydrocarbon oil induces lupus-like systemic autoimmune syndrome, characterized by autoantibodies, immune complex glomerulonephritis, and arthritis. In the present study, whether the farmed salmon that received oil-adjuvanted vaccine have autoimmune syndrome similar to adjuvant oil-injected rodents was examined. Sera and tissues were collected from vaccinated or unvaccinated Atlantic salmon (experimental, seven farms) and wild salmon. Autoantibodies (immunofluorescence, ELISA, and immunoprecipitation) and IgM levels (ELISA) in sera were measured. Kidneys and livers were examined for pathology. Autoantibodies were common in vaccinated fish vs unvaccinated controls and they reacted with salmon cells/Ags in addition to their reactivity with mammalian Ags. Diffuse nuclear/cytoplasmic staining was common in immunofluorescence but some had more specific patterns. Serum total IgM levels were also increased in vaccinated fish; however, the fold increase of autoantibodies was much more than that of total IgM. Sera from vaccinated fish immunoprecipitated ferritin and approximately 50% also reacted with other unique proteins. Thrombosis and granulomatous inflammation in liver, and immune-complex glomerulonephritis were common in vaccinated fish. Autoimmunity similar to the mouse model of adjuvant oil-induced lupus is common in vaccinated farmed Atlantic salmon. This may have a significant impact on production loss, disease of previously unknown etiology, and future strategies of vaccines and salmon farming.

Primary splenic diffuse large B-cell lymphoma manifesting in red pulp.

We evaluated six cases of diffuse large B-cell lymphoma (DLBCL) involving the red pulp of the spleen. All had B symptoms and an aggressive clinical course. The lymphoma cells proliferated diffusely and non-cohesively in the cords of the red pulp. The lymphoma involved the bone marrow in four of the five patients and the liver in all four of the patients examined. However, lymph node (LN) involvement was rare at presentation, and systemic LN involvement was not observed even in the terminal phase. The lymphoma cells infiltrated the intrasinusoidal/intravascular and interstitial spaces of the involved tissues and were detected in the peripheral blood in two of the six patients. CD5-expressing lymphoma cells were detected in four of the five patients examined. Because these cases had some unique clinical features and occurred in distinct splenic sites, we proposed that primary splenic DLBCL manifesting in red pulp is a distinct clinicopathological entity.

Large mediastinal cyst of an ectopic thyroid with small nodules diagnosed as papillary carcinoma.

A 49-year-old man was admitted to hospital for investigation of a mediastinal shadow seen on a chest radiograph. Chest completed tomography revealed a mediastinal mass of 65 x 55mm. At surgery, the mass was found to be contained within the upper mediastinum and adherent to the vertebrae, esophagus, trachea, and superior vena cava. We therefore selected sequential approaches using a lateral incision for the thoracotomy and a modified transmanubrial approach. The lateral incision enabled detachment of the adhesion between the mass and the posterior to median mediastinum, and the modified transmanubrial approach was useful for separating the mass from the upper to anterior mediastinum. The mass had no connection to the cervical thyroid gland. Histological examination revealed a large mediastinal cyst of an ectopic thyroid with small nodules diagnosed as papillary carcinoma. There was no recurrence 14 months after surgery.

Localized necrotizing angiitis of the ileum.

A 20-year-old woman was hospitalized repeatedly because of intermittent bouts of intestinal obstruction and the symptoms usually improved with conservative treatments. One year after the first admission the patient was hospitalized in emergency and a laparotomy revealed a circular stricture with a pinhole perforation in the ileum. Histological sections of the stricture showed the characteristic features of microscopic polyangiitis varying from active to resolving stages, which were localized in the ileum. Fibrinoid necrosis, fibroblastic and fibrous proliferation of the intima and fibrous replacement of the media with a variable pan- and perivascular inflammatory cell infiltrate were characteristic in the muscular arteries and arterioles. Vascular occlusion by pale eosinophilic, fibrillar-like materials resembling livedo racemosa of the skin, was noticed in the small arterioles and capillaries. Under no prophylaxis, the postoperative course was uneventful with no recurrence of the illness at an 18-month follow up. The pathological alterations were distributed focally, occasionally segmentally, and haphazardly, and required detailed examination by stepwise sections for the histological diagnosis.

[A case of membranous nephropathy with ANCA-associated necrotizing glomerulonephritis during oral administration of PTU for Graves' disease].

We experienced a coincidental case of two types of glomerulopathy associated with Graves' disease. A 64-year-old man, who had been treated with propylthiouracil(PTU) for Graves' disease for 15 years, was admitted to our hospital for macroscopic hematuria and rapidly progressive deterioration of renal function. Although his thyroid function had been within the normal range during treatment, the level of thyrotropin receptor antibody(TRAb) gradually increased from a year before admission. Serological tests revealed that he was positive for myeloperoxidase-antineutrophil cytoplasmic antibody(MPO-ANCA). The renal biopsy specimen showed necrotizing and crescentic glomerulonephritis(GN) superimposed on membranous nephropathy(MN). This is a rare case of MN complicated with ANCA associated crescentic GN in a Graves' disease patient. Association of these two renal alterations was not clearly defined. MN involved with Graves' disease also has been rarely reported. Some reports demonstrated deposition of thyroglobulin and other thyroid related antigens in the glomeruli. In the present case, long-term impairment of Graves' disease and elevation of TRAb might have been responsible for the formation and deposition of thyroid-associated immune complex in the glomeruli. As for crescentic GN, PTU might have induced ANCA-associated GN independently of MN. This case is instructive for considering the relation between Graves' disease and renal injury.

Infectious mononucleosis lymphoadenitis showing histologic findings indistinguishable from toxoplasma lymphadenitis. A report of three cases.

Lymph node lesions in infectious mononucleosis (IM) show a marked histologic diversity. We report here three cases of IM lymphadenitis with histologic findings indistinguishable from those of toxoplasmic lymphadenitis. The histologic findings of the three cases presented here showed a histologic triad of toxoplasmic lymphadenitis, including (i) numerous lymphoid follicles with hyperplastic germinal centers; (ii) small clusters or single epithelioid histiocytes; and (iii) multiple foci of monocytoid B-cells. Moreover, all three lesions contained isolated or small clusters of epithelioid histiocytes within the hyperplastic germinal centers and the periphery of lymphoid follicles, which are the most specific histologic findings of toxoplasmic lymphadenitis. However, serologic findings confirmed EBV infection in all three cases. On in situ hybridization, numerous Epstein-Barr virus (EBV)-encoded small RNA (EBER)-positive cells were demonstrated in the germinal center, as well as in interfollicular areas in all three cases. Toxoplasmosis gondii infection was excluded in at least one case, based on serologic findings. Polymerase chain reaction analysis also demonstrated that there was no T. gondii DNA in the remaining two cases. Two of our three cases showed atypical clinical presentations, including an absence of atypical lymphocytosis in peripheral blood in two cases, age more than 30 years, and an absence of systemic symptoms in one case. It appears that previous descriptions emphasize the differential diagnostic problems between IM lymphadenitis and malignant lymphomas. However, from a therapeutic perspective, it is important to discriminate IM lymphadenitis from toxoplasmic lymphadenitis particularly in patients showing atypical clinical features.

[Thyroid crisis and protein C deficiency in a case of superior sagittal sinus thrombosis].

We report the case of a 28-year-old woman who presented simultaneously with superior sagittal sinus thrombosis and thyroid crisis, and was subsequently found to have protein C deficiency. February 3, 2003, she admitted complaining of abdominal pain. The diagnosis of appendicitis was made, and she was operated on under lumbar anaesthesia. Day 7, she developed acute headache and distal weakness of the left lower limb. On examination she was alert, with a temperature of 38 degrees C, a sinus tachycardia of 124/min and blood pressure 164/84 mmHg. Neurological examination revealed neck stiffness and left hemiparesis, predominantly in her lower limb. Gadlinium-enhanced brain MRI revealed extensive superior sagittal sinus thrombosis. CT scan demonstrated infarction in the right frontal cortex, and subarachnoid hemorrhage adjacent to the right cerebellar tentorium. The patient was treated with a free radical scavenger edarabon, and glycerin. No anticoagulant therapy was instituted. Over the next 24 hours, her condition worsened. She became comatose, as well as developing a generalized tonic-clonic seizure. Day 12, laboratory examinations revealed an undetectable TSH-level CTSH (thyroid stimulating hormone) <0.005 mcIU/ml), with a level of free thyroxin 7.77 ng/dl (0.9-1.7), free triiodothyronin 29.6 pg/ml (2.3-4.3), and positive anti-TSH receptor antibodies determined subsequently. Coagulation factor VIII activity was 155% (normal range 60-150). Protein C deficiency (antigen 59%, activity 49%) was also present, suggesting a congenital type I heterozygous deficiency. A diagnosis of thyroid crisis on the basis of Graves' disease was made. The patient remained comatose and died on Day 16, with renal failure. The patient had protein C deficiency, a well-established risk factor for cerebral venous thrombosis (CVT). However, additional risk factors are required in most cases to precipitate CVT. In our case, this trigger was most likely thyroid crisis, suggesting that thyrotoxicosis, probably through hypercoagulability, may be a predisposing factor for the development of CVT.

Epstein-Barr virus-related reactive lymphoproliferative disorders in middle-aged or elderly patients presenting with atypical features. A clinicopathological study of six cases.

We report six cases of Epstein-Barr virus (EBV)-associated lymphoproliferative disorders (LPDs) in middle-aged and elderly patients exhibiting atypical clinical findings. The patients, two males and four females, ranged in age from 52 to 74 years, with a median age of 64 years. Clinically, they were characterized by tonsillar tumor, cervical lymphadenopathy, and absence of atypical lymphocytosis of the peripheral blood. "B"symptoms were recorded in only two cases. Pancytopenia was recorded in one case during the disease course. The clinical course was self-limited. Histologically, all lesions were characterized by effacement of the follicles and expansion of the interfollicular area with proliferation of small vessels, indicating atypical lymphoid proliferation. In the interfollicular area, there was a mixed infiltrate, including small-to-medium-sized lymphocytes, plasma cells, and T-and B-immunoblasts. Immunoblasts resembling Reed-Sternberg cells were observed in four lesions. Three lesions contained numerous mature plasma cells, plasmacytoid cells, and immature plasma cells in some areas. In situ hybridization demonstrated a varying number of EBV-infected lymphocytes in the interfollicular area. The overall histomorphologic findings of the present six cases were similar to those of infectious mononucleosis (IM) in younger patients. However, the clinical findings were quite different from those of IM in the younger age population. To avoid overdiagnosis and overtreatment, we emphasize the need to be aware of the atypical clinical presentation of EBV-related LPDs in middle-aged or elderly patients, and to turn careful attention to these clinical and laboratory findings as well as to the morphologic features.

Regulatory role of hepatocyte nuclear factor-4alpha on gastric choriocarcinoma function.

Gastric choriocarcinoma is a highly aggressive carcinoma, most probably originating from somatic cells in the gastric mucosal layer. We herein investigated the regulatory role of hepatocyte nuclear factor (HNF)-4alpha, a transcriptional regulator expressed in non-neoplastic and neoplastic gastric tissues, on functions of gastric choriocarcinoma cells. HNF-4alpha cDNA was stably transfected to a gastric choriocarcinoma cell line, SCH. Alterations in SCH cell functions such as histology, ultrastructure, proliferation, production of trophoblast-specific proteins, and chemosensitivity to methotrexate (MTX) were examined. Neither in vitro and in vivo proliferations nor HLA-G expression differed significantly between the mock-transfected and HNF-4alpha-transfected SCH cells, while suppressed human chorionic gonadotropin (hCG) secretions, increased human placental lactogen (hPL) and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) immunoreactivity, and decreased chemosensitivity to MTX were seen in HNF-4alpha-transfected SCH cells. General histologic features in xenograft nodules were unaltered, but, ultrastructurally, fascicles of paranuclear filaments were significantly more numerous in HNF-4alpha-transfected SCH cells. These results indicated an HNF-4alpha-rendered functional regulation in SCH cells, suggesting a role of transcriptional factors abundant in gastric but not in trophoblastic tissues/cells on the functional modulation of gastric choriocarcinoma cells.

Region-dependent role of the mucous/glycocalyx layers in insulin permeation across rat small intestinal membrane.

The regional difference in the contribution of the mucous/glycocalyx layers in rat small intestine, as a diffusional or enzymatic barrier, to the absorption of insulin was investigated by in vitro studies. The mucous/glycocalyx layers from the duodenum, the jejunum, and the ileum in rat were successfully removed without damaging membrane integrity, by exposing them to a hyaluronidase solution in situ. In an in vitro transport experiment, the apparent permeability coefficient (P(app)) of insulin for the hyaluronidase-pretreated group was significantly increased compared to the PBS-pretreated (control) group in all small intestinal regions, and the P(app) of insulin in both PBS- and hyaluronidase-pretreated groups increased in the following order: duodenum < jejunum < ileum. On the other hand, irrespective of small intestinal regions, the P(app) of FD-4 and of antipyrine, respectively the passive para- and transcellular permeation marker, exhibited no significant differences between PBS- and hyaluronidase-pretreated group. In addition, a significant amount of insulin was degraded in the mucous/glycocalyx layers compartment removed by hyaluronidase pretreatment, and the degradation activity in the mucous/glycocalyx layers showed regional differences in the following order: duodenum > jejunum > ileum. These findings suggest that, irrespective of small intestinal regions, the mucous/glycocalyx layers contributed to insulin permeation predominantly as an enzymatic barrier, and not as a diffusional barrier. Furthermore, the variation of the enzymatic activities in the mucous/glycocalyx layers and in the brush-border membrane would be one factor that accounts for the regional differences in the transport of insulin.

Fc receptor-independent development of autoimmune glomerulonephritis in lupus-prone MRL/lpr mice.

OBJECTIVE: To determine the role of Fc receptors (FcR), which play crucial roles in antibody and immune complex-mediated inflammation and autoimmunity, including glomerulonephritis (GN), in the development of autoimmune GN and vasculitis in MRL/lpr mice, one of the most widely used lupus-prone mouse models. METHODS: FcRgamma(-/-) MRL/lpr mice were generated by backcrossing for 8 generations. The development of GN and vasculitis of various sized vessels was analyzed histopathologically in the kidney, lung, and skin. Autoantibody and immune complex levels were determined biochemically at 16-24 weeks of age and compared with the findings in FcRgamma(+) MRL/lpr mice. The lifespan of the mice was also recorded. RESULTS: Diffuse proliferative GN, with deposition of IgG and C3, developed in both FcRgamma(-/-) and FcRgamma(+) MRL/lpr mice. There was no difference in the survival rate and degree of proteinuria between FcRgamma(+) and FcRgamma(-/-) MRL/lpr mice. Regardless of the level of FcR expression, there were no significant differences in the levels of serum IgG, anti-DNA antibody, or circulating immune complexes between the two types of mice. Necrotizing vasculitis in medium-sized arteries of the kidneys and lungs as well as small-vessel vasculitis in the skin was observed in both in FcRgamma(+) and FcRgamma(-/-) MRL/lpr mice. In contrast, the Arthus reaction was induced in FcRgamma(+) MRL/lpr mice, but not in FcRgamma(-/-) MRL/lpr mice. CONCLUSION: Unlike (NZB x NZW)F(1), the other strain of lupus-prone mice that develops GN in an FcR-dependent manner, the development of autoimmune GN and vasculitis in MRL/lpr mice was FcR-independent, implying heterogeneity of the contribution of FcR to the development of autoimmune disease.

Role of RANTES in the development of autoimmune tissue injuries in MRL-Fas lpr mice.

MRL-Fas lpr mice spontaneously develop a severe autoimmune disease closely resembling human SLE. To investigate the possible role of RANTES in autoimmune tissue injuries, we have constructed RANTES-deficient MRL-Fas lpr mice by gene targeting. In the RANTES-deficient mice, axillary lymph nodes were significantly reduced in size compared with those of RANTES-intact mice. Flow cytometric analysis revealed that double-negative (DN) T cells were significantly reduced. Image analyzer showed that cell-infiltrated areas in peribronchial lesions were decreased in the lung of RANTES-deficient MRL-Fas lpr mice. Furthermore, we detected continuous expression of RANTES mRNA in the lung of MRL-Fas lpr mice. In contrast, the degree of histological renal injuries and survival rate was similar in both genotypes. We speculate that RANTES is involved in the development of peribronchial pulmonary lesions in MRL-Fas lpr mice. Further studies using RANTES-deficient mice might contribute to the elucidation of the role of RANTES in autoimmune tissue injuries.

Predominant role of FcgammaRIII in the induction of accelerated nephrotoxic glomerulonephritis.

BACKGROUND: Nephrotoxic glomerulonephritis is induced by the administration of antibody against the glomerular basement membrane (GBM). We demonstrated previously that Fc receptors for immunoglobulin G (IgG) (FcgammaR) play crucial roles in the induction of accelerated nephrotoxic glomerulonephritis by using FcRgamma-deficient (-/-) mice. Since FcRgamma-/- mice lack the cell surface expression of two activating FcgammaRs, FcgammaRI and FcgammaRIII. The present study aims to identify the FcgammaR responsible for the induction of nephrotoxic glomerulonephritis. METHODS: Accelerated anti-GBM glomerulonephritis was induced in FcgammaRI-/-, FcgammaRIII-/-, and FcRgamma-/- mice by preimmunization with rabbit IgG followed by inoculation of rabbit anti-GBM antibody. Histologic analysis and immunostaining of renal sections were performed. RESULTS: FcgammaRI-/- mice as well as wild-type mice showed severe glomerulonephritis with hypernitremia by the administration of anti-GBM antibody. In contrast, FcgammaRIII-/- mice showed much milder renal involvement, similar to FcRgamma-/- mice. Histologically, FcgammaRI-/- mice showed intracapillary proliferation, glomerular thrombosis, and crescent formation, whereas FcgammaRIII-/- mice showed only glomerular hypercellular changes. The depositions of anti-GBM antibodies, autologous antibodies and complement C3 along the GBM were equally observed among all three FcR-/- mouse types by immunostaining. CONCLUSIONS: Accelerated nephrotoxic glomerulonephritis is induced predominantly through FcgammaRIII but not FcgammaRI.