Littoral cell angioma of the spleen.

We report for the first time on the contrast-enhanced ultrasound (CEUS) features of littoral cell angioma of the spleen (LCA). A patient presented with the incidental finding of splenomegaly which was investigated using modern ultrasound techniques. B-mode technique revealed heterogenous splenic parenchyma and small hypoechoic lesions up to 30 mm in size. Colour Doppler imaging revealed no specific vascularity. CEUS showed arterial hyper- and hypoenhancement with pronounced demarcation in the late phase. In an assumption of malignancy the lesions were biopsied using ultrasound guidance. Histology showed LCA. In this case report we discuss LCA in the light of new ultrasound techniques and present a review of the literature.

Imaging of gastrointestinal stromal tumours with modern ultrasound techniques - a pictorial essay.

Gastrointestinal stromal tumours (GIST) are rare tumours of the gastrointestinal tract. Dealing with these tumours requires a profound knowledge of the nature of the lesions and their malignant potentials. Modern ultrasound techniques provide the necessary tools to give the clinician the information he needs to diagnose and treat the patient. This article reviews the actual pathophysiological knowledge of GIST and provides a broad spectrum of ultrasound findings to introduce the reader into modern ultrasound investigation methods of subepithelial tumours. It covers the transcutaneous as well as the endoscopic ultrasound approach. Different conditions of GIST like the low risk or high risk form as well as the metastatic form will be discussed in diagnosis and treatment with plenty of examples. Special attention is paid to contrast-enhanced ultrasound techniques and elastography from the transcutaneous as well as the endoscopic route. Other diagnostic methods like CT, MRI and PET CT are additionally reviewed and their role in clinical practice is compared with that of ultrasound. The aim of the article is to introduce the reader into the new ultrasound techniques and special diagnostic behaviour of GIST and outline clinical pathways to deal correctly with different stages of the disease.

Biliary papillomatosis and new ultrasound imaging modalities.

Biliary papillomatosis (BP) is a rare disorder of the biliary tract with a significant risk of malignant transformation and a high recurrence rate after operation due to the diffuse distribution of the disease. Preoperative diagnosis is difficult also by reason of the low sensitivity and specificity of conventional ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI), endoscopic retrograde cholangiography (ERC) and positron emission tomography (PET). Therefore, the introduction of new diagnostic imaging methods is of importance to improve the preoperative diagnosis of this originally as benign described disease which is reflected in the term of "benign papillomatosis of the biliary tree". The present review summarizes the literature and discusses new sonographic imaging techniques including contrast-enhanced ultrasound (CEUS), contrast-enhanced low mechanical endoscopic ultrasound (CELMI-EUS) and endoscopic ultrasound elastography.

Contrast-enhanced ultrasound in diagnosing liver malignancy.

PURPOSE: The use of contrast enhancers has widened the possibilities of sonographic imaging, and allows the differentiation of characteristic enhancement patterns leading to diagnosis in focal liver lesions. The aim of our study was to evaluate contrast ultrasound signs in diagnosing malignant liver lesions. METHODS: 86 patients with 100 solid liver lesions were enrolled. A baseline gray-scale sonogram was obtained with a multifrequency 4 C convex array probe, followed by contrast-enhanced sonography with a low mechanical index (<0.2) over 300 seconds. Final diagnosis was confirmed by histology or in case of haemangioma by CT/NMR and quantitative contrast harmonic imaging (CHI) with perfusion analysis (contrast). RESULTS: 55 malignant (6 HCC, 46 secondary malignant lesions - 3 of them lymphoma, 3 cholangiocarcinoma), and 45 benign lesions (8 FNH, 1 von Meyenburg complex, 1 granuloma, 3 adenoma, 21 hemangioma, 2 focal fat storage imbalances, 7 abscesses, one scar, and in one case normal liver) were found. 51/55 malignant (all but one filia and three HCC), but also 17/45 benign lesions showed hypoperfusion in the late phase. The ultrasound pattern in the arterial phase differed in malignant lesions: 22 lesions were initially hypervascular, 20 had rim enhancement and in 13 lesions there was a non-specific vascularisation. In all but one malignant lesion a diminishing of contrast agent in the late phase compared to the arterial phase with respect to the surrounding liver tissue was observed. Only three benign lesions with this later sign were falsely diagnosed as malignant: one adenoma, one epitheloid granuloma, and a scar. Quantitative perfusion pattern was analyzed exemplary. Diminishing of contrast agent in the late phase compared to the arterial phase with respect to the surrounding liver tissue as a sign for malignancy had a positive predictive value of 95%, a sensitivity of 98%, a negative predictive value of 98%, and a specificity of 93%. CONCLUSIONS: Diminishing of contrast agent in the late phase compared to the arterial phase with respect to the surrounding liver tissue is a helpful sign in contrast enhanced ultrasound to diagnose malignancies.

Exploration of the APC/beta-catenin (WNT) pathway and a histologic classification system for pulmonary artery intimal sarcoma. A study of 18 cases.

APC, a tumor suppressor gene in the Wnt pathway, stabilizes beta-catenin and controls cell growth. Mutation of APC or beta-catenin leads to nuclear accumulation of beta-catenin and transcription of cyclin D1/cyclin A. Pulmonary artery sarcoma (PAS) were studied by morphologic, immunohistochemical, and molecular genetic methods of the Wnt pathway. Eighteen cases were included: mean age 52 years, primary intraluminal location with typical clinical presentation. PAS were classified as epithelioid (n = 4) or malignant fibrous histiocytoma (MFH; spindled/pleomorphic, n = 4), myxofibrosarcoma (n = 8), and one each hemangiopericytoma-like or malignant inflammatory myofibroblastic tumor-like. The tumor cells demonstrated vimentin, focal actins, and rare focal desmin positivity. All but one were grade 2 or 3 by FNCLCC grading. Alteration in chromosome 5q21 (APC) was found in 4/14 PAS by LOH, mostly epithelioid-type; an MFH-type case demonstrated microsatellite instability (MSI) and nuclear beta-catenin. Cyclin D1 was expressed in seven tumors, all myxofibrosarcoma-type. No mutations were detected in APC or beta-catenin. In summary, PAS are predominantly intermediate grade myxofibrosarcoma in middle-aged males, and fatal in two-thirds of patients. Despite myofibroblastic phenotype, APC/beta-catenin pathway changes are rare. Cyclin D1, only expressed in the myxofibrosarcoma-type, is likely transcribed via factors other than beta-catenin.

Frequent loss of SFRP1 expression in multiple human solid tumours: association with aberrant promoter methylation in renal cell carcinoma.

Oncogenic wingless-related mouse mammary tumour virus (Wnt) signalling, caused by epigenetic inactivation of specific pathway regulators like the putative tumour suppressor secreted frizzled-related protein 1 (SFRP1), may be causally involved in the carcinogenesis of many human solid tumours including breast, colon and kidney cancer. To evaluate the incidence of SFRP1 deficiency in human tumours, we performed a large-scale SFRP1 expression analysis using immunohistochemistry on a comprehensive tissue microarray (TMA) comprising 3448 tumours from 36 organs. This TMA contained 132 different tumour subtypes as well as 26 different normal tissues. Although tumour precursor stages of, for example kidney, colon, endometrium or adrenal gland still exhibited moderate to abundant SFRP1 expression, this expression was frequently lost in the corresponding genuine tumours. We defined nine novel tumour entities with apparent loss of SFRP1 expression, i.e., cancers of the kidney, stomach, small intestine, pancreas, parathyroid, adrenal gland, gall bladder, endometrium and testis. Renal cell carcinoma (RCC) exhibited the highest frequency of SFRP1 loss (89% on mRNA level; 75% on protein level) and was selected for further analysis to investigate the cause of SFRP1 loss in human tumours. We performed expression, mutation and methylation analysis in RCC and their matching normal kidney tissues. SFRP1 promoter methylation was frequently found in RCC (68%, n=38) and was correlated with loss of SFRP1 mRNA expression (p<0.05). Although loss of heterozygosity was found in 16% of RCC, structural mutations in the coding or promoter region of the SFRP1 gene were not observed. Our results indicate that loss of SFRP1 expression is a very common event in human cancer, arguing for a fundamental role of aberrant Wnt signalling in the development of solid tumours. In RCC, promoter hypermethylation seems to be the predominant mechanism of SFRP1 gene silencing and may contribute to initiation and progression of this disease.

Smoking and cancer-related gene expression in bronchial epithelium and non-small-cell lung cancers.

Tobacco smoking is the leading cause of lung cancer worldwide. Gene expression in surgically resected and microdissected samples of non-small-cell lung cancers (18 squamous cell carcinomas and nine adenocarcinomas), matched normal bronchial epithelium, and peripheral lung tissue from both smokers (n = 22) and non-smokers (n = 5) was studied using the Affymetrix U133A array. A subset of 15 differentially regulated genes was validated by real-time PCR or immunohistochemistry. Hierarchical cluster analysis clearly distinguished between benign and malignant tissue and between squamous cell carcinomas and adenocarcinomas. The bronchial epithelium and adenocarcinomas could be divided into the two subgroups of smokers and non-smokers. By comparison of the gene expression profiles in the bronchial epithelium of non-smokers, smokers, and matched cancer tissues, it was possible to identify a signature of 23 differentially expressed genes, which might reflect early cigarette smoke-induced and cancer-relevant molecular lesions in the central bronchial epithelium of smokers. Ten of these genes are involved in xenobiotic metabolism and redox stress (eg AKR1B10, AKR1C1, and MT1K). One gene is a tumour suppressor gene (HLF); two genes act as oncogenes (FGFR3 and LMO3); two genes are involved in matrix degradation (MMP12 and PTHLH); three genes are related to cell differentiation (SPRR1B, RTN1, and MUC7); and five genes have not been well characterized to date. By comparison of the tobacco-exposed peripheral alveolar lung tissue of smokers with non-smokers and with adenocarcinomas from smokers, it was possible to identify a signature of 27 other differentially expressed genes. These genes are involved in the metabolism of xenobiotics (eg GPX2 and FMO3) and may represent cigarette smoke-induced, cancer-related molecular targets that may be utilized to identify smokers with increased risk for lung cancer.

[Renal cell carcinoma metastases to the thyroid gland -- report of 3 cases and review of the literature]. / Schilddrüsenmetastasen eines Nierenzellkarzinoms -- drei Fallvorstellungen und Ubersicht der Literatur.

Clinically significant, solitary metastasis to the thyroid gland is a rare occurrence. The clear cell carcinoma of the kidney (RCC) is the most common primary tumor site. Late recurrence is a notable feature of renal carcinoma. Solitary metastases in the thyroid gland occur as late as 100-120 months from the date of nephrectomy. There is a clear survival benefit in selected cases if surgical approach to the thyroid metastases is chosen. In those patients who have undergone complete resection, 5-year-survival-rates of 50 % have been reported. We describe 3 cases of surgically treated thyroid metastases of RCC, and review the literature.

Defining high-fat-diet rat models: metabolic and molecular effects of different fat types.

High-fat (HF)-diet rodent models have contributed significantly to the analysis of the pathophysiology of the insulin resistance syndrome, but their phenotype varies distinctly between different studies. Here, we have systematically compared the metabolic and molecular effects of different HF with varying fatty acid compositions. Male Wistar rats were fed HF diets (42% energy; fat sources: HF-L - lard; HF-O - olive oil; HF-C - coconut fat; HF-F - fish oil). Weight, food intake, whole-body insulin tolerance and plasma parameters of glucose and lipid metabolism were measured during a 12-week diet course. Liver histologies and hepatic gene expression profiles, using Affymetrix GeneChips, were obtained. HF-L and HF-O fed rats showed the most pronounced obesity and insulin resistance; insulin sensitivity in HF-C and HF-F was close to normal. Plasma omega-3 polyunsaturated fatty acid (omega-3-PUFA) and saturated fatty acid (C(12)-C(14), SFA) levels were elevated in HF-F and HF-C animals respectively. The liver histologies showed hepatic steatosis in HF-L, HF-O and HF-C without major inflammation. Hepatic SREBP1c-dependent genes were upregulated in these diets, whereas PPARalpha-dependent genes were predominantly upregulated in HF-F fed rats. We detected classical HF effects only in diets based on lard and olive oil (mainly long-chain, saturated (LC-SFA) and monounsaturated fatty acids (MUFA)). PUFA- or MC-SFA-rich diets did not induce insulin resistance. Diets based on LC-SFA and MUFA induced hepatic steatosis with SREBP1c activation. This points to an intact transcriptional hepatic insulin effect despite resistance to insulin's metabolic actions.

Efficient analysis of hepatic glucose output and insulin action using a liver slice culture system.

BACKGROUND: Liver slices have been reported to retain histological integrity and metabolic capacity for over 24 hours in flask culture systems, and they have been used for pharmacological and toxicological studies before. However, whether this method is suitable to measure hepatic glucose output is unknown. METHODS: Precision-cut liver slices were prepared from fresh male rat liver. After high-glucose pre-incubation (11.2 mmol/l), medium was changed to low-glucose conditions (0.5 mmol/l). Glucose and lactate levels as well as aspartate aminotransferase activity were monitored for 50 minutes with or without addition of insulin (600 pmol/l) and/or epinephrine (0.5 micromol/l). Slice potassium content and histology were examined to prove liver viability. RESULTS: We observed a stable glucose production from the liver slices of 0.3-0.4 micromol/g liver/min. Epinephrine increased (by 82+/-30%) and insulin decreased (by 80+/-8%) liver slice glucose output. Significant signs of ischemia were not detected. CONCLUSIONS: Hepatic glucose release can be reliably measured in a liver slice culture system, and it is regulated by major hormone systems. This method may be helpful for further characterization of direct insulin action and resistance in a complex tissue as the liver; however, pharmacological applications such as the analysis of drug effects on hepatic glucose metabolism can also be envisioned.

Quantitative gene expression analysis of fractalkine using laser microdissection in biopsies from kidney allografts with acute rejection.

Percutaneous biopsy of the kidney remains the gold standard to establish a diagnosis in renal diseases. Only semiquantitative assessments of gene expression on biopsies have been possible so far. We studied gene expression of the chemokine fractalkine (FKN) in 12 biopsies from laser microdissected kidney allografts that showed histologic signs of acute rejection and 10 controls. As quantified by real-time PCR, the relative tubular FKN expression increased from 1.0 [0.81 to 2.95] (median [range]) in controls to 12.44 [0.90 to 191.0] in acute rejection (P < .01); glomerular FKN expression from 1.3 [0.07 to 27.44] to 12.22 [1.32 to 50.23] (P < .05); and vascular expression, from 0.72 [0.37 to 5.11] to 7.07 [1.19 to 73.49] (P < .01). Furthermore, there was a trend toward higher glomerular FKN expression among patients with more severe rejection. Our results suggest a role of FKN in acute renal allograft rejection.

[Autoimmune cholangitis with vasculitic ulcers, rheumatoid arthritis and IgA glomerulonephritis]. / Autoimmuncholangitis mit vaskulitischen Ulzera, rheumatoider Arthritis und IgA-Glomerulonephritis.

HISTORY AND ADMISSION FINDINGS: A 51-year-old woman was admitted because of relapsing episodes of fever and leg ulcers for 14 years. In addition, she had polyserositis, polyarthralgias and polyarthritides, renal failure with proteinuria and elevation of gamma-GT and alkaline phosphatase. The patient was in a reduced general condition and cachectic nutritional state. She had slight scleral icterus, the liver being palpable 5 cm under the costal margin, edema of the lower limbs and two ulcers at the right foot. INVESTIGATIONS: Laboratory examinations revealed leukocytosis, anemia, elevation of cholestasis and inflammation parameters as well as renal failure. During a 24 hour collection period, a significant proteinuria was demonstrated. Immunoserologically, an ANA titer of 1:100 and a positive rheumatoid factor were found, ANCAs and AMAs were negative. On ultrasound, both kidneys exhibited a blurred pelvic parenchymal border. Thyroid ultrasound demonstrated parenchymal changes consistent with Hashimoto's disease. Ultrasound of the wrist revealed extensive arthritis with tendovaginitis. A renal biopsy revealed mesangioproliferative glomerulonephritis. DIAGNOSIS, THERAPY AND CLINICAL COURSE: Due to serologically persistent cholestasis, a liver biopsy was performed which, together with negative AMAs, revealed the diagnosis of an autoimmune cholangitis (AIC; AMA-negative primary-biliary cirrhosis (PBC)). In addition, the patient presented with rheumatoid arthritis, polyserositis, IgA glomerulonephritis, vasculitic leg ulcers and Hashimoto's thyreoiditis which were interpreted as extra-hepatic manifestations of the AIC. After initiation of high dosage corticosteroid therapy, rapid healing of the leg ulcers occurred. Therapy of the AIC consisted in ursodeoxycholic acid. CONCLUSION: The multitude of associated immunological phenomena in this patient resulted in a delay of the diagnosis. A AIC/PBC, however, should, always be considered in case of cholestasis.

Discrepancy between mRNA and protein expression of tumour suppressor maspin in synovial tissue may contribute to synovial hyperplasia in rheumatoid arthritis.

OBJECTIVE: To investigate the expression of maspin in RA synovial tissue and compare it with the expression in osteoarthritis (OA) and normal synovial tissue (NS). METHODS: Using specific primers for maspin, a 237 bp fragment was amplified from cDNA obtained from cultured RA, OA, and normal synovial fibroblasts (SF) by RT-PCR. Additionally, mRNA expression levels were determined quantitatively by real time PCR. mRNA expression of maspin was investigated on snap frozen and paraffin embedded synovial tissue sections by in situ hybridisation. Immunohistochemistry was used to identify the cell type expressing maspin. SDS-PAGE and western blotting were performed to evaluate the protein expression in cultured SF. To confirm protein synthesis in situ, immunohistochemistry with specific anti-maspin antibodies was performed in synovial tissue sections of patients with RA. RESULTS: RT-PCR showed expression of maspin in all cDNA samples from cultured SF. Maspin mRNA was found to be decreased in RA SF twofold and 70-fold compared with OA SF and NS SF, respectively. Maspin mRNA was expressed in RA, OA, and normal synovial tissue. Importantly, maspin transcripts were also found at sites of invasion into cartilage and bone. At the protein level, maspin could be detected in RA and, less prominently, OA SF. In RA synovial tissue, maspin protein was detected in only a few synovial lining cells. CONCLUSION: Maspin is expressed intensively in RA SF at the mRNA level, but only slightly at the protein level, possibly owing to down regulation of maspin; this may contribute to the hyperplasia of synovial tissue in RA.

A patient with myelofibrosis complicated by refractory ascites and portal hypertension: to tips or not to tips? A case report with discussion of the mechanism of ascites formation.

In patients with myelofibrosis, clinically significant portal hypertension is known to be predominantly presinusoidal; however, the exact mechanisms are still controversial. The pathophysiology is particularly enigmatic in those patients without histological and angiographic evidence of significant intra- or extrahepatic obstruction to portal blood flow, respectively. Moreover, ascites formation has been reported in such cases, but in general is rare in presinusoidal portal hypertension. Here we present such a patient in which ascites developed even in the presence of unchanged serum protein levels (oncotic pressure) and was refractory to sodium restricted diet and high-dose diuretic treatment. A discussion on the parameters influencing fluid exchange and ascites formation particularly emphasizing the potential importance of the hyperdynamic circulation in this case is given. Finally, the patient was treated by implanting a transjugular intrahepatic shunt (TIPS), exerting a diuretic effect sufficient enough to avoid re-formation of ascites for several months. However, ascites re-accumulated potentially due to the appearance of ectopic peritoneal myeloid metaplasia and the patient died soon afterwards. In conclusion, TIPS may be considered as rescue management for refractory ascites secondary to portal hypertension, but caution in respect to the presence and/or development of peritoneal or other ectopic haematopoesis has to be taken.

["Tingling feet," forgetfulness, and progressive personality changes in a 63-year-old patient]. / "Fusskribbeln", Vergesslichkeit und progrediente Wesensveränderung bei einer 63-jährigen Patientin.

A 63-year-old female was admitted to the hospital with leg and forearm paresthesias. We found progressive ataxia, dementia, and psychosocial deterioration. The clinical symptoms, the neurologic and psychiatric abnormalities together with the inflammatory cerebrospinal fluid alteration and the cerebral magnetic resonance imaging changes suggested a paraneoplastic etiology. It was confirmed by paraneoplastic antineuronal antibodies in the patient's serum and the histological diagnosis of a small cell bronchial carcinoma. The prognosis of patients with paraneoplastic symptoms is the better the earlier a diagnosis is established and antitumor therapy is initiated.

Correlation between neovascularisation and neuroendocrine differentiation in prostatic carcinoma.

Neuroendocrine (NE) differentiated tumor cells are found in almost all prostatic carcinomas. Prostatic carcinomas with a high NE differentiation have a poor prognosis and increased metastatic potential. A relationship between the neovascularisation density in the tumor and the metastatic potential in prostatic carcinoma is well known. NE cells and microvessels were demonstrated immunohistochemically on 102 radical prostatectomy specimens using antibodies against Chromogranin A and CD34. Standard areas (7.9 mm2) of maximal Chromogranin A expression and highest vascularisation were determined and topographically related by light microscopy. Area density of microvessels was evaluated morphometrically. NE tumor cells were present in all prostatic carcinomas studied. High grade prostatic carcinomas expressed significantly more NE tumor cells and exhibited a higher neovascularisation than low grade carcinomas. There was significantly higher neovascularisation in high grade tumors with many, as compared to high grade tumors with few, NE tumor cells. Poorer pathological staging correlated with increased neovascularisation and stronger NE differentiation. A topographical relationship between the area of maximal NE tumor cells and the area of highest neovascularisation was found in 80.4% of all cases. An analysis of variance revealed a large number of NE tumor cells as the only predictor of an increased neovascularisation (p = 0.0006). These observations support the concept that increased neovascularisation is influenced not only by poor pathological grading but also by a high NE differentiation.

A rare fatal course of disease in a patient with spontaneous pituitary apoplexy. Case report and literature review.

A rare fatal course of a spontaneous pituitary apoplexy is described and its histological and pathophysiological causes are discussed. A review of the literature gives an overview of the historical and epidemiological data.

[Cavernous hemangioma of the rectum--a rare cause of peranal hemorrhage]. / Das cavernöse Hämangiom des Rectums--eine seltene Ursache peranaler Blutung.

We report the case of a 34-year-old woman with severe rectal bleeding since the age of 17. The cause of the bleeding was a cavernous haemangioma of the rectum. The extent of the disease was not realised for many years. Sclerosing injections, laser coagulation and even suture ligation were helpful in acute bleeding episodes but did not result in definitive healing. Finally cure was achieved by resection of the rectum and colo-anal sleeve anastomosis. The clinical presentation and the management are described and discussed.