Small cell carcinoma of the kidney: a clinicopathologic study of 14 cases.

Small cell carcinoma of the kidney is distinctively rare. We searched pathology files in 2 institutions and found 14 cases of renal small cell carcinoma. The patients' mean age at diagnosis was 59 years (range, 22-75 years); 8 were women, and 6 were men. Patients usually presented with hematuria (n = 6) and abdominal pain (n = 5). The mean tumor size was 7.1 cm (range, 3.5-14.0 cm). The small cell carcinoma was pure in 9 cases and mixed with high-grade urothelial carcinoma in 5 cases. None was associated with any type of renal cell carcinoma. Tumor necrosis was present in all cases, and lymphovascular invasion was identified in 6 cases. The tumor invaded the perinephric adipose tissue in 13 cases and was confined to the kidney in only 1 case. Lymph node metastases were identified in all patients who underwent lymph node dissection (5/5). On immunostains, the small cell carcinoma cells were positive for pancytokeratin (11/12), chromogranin (6/9), and synaptophysin (8/9). Follow-up data were available for 13 patients, and 11 died of small cell carcinoma at a mean of 15 months (range, 4-31 months) after diagnosis. Of the 2 surviving patients, 1 was alive at 5 months after diagnosis, and the other, whose disease was confined to the kidney, was alive with no evidence of disease at 137 months. In summary, renal small cell carcinoma is a highly aggressive disease that often presents at an advanced stage with widespread metastases. Patients usually have a poor clinical outcome despite multimodal therapy. The frequent coexistence of small cell carcinoma with urothelial carcinoma suggests that renal small cell carcinomas may evolve from a preexisting urothelial carcinoma.

TMPRSS2-ERG gene fusion in small cell carcinoma of the prostate.

Recent studies have shown that most prostate cancers carry the TMPRSS2-ERG gene fusion. Here we evaluated the TMPRSS2-ERG gene fusion in small cell carcinoma of the prostate (n = 12) in comparison with small cell carcinoma of the urinary bladder (n = 12) and lung (n = 11). Fluorescence in situ hybridization demonstrated rearrangement of the ERG gene in 8 cases of prostatic small cell carcinoma (67%), and the rearrangement was associated with deletion of the 5' ERG gene in 7 cases, but rearrangement of the ERG gene was not present in any small cell carcinoma of the urinary bladder or lung. Next we evaluated the TMPRSS2-ERG gene fusion in nude mouse xenografts that were derived from 2 prostatic small cell carcinomas carrying the TMPRSS2-ERG gene fusion. Two transcripts encoded by the TMPRSS2-ERG gene fusion were detected by reverse transcriptase polymerase chain reaction, and DNA sequencing demonstrated that the 2 transcripts were composed of fusions of exon 1 of the TMPRSS2 gene to exon 4 or 5 of the ERG gene. Our study demonstrates the specific presence of TMPRSS2-ERG gene fusion in prostatic small cell carcinoma, which may be helpful in distinguishing small cell carcinoma of prostatic origin from nonprostatic origins. The high prevalence of the TMPRSS2-ERG gene fusion in prostatic small cell carcinoma as well as adenocarcinoma implies that small cell carcinoma may share a common pathogenic pathway with adenocarcinoma in the prostate.

Expression of master regulatory genes controlling skeletal development in benign cartilage and bone forming tumors.

Recent progress in skeletal molecular biology has led to the clarification of the transcriptional mechanisms of chondroblastic and osteoblastic lineage differentiation. Three master transcription factors-Sox9, Runx2, and Osterix-were shown to play an essential role in determining the skeletal progenitor cells' fate. The present study evaluates the expression of these factors in 4 types of benign bone tumors-chondromyxoid fibroma, chondroblastoma, osteoid osteoma, and osteoblastoma-using immunohistochemistry and tissue microarrays. Osteoid osteoma and osteoblastoma showed strong nuclear expression of Osterix and Runx2. In contrast, only a few chondroblastomas showed positive nuclear expression of Osterix. Strong nuclear expression of Sox9 was detected in all chondroblastomas, whereas nearly half of the osteoblastomas showed focal weak cytoplasmic expression of Sox9.

Expression of Galectin-3 in renal neoplasms: a diagnostic, possible prognostic marker.

CONTEXT: Galectin-3, a member of the lectin family, was shown to be expressed in normal distal tubular cells and in renal cell carcinomas (RCC). However, its diagnostic and prognostic significance in RCC is as yet undefined. OBJECTIVES: To describe the expression of Galectin-3 among different histologic subtypes of renal neoplasms and to determine their diagnostic and prognostic significances. DESIGN: The expression of Galectin-3 was evaluated in 217 renal neoplasms by tissue microarray and immunohistochemistry with semiquantitative analysis. RESULTS: Strong expression of Galectin-3 was observed in 92 of 217 of renal neoplasms (42.4%). Although 22 of 23 oncocytomas (95.7%) and 19 of 21 chromophobe RCCs (90.5%) express Galectin-3, only 4 of 32 papillary RCCs (12.5%) and 47 of 137 clear cell RCCs (34.3%) express Galectin-3, suggesting that it may be used as a potential diagnostic marker. Galectin-3 expression was seen in 55% of high-grade (Fuhrman nuclear grades 3 and 4) versus 21% low-grade (grades 1 and 2) clear cell RCCs (P < .001). CONCLUSIONS: This study confirms that Galactin-3 is strongly overexpressed in renal cell neoplasms of distal tubular differentiation, that is, oncocytoma and chromophobe RCCs, suggesting it might be used as a possible differential diagnostic tool for renal cell neoplasm with oncocytic or granular cells. Furthermore, we observed a strong association of overexpression of Galectin-3 and high nuclear grade in clear cell RCC. These results also suggest a possible pivotal role for Galectin-3 in the differentiation and prognosis of clear cell RCC.

Immunohistochemical comparison of chordoma with chondrosarcoma, myxopapillary ependymoma, and chordoid meningioma.

Chordoma originates from embryonic notochordal remnants in the midline along the spinal axis and is characterized by cords and lobules of neoplastic cells arranged within myxoid matrix. Because of histologic similarities with myxoid matrix and overlapping immunohistochemical profile, chondrosarcoma, myxopapillary ependymoma, and chordoid meningioma enter in the histologic differential diagnosis at this site. Therefore, the judicious use of a panel of selected immunostains is unquestionably helpful in diagnostically challenging cases. To find useful immunohistochemical markers for assisting in differential diagnosis between chordoma and other tumors with chordoid morphology, an immunohistochemical study using D2-40, epithelial membrane antigen (EMA), pan-cytokeratin (panCK), glial fibrillary acidic protein (GFAP), S-100 protein, galectin-3, neural cell adhesion molecule (NCAM), beta-catenin, E-cadherin, and carcinoembryonic antigen was performed on 14 chordomas, 7 chondrosarcomas, 9 myxopapillary ependymomas, and 4 chordoid meningiomas. Chordoma typically showed positive for EMA and panCK and negative for D2-40 and GFAP; whereas chondrosarcoma revealed positive for D2-40, and negative for EMA, panCK, and GFAP; myxopapillary ependymoma positive for GFAP and negative for EMA; and chordoid meningioma positive for EMA, and negative for panCK and GFAP. On the basis of our immunohistochemical study, a panel of D2-40, EMA, panCK, and GFAP allowed the correct recognition of all tumors examined. Other immunohistochemical markers including S-100 protein, galectin-3, NCAM, beta-catenin, E-cadherin, and carcinoembryonic antigen were of little value in differential diagnosis. In summary, the best immunohistochemical markers useful for the evaluation of tumors with chordoid morphology were D2-40, EMA, cytokeratin, and GFAP. D2-40 was a true chondroid marker to be useful for the differential diagnosis with chordoma.

Clinicopathologic study of 24 patients with primary cardiac sarcomas: a 10-year single institution experience.

Primary cardiac sarcomas are exceptionally rare. We present a 10-year, single-institution experience with 24 primary adult cardiac sarcomas. These cases were retrieved from the Department of Pathology data file of the Methodist Hospital at Houston, TX. Clinical presentation and pathologic features were analyzed. Histologic classification was followed according to the criteria set by the World Health Organization, and grading according to the system proposed by the Federation Nationale des Centres de Lutte Contrele Cancer. There were 14 men and 10 women (male/female, 1.4:1) with a mean age of 42.2 years (range 20-68 years). The tumors involved the right atrium in 14 cases, left atrium in 6 cases, right ventricle in 2 cases, and left ventricle in 2 cases. The tumor size ranged from 2.0 to 17.0 cm (mean 7.2 cm), and, histologically, there were 10 angiosarcomas, 9 unclassified sarcomas, 3 synovial sarcomas, and 2 leiomyosarcomas. All 10 angiosarcomas originated from the right atrium, whereas 5 of the unclassified sarcomas were from the left atrium. Although cases were limited, no predilection site was found for the other histologic types. All tumors were graded as 2 (5 cases) or 3 (19 cases) in differentiation. The prognosis was poor with a median survival time of 25 months after diagnosis. The grade was not statistically significant on survival (P = .14). In conclusion, angiosarcoma and unclassified sarcomas are the most common sarcomas of the heart accounting for 76%, but rare tumors such as synovial sarcoma and leiomyosarcoma may also occur in this organ. The survival of cardiac sarcomas is poor.

Fine needle aspiration of poorly defined indurated and well-defined breast lesions: a cytopathologic comparative study.

OBJECTIVE: To compare the cytologic findings and diagnoses of breast fine needle aspiration (FNA) samples of well-defined lesions (WDL) with those of poorly defined indurated lesions. STUDY DESIGN: We examined 371 consecutive breast FNA specimens obtained without diagnostic image guidance. Fifty-eight lesions were described by the examining pathologists as PDILs, and the remaining 313 lesions were described as WDLs. RESULTS: Compared with WDLs, PDILs were more likely to yield hypocellular specimens deemed unsatisfactory for diagnostic evaluation (37.9% vs. 14.1%). However, a substantial number of atypical, suspicious for malignancy and malignant cases (12.1%, 5.2%, and 13.8%, respectively) were identified with PDILs. In addition, benign diagnoses were more frequently rendered with aspirates of WDLs, compared with PDILs (47.9% vs. 31.0%). In our study, FNAs of PDILs were more often diagnostic in white women < 49 years of age and in lesions measuring > 2 cm. CONCLUSION: Given the relatively high frequency of malignant, suspicious and atypical lesions detected with PDILs, FNA is a suitable first diagnostic approach for PDILs, especially considering the relatively low cost and simplicity of FNA procedures without diagnostic imaging guidance.

Coexpression of EGFR and HER-2 in pancreatic ductal adenocarcinoma: a comparative study using immunohistochemistry correlated with gene amplification by fluorescencent in situ hybridization.

Pancreatic ductal adenocarcinoma (PDAC) is the major pancreatic tumor and carries an extremely poor prognosis. Coexpression of epidermal growth factor receptor (EGFR) and the HER-2 oncoprotein has been reported to be related to the invasion and an adverse clinical outcome of human pancreatic ductal adenocarcinomas. HER-2 amplification, as determined by fluorescent in situ hybridization (FISH) analysis, has been identified as a positive predictor of response to EGFR tyrosine kinase inhibitor treatment in some other cancers. The aim of this study was to investigate the coexpression rate and amplification status of HER-2 oncogene in EGFR positive pancreatic ductal adenocarcinoma (PDAC) by immunohistochemistry and FISH. Overexpression of EGFR (>or=2+) was seen in 65% (21/32) of the study cases. EGFR gene amplification was not detected in any of the 32 PDACs. Overexpression of HER-2 protein (>or=2+) was seen in 17% (5/28) of the study cases and in 24% (5/21) of EGFR positive cases. None of the EGFR negative tumors showed HER-2 overexpression or gene amplification. The HER-2 gene locus was amplified in 11% (3/28) of the study cases and in 14% (3/21) of EGFR positive PDACs. There was 60% concurrence between HER-2 gene amplification and HER-2 protein expression in this study. These results suggest that HER-2 is an important cooperating member of the EGFR signal pathway in a subset of PDAC.

Beta-ketoacyl-acyl carrier protein synthase III from pea (Pisum sativum L.): properties, inhibition by a novel thiolactomycin analogue and isolation of a cDNA clone encoding the enzyme.

A beta-ketoacyl-acyl carrier protein (ACP) synthase III (KAS III; short-chain condensing enzyme) has been partly purified from pea leaves. The enzyme, which had acetyl-CoA:ACP acyltransferase (ACAT) activity, was resolved from a second, specific, ACAT protein. The KAS III enzyme had a derived molecular mass of 42 kDa (from its cDNA sequence) and operated as a dimer. Its enzymological characteristics were similar to those of two other plant KAS III enzymes except for its inhibition by thiolactomycin. A derivative of thiolactomycin containing a longer (C8 saturated) hydrophobic side-chain (compound 332) was a more effective inhibitor of pea KAS III and showed competitive inhibition towards malonyl-ACP whereas thiolactomycin showed uncompetitive characteristics at high concentrations. This difference may be due to the better fit of compound 332 into a hydrophobic pocket at the active site. A full-length cDNA for the pea KAS III was isolated. This was expressed in Escherichia coli as a fusion protein with glutathione S-transferase in order to facilitate subsequent purification. Demonstrated activity in preparations from E. coli confirmed that the cDNA encoded a KAS III enzyme. Furthermore, the expressed KAS III had ACAT activity, showing that the latter was inherent. The derived amino acid sequence of the pea cDNA showed 81-87% similarity to that for other plant dicotyledon KAS IIIs, somewhat less for Allium porrum (leek, 71%) and for Porphyra spp. (62%), Synechocystis spp. (65%) and various bacteria (42-65%). The pea KAS III exhibited four areas of homology, three of which were around the active-site Cys(123), His(323) and Asn(353). In addition, a stretch of 23 amino acids (residues 207-229 in the pea KAS III) was almost completely conserved in the plant KAS IIIs. Modelling this stretch showed they belonged to a peptide fragment that fitted over the active site and contained segments suggested to be involved in substrate binding and in conformational changes during catalysis, as well as an arginine suggested to participate in the acid-base catalytic mechanism.

Lipid composition of Botrytis cinerea and inhibition of its radiolabelling by the fungicide iprodione.

• Botrytis cinerea is an important plant pathogen that causes grey mould in over 200 hosts. It is often controlled by dicarboximides, which have various proposed mechanisms of action, including effects on lipids. Here we have examined the effect of one dicarboximide, iprodione, on lipid metabolism. • B. cinerea, cultured in malt extract media, was challenged with iprodione and its lipids extracted, separated by TLC, and analysed by GLC. Lipid metabolism was followed using [1-14 C]acetate. • Triacylglycerol was the major nonpolar and phosphatidylcholine the main polar lipid in B. cinerea. Linoleate, followed by α-linolenate, were the major fatty acids and most lipid classes had compositions broadly similar to the total fatty acid pattern. Iprodione, at concentrations causing a cessation of growth (5 µM) caused a decrease in polar lipid but not total nonpolar lipid labelling. Within the nonpolar lipids, DAG was better labelled. • The data show that iprodione had a selective effect on lipid metabolism. The altered pattern of labelling suggested that choline (ethanolamine) phosphotransferase would be worth investigating as a primary site of action.