Coexistence of amyloidosis and light chain deposition disease in the heart.

There are few reports on the coexistence of cardiac amyloid light-chain (AL) amyloidosis and light chain deposition disease (LCDD), despite their similar pathophysiologies caused by plasma-cell dyscrasia. Herein, we report the coexistence of these diseases. A 59-year-old man was referred to our hospital because of exertional dyspnea and hypotension. Renal dysfunction of unknown etiology had been present for 4 years and hemodialysis had been introduced. Severe systolic and diastolic cardiac dysfunction was apparent, accompanied with dilatation and granular sparkling, but not with left ventricular hypertrophy. The plasma-free light chain κ was found to be extremely high, with a κ/λ ratio of 1,919. Light microscopic examination of the endomyocardial biopsy revealed spotty and homogenous deposits, which positively stained with Congo red, and exhibited a blazing apple-green color under polarized light. Based on these results, cardiac amyloidosis was diagnosed. In specimens prepared for electron microscopy, no amyloid fibrils could be found. Instead, we observed amorphous nonfibrillar deposits around several small vessels including capillaries and small arteries, which were consistent with light-chain deposits. LCDD was diagnosed based on the systemic increase in κ light chain and the ultrastructural findings of the endomyocardial biopsy specimens. Coexistence of cardiac amyloidosis and LCDD was thus confirmed in our patient. An electron microscopic assessment in addition to Congo red staining may be useful to diagnose latent LCDD in patients with suspected cardiac light-chain amyloidosis.

Hereditary cardiac amyloidosis associated with Pro24Ser transthyretin mutation: a case report.

BACKGROUND: Transthyretin amyloidosis is a systemic disorder caused by extracellular deposition of insoluble amyloid fibrils in peripheral and autonomic nerves, heart, kidney, gastrointestinal tract, and other organs. Hereditary transthyretin amyloidosis is an autosomal dominant disease. More than 120 mutations have been reported in the transthyretin gene with considerable phenotypic heterogeneity and geographic diversity. Among them, a sporadic case of hereditary transthyretin amyloidosis with cardiac-predominant phenotype is very rare, progressive, and potentially fatal if left undiagnosed. However, a clinical diagnosis of cardiac amyloidosis still remains challenging due to non-specific symptoms, and less sensitivity and specificity of medical examinations. CASE PRESENTATION: A 60-year-old Japanese man with a history of embolic stroke and hypertrophic cardiomyopathy visited our department for heart failure. The present case exhibited only cardiomyopathy without any clinical signs of systemic amyloidosis manifested as carpal tunnel syndrome, polyneuropathy, or autonomic dysfunction. An echocardiogram revealed severe asymmetric left ventricular hypertrophy, biatrial dilatation, pericardial effusion, and preserved left ventricular ejection fraction of 50% with severe diastolic dysfunction. Technetium pyrophosphate scintigraphy indicated marked diffuse myocardial uptake of technetium pyrophosphate, strongly suggesting transthyretin cardiac amyloidosis, which was firmly confirmed by a left ventricular endomyocardial biopsy. Genetic analysis demonstrated a transthyretin C70T (Pro24Ser) heterozygous mutation. Tafamidis, a transthyretin stabilizer, was started. His cardiac symptoms remained unchanged for 12 months. CONCLUSIONS: Here we report the case of a patient with hereditary cardiac amyloidosis associated with a Pro24Ser mutation in transthyretin, which is the first case reported in Japan. Technetium pyrophosphate scintigraphy was extremely useful for definitive diagnosis. Thus, we propose that the nuclear imaging technique should be taken into account even for an exploratory diagnosis of transthyretin cardiac amyloidosis.

[A Case Report of Disappearance of Gastric Metastasis of Breast Cancer Treated with Combination Therapy Consisting of Paclitaxel and Cisplatin].

A 63-year-old postmenopausal woman was treated with combination therapy consisting of paclitaxel(PTX)and cisplatin (CDDP)for gastric metastasis of breast cancer; she achieved a complete response as revealed by pathological examination. Combination therapy with PTX and CDDP seems to be an optional treatment for gastric metastasis of breast cancer.

Subarachnoid hemorrhage due to nonbranching aneurysm of the middle cerebral artery in a young adult with a history of Kawasaki disease.

BACKGROUND: The incidence of subarachnoid hemorrhage (SAH) in young adults is relatively rare. Kawasaki disease is a systemic vasculopathy that is known to cause coronary artery aneurysms; however, its effect on cerebral arteries remains largely unclear. CASE DESCRIPTION: We report the case of a 20-year-old male with a history of Kawasaki disease who presented with SAH caused by the rupture of a nonbranching middle cerebral artery aneurysm. This is the third report of SAH associated with Kawasaki disease. Preoperative echocardiography of the patient rejected the presence of bacterial endocarditis and other heart abnormalities. An emergency craniotomy and clip occlusion of the aneurysm was successfully performed without obstructing the parent artery. Two weeks later, the patient was discharged without any apparent neurological deficit. We also performed a circumstantial pathological study on specimens obtained from the aneurysm wall. Our histological findings suggest that the elastic lamina and tunica intima were completely destroyed during the acute vasculitis phase of Kawasaki disease, which possibly led to the aneurysmal formation. CONCLUSIONS: Lack of active inflammatory changes and atherosclerotic lesions may explain the chronic feature of Kawasaki disease, not a typical aneurysmal formation.

An autopsy case of macroglobulinemia complicated with syndrome of inappropriate secretion of ADH (SIADH) like hyponatremia, hypopituitarism and AL amyloidosis.

An 88-year-old male patient with macroglobulinemia was admitted to our hospital because of severe hyponatremia and unconsciousness. Laboratory findings showed decreased inhibition of antidiuretic hormone (ADH) and he was diagnosed with syndrome of inappropriate secretion of ADH (SIADH). Hyponatremia improved with only limitation of water intake and the patient was followed up on a continuing outpatient basis. However, soon after discharge from hospital, his legs started swelling with edema and hyponatremia worsened. He was re-admitted due to a fall at home. Hyponatremia was observed at re-admission. A CRH challenge test showed partial dysfunction of ACTH secretion. Corticosteroid therapy was performed, but the patient subsequently died from pneumonia. Pathological findings at autopsy revealed invasion of plasma cells and amyloid depositions in multiple organs, including the pituitary, adrenal cortex, heart, liver, kidney, lymph nodes and bone marrow. Consistent with these results, fibrosis was observed in the anterior lobe of the pituitary, suggesting that the autopsy findings were related to the clinical observations and diagnosis. This is the first reported case of macroglobulinemia complicated with multiple hormone dysfunction.

Olfactory dysfunction related to TDP-43 pathology in amyotrophic lateral sclerosis.

AIMS: To clarify a possible contribution of TDP-43 pathology to odor dysfunction in amyotrophic lateral sclerosis patients. CASE REPORT: An 83-year-old woman suffered from muscle weakness, which started to deteriorate during the previous half year. In addition to her pyramidal signs, lower motor involvement was shown by needle electromyography; this upper and lower motor neuron involvement was suggestive of probable ALS. She presented with severe odor impairments but relatively preserved cognitive functions. Her autopsy findings revealed TDP-43-positive inclusions in the spinal motor neurons and cerebral limbic system without significant tau or α-synuclein deposits. DISCUSSION: This case showed evidence suggesting that olfactory dysfunction was probably related to limbic TDP-43 pathology and was possibly independent of her Alzheimer pathology. Olfactory dysfunction does not necessarily indicate the presence of tau or α-synuclein pathology and could be an early sign of ALS with the limbic involvement of TDP-43 pathology even when cognitive functions are preserved.

Somatic mutations in PIK3CA and activation of AKT in intraductal tubulopapillary neoplasms of the pancreas.

Intraductal tubulopapillary neoplasm (ITPN) is a recently recognized rare variant of intraductal neoplasms of the pancreas. Molecular aberrations underlying the neoplasm remain unknown. We investigated somatic mutations in PIK3CA, PTEN, AKT1, KRAS, and BRAF. We also investigated aberrant expressions of phosphorylated AKT, phosphatase and tensin homolog (PTEN), tumor protein 53 (TP53), SMAD4, and CTNNB1 in 11 cases of ITPNs and compared these data with those of 50 cases of intraductal papillary mucinous neoplasm (IPMN), another distinct variant of pancreatic intraductal neoplasms. Mutations in PIK3CA were found in 3 of 11 ITPNs but not in IPMNs (P = 0.005; Fisher exact test). In contrast, mutations in KRAS were found in none of the ITPNs but were found in 26 of the 50 IPMNs (P = 0.001; Fisher exact test). PIK3CA mutations were associated with strong expression of phosphorylated AKT (P < 0.001; the Mann-Whitney U test). Moreover, the expression of phosphorylated AKT was apparent in most ITPNs but only in a few IPMNs (P < 0.001; the Mann-Whitney U test). Aberrant expressions of TP53, SMAD4, and CTNNB1 were not statistically different between these neoplasms. Mutations in PIK3CA and the expression of phosphorylated AKT were not associated with age, sex, tissue invasion, and patients' prognosis in ITPNs. These results indicate that activation of the phosphatidylinositol 3-kinase pathway may play a crucial role in ITPNs but not in IPMNs. In contrast, the mutation in KRAS seems to play a major role in IPMNs but not in ITPNs. The activated phosphatidylinositol 3-kinase pathway may be a potential target for molecular diagnosis and therapy of ITPNs.

Histopathological aspects of cardiac biopsy in pediatric patients with dilated cardiomyopathy.

BACKGROUND: Dilated cardiomyopathy (DCM) is a heart muscle disease with cardiac dysfunction and a heterogeneous disorder. This disease may show various histopathological aspects of the myocardium, but little is known about these in children. METHODS: Histopathological findings of endomyocardial biopsy from 20 pediatric patients with DCM were analyzed and compared with those in adult patients. RESULTS: Advanced histopathology, including myocytolysis and/or fragmentation of muscle bundles, was frequently observed in patients with poor prognosis. Patchy fibrosis was predominantly demonstrated in the pediatric patients, whereas perivascular fibrosis was mostly observed in the older adults. The myocarditic index, assessed in terms of the findings of fibrosis, size variation of myocytes, disarrangement of muscle bundles and mononuclear cell infiltration was higher in the pediatric patients than in the older adults (P < 0.05). Bizarre myocardial hypertrophy with disorganization, which tends to be frequently demonstrated in hypertrophic cardiomyopathy, was revealed in 30% of the pediatric patients, whereas it was disclosed in none of the older adult patients (P < 0.05). CONCLUSION: These results suggest that the major pathogenetic factors of DCM in children may be different from those in adults.

Myocardial fat at cardiac imaging: how can we differentiate pathologic from physiologic fatty infiltration?

Myocardial fat is often seen at cardiac computed tomography (CT) and magnetic resonance (MR) imaging of healthy adults and patients with myocardial diseases. Physiologic myocardial fat develops with aging and is commonly seen at CT in the anterolateral right ventricular (RV) free wall and RV outflow tract with normal or thickened RV myocardium and a normal-sized RV in elderly patients. Pathologic conditions with myocardial fat include healed myocardial infarction (MI); arrhythmogenic RV cardiomyopathy or dysplasia (ARVC); and others, such as cardiac lipoma, lipomatous hypertrophy of the interatrial septum, tuberous sclerosis complex, dilated cardiomyopathy, and cardiomyopathy with muscular dystrophy. In patients with healed MI, CT and MR imaging show fat in left ventricular myocardium that is of normal thickness or thin and follows the distribution of the coronary artery; CT often depicts fat in mostly subendocardial regions. In patients with ARVC, characteristic CT and MR imaging findings include a thin RV outflow tract and free wall caused by subepicardial fatty infiltration; fat in the RV moderator band, trabeculae, and ventricular septum; and RV enlargement and wall motion abnormality. Recognition of patient age, characteristic locations of myocardial fat, myocardial thickness, and ventricular size helps in differentiating physiologic and pathologic myocardial fat at cardiac imaging; findings of wall motion abnormality and late gadolinium enhancement at MR imaging help narrow the diagnosis.

A mouse model of autoimmune pancreatitis with salivary gland involvement triggered by innate immunity via persistent exposure to avirulent bacteria.

The pathogenesis of autoimmune pancreatitis (AIP) remains unknown. Here, we investigated the possible involvement of chronic, persistent exposure to avirulent bacteria in the pathogenesis of AIP. C57BL/6 mice were inoculated with heat-killed Escherichia coli weekly for 8 weeks. At 1 week and up to 12 months after the final inoculation, the mice were killed to obtain samples. At 1 week after the final E. coli inoculation, marked cellular infiltration with fibrosis was observed in the exocrine pancreas. Cellular infiltration in the exocrine pancreas was still observed up to 12 months after the completion of E. coli inoculation. At 10 months after the final inoculation, duct-centric fibrosis became obvious. Inflammation around the ducts in the salivary glands was also observed. Furthermore, sera from heat-killed E. coli-inoculated mice possessed anti-carbonic anhydrase, anti-lactoferrin, and antinuclear antibodies. Exposure to E. coli-triggered AIP-like pancreatitis in C57BL/6 mice. We propose a hypothetical mechanism for AIP pathogenesis. During the initiation phase, silently infiltrating pathogen-associated molecular patterns (PAMP) and/or antigen(s) such as avirulent bacteria might trigger and upregulate the innate immune system. Subsequently, the persistence of such PAMP attacks or stimulation by molecular mimicry upregulates the host immune response to the target antigen. These slowly progressive steps may lead to the establishment of AIP and associated extrapancreatic lesions. Our model might be useful for clarifying the pathogenesis of AIP.

Engulfment of gram-positive bacteria by pancreatic stellate cells in pancreatic fibrosis.

OBJECTIVES: We previously reported the finding that pancreatic stellate cells (PSCs) have a phagocytic function. The aim of the present study was to investigate whether engulfment of gram-positive bacteria by PSCs plays any role in the pathogenesis of pancreatic fibrosis. METHODS: Rat PSCs were cultured with lipoteichoic acid (LTA) or bacteria and analyzed for α-smooth muscle actin expression and collagen secretion. Human pancreata were obtained from routine autopsies of 20 cases; a diagnosis of gram-positive sepsis was made in 10 of the cases (sepsis group), but sepsis had not been diagnosed in the other 10 cases (control group). Pancreatic tissue was stained with anti-LTA antibody, and the severity of pancreatic fibrosis was evaluated by histological scoring. RESULTS: Bacteria and LTA were internalized into the cytoplasm of cultured PSCs. Exposure to LTA or bacteria significantly increased α-smooth muscle actin expression and collagen secretion. Blockade of toll-like receptor 2 significantly inhibited the increase in collagen secretion in response to LTA. There was no significant difference in the severity of pancreatic fibrosis between the sepsis group and the control group. CONCLUSIONS: The fibrogenic action of PSCs seems to be more strongly associated with activation of the toll-like receptor-dependent pathway than it is with phagocytosis of bacteria by PSCs.

Intraductal tubulopapillary neoplasms of the pancreas distinct from pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms.

We have encountered cases of unusual intraductal pancreatic neoplasms with predominant tubulopapillary growth. We collected data on 10 similar cases of "intraductal tubulopapillary neoplasms (ITPNs)" and analyzed their clinicopathologic and molecular features. Tumor specimens were obtained from 5 men and 5 women with a mean age of 58 years. ITPNs were solid and nodular tumors obstructing dilated pancreatic ducts and did not contain any visible mucin. The tumor cells formed tubulopapillae and contained little cytoplasmic mucin. The tumors exhibited uniform high-grade atypia. Necrotic foci were frequently observed, and invasion was observed in some cases. The ITPNs were immunohistochemically positive for cytokeratin 7 and/or cytokeratin 19 and negative for trypsin, MUC2, MUC5AC, and fascin. Molecular studies revealed abnormal expressions of TP53 and SMAD4 in 1 case, but aberrant expression of beta-catenin was not observed. No mutations in KRAS and BRAF were observed in the 8 cases that were examined. Eight patients are alive without recurrence, 1 patient died of liver metastases, and 1 patient is alive but had a recurrence and underwent additional pancreatectomy. The mitotic count and Ki-67 labeling index were significantly associated with invasion. All the features of ITPN were distinct from those of other known intraductal pancreatic neoplasms, including pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasm, and the intraductal variant of acinar cell carcinoma. Intraductal tubular carcinomas showed several features that were similar to those of ITPN, except for the tubulopapillary growth pattern. In conclusion, ITPNs can be considered to represent a new disease entity encompassing intraductal tubular carcinoma as a morphologic variant.

[A case of bilharziasis diagnosed 10 years later].

A 31-year-old Japanese man had macroscopic hematuria 5 or 6 years previously. When he was examined at a local hospital, he was pronounced normal. However he still had macroscopic hematuria, so he visited our department. Urine cytodiagnosis was class II. Cystoscopy revealed irregular mucosa at the anterior wall and dome of the bladder. CT and MRI also demonstrated irregular thickness at the anterior wall of the bladder. A diagnosis of bilharziasis was made by histological specimen obtained by TUR-biopsy. The specimen did not show evidence of malignancy. When questioned about overseas travel, he said he had visited Malawi in Africa when he was 20 years old. As international exchange between Japan and other countries is now increasing, we will be examining more patients who have traveled to epidemic areas. In such patients, we should consider the possibility of Schistosomiasis.

Anti-glomerular basement membrane antibody disease with granulomatous lesions on renal biopsy.

We present the case of a 56-year-old woman with anti-glomerular basement membrane (anti-GBM) antibody disease accompanied by granulomatous reaction in the kidney. Three months prior to admission to our kidney center, she had suffered from interstitial pneumonia and had a slightly elevated level of MPO-ANCA (13 EU). Her serum level of creatinine was normal (0.72 mg/dl) but proteinuria (1+) and hematuria (2+, 1-4/HF) were present. She was admitted to our hospital because of general fatigue, loss of appetite, high fever (over 38.5 degrees C) and a rapid decline in renal function (creatinine 8.50 mg/dl). Hemodialysis therapy was started immediately after admission. The serological study was negative for MPO-ANCA and PR3-ANCA but positive for anti-GBM antibody (139 EU). Renal biopsy demonstrated necrotizing glomeruli, cellular crescents and grauloma formation with multinucleated giant cells. Immunofluorescence microscopy revealed linear staining of IgG and C3. We diagnosed graulomatous, crescentic and necrotizing glomerulonephritis, patho-logically. She was diagnosed as having anti-GBM antibody disease because alveolar hemorrhage was absent. Steroid therapy including methylprednisolone pulse therapy (500 mg/day, 3 days) and 2 courses of plasma exchange were effective in reducing the fever, anti-GBM antibody titer and C-reactive protein level. Her renal function recovered and she was able to quit hemodialysis therapy 68 days after the start of hemodialysis and she has shown no signs of pulmonary alveolar hemorrhage to date. The present case suggests that intensive therapy may restore renal function in anti-GBM disease even though renal function was sufficiently damaged and required hemodialysis therapy and active pathological changes were observed in renal biopsy specimens.

Undifferentiated spindle-cell carcinoma of the gallbladder: an immunohistochemical study.

A case of undifferentiated spindle-cell carcinoma of the gallbladder is described. A 72-year-old man presented with right hypochondralgia and fever. Imaging studies revealed a well-demarcated solid tumor (with a necrotic center) in the gallbladder that invaded the liver and transverse colon. On gross examination of the surgical specimen, the cut surface of the polypoid tumor showed nodular invasive growth. Microscopically, the tumor was composed of atypical spindle-shaped tumor cells that proliferated in a whirling or interlacing pattern. The tumor also showed foci with a malignant epithelial component that simulated a carcinosarcoma. Immunohistochemically, the biphasic differentiation of the tumor was highlighted by the different immunoreactivity to antibodies against cytokeratins, epithelial membrane antigen (EMA), and vimentin shown by the malignant epithelial components and the spindle-cell components. However the latter showed faint positivity for cytokeratin antibody. These results suggested that the spindle-cell carcinoma of the gallbladder originated from cholecystic mucosa and showed sarcomatous reaction or dedifferentiation, as indicated by the presence of vimentin-positive cells. The proliferation index, as detected by ki-67, in the spindle-cell component was higher than that in the epithelial component, which may account for the more aggressive biological behavior of the spindle-cell component.

A case report of dystrophic localized amyloidosis that developed in the left thigh.

We report on a 50-year-old man with dystrophic localized amyloidosis who noticed a soft tumor in his left thigh about 20 years ago, after which the tumor has gradually enlarged. The multicystic tumor showed hemorrhage, hematoma, necrosis, fibrosis, and tiny nodules and various polymorphous granulomas were observed. One was rich in eosinophilic amorphous materials and cholesterol crystals, and was poor in cell reaction. Another was formed by granuloma consisting of multinucleated giant cells, foamy cells, and macrophages. Transitional granulomas between the two were also observed. The materials showed eosinophilia and red staining and apple-green birefringence in polarized light by alkaline Congo-red stain, and they were also resistant to potassium permanganate pretreatment. They were also positive for amyloid P component and consistently negative for amyloid A, kappa- and lambda-light chains, beta2-microglobulin, and transthyretin. Therefore, it was suggested that this might be an amyloid derived from the hematoma, which has not been reported to date.

Solitary neurocysticercosis case caused by Asian genotype of Taenia solium confirmed by mitochondrial DNA analysis.

A Japanese woman presenting with neurologic symptoms was presumptively diagnosed with neurocysticercosis based on imaging findings. Hooklets in the scolex of the resected lesion were not confirmed through histopathological observation. However, the illness was confirmed by mitochondrial DNA analysis to be a solitary neurocysticercosis case caused by the Asian genotype of Taenia solium.