Renal papillary adenoma--a putative precursor of papillary renal cell carcinoma.

The precursor lesions of renal cell carcinoma (RCC) are unknown. The purpose of this study is to determine the incidence, histomorphological features, and immunohistochemical features of papillary adenoma and elucidate its potential relationship to RCC. We reviewed 542 consecutive nephrectomy specimens over an 8-year period. Immunohistochemistry was carried out with antibodies specific for alpha-methyl-coenzyme A racemase (AMACR) and glutathione S-transferase alpha (clear-cell RCC marker). Thirty-eight (7%) nephrectomy specimens showed histologic evidence of papillary adenoma. Of these 38 cases, 18 (47%) arose in the setting of papillary RCC (PRCC). Seven papillary adenomas (18%) occurred in the setting of acquired polycystic kidney disease (APKD), 6 in clear-cell RCCs, 3 in chromophobe RCCs, 2 in end-stage kidney disease, 1 in oncocytoma, 1 in angiomyolipoma, and 1 in renal schwannoma. Furthermore, papillary adenomas were more commonly found in kidneys removed for PRCC (25%, 18/71) than in kidneys harboring clear-cell RCC (1.9%, 6/318). Histomorphologically, papillary adenomas were characterized by varying proportions of papillae and tubules formed by cuboidal cells with scant basophilic cytoplasm similar to those in type 1 PRCC. Adenomas associated with PRCC tend to be multiple in number (61% [11/18] of cases had >2 adenomas; mean, 5). In contrast, 100% of papillary adenomas arising in other conditions had less than 2 adenomas. Most of the adenomas (82%, 31/38) stained strongly for AMACR in a fashion similar to that of PRCC. The 7 AMACR-negative cases all arose in the setting of APKD. In this study of surgical specimens, the high coincidence, multifocality, and histologic and immunohistochemical similarities between papillary adenoma and PRCC suggest that the 2 are strongly associated and may represent a continuum of 1 biologic process. In contrast, adenomas associated with APKD exhibit distinct morphological and immunohistochemical features and, therefore, may have an entirely different pathogenesis.

Expression of annexin A1 in esophageal and esophagogastric junction adenocarcinomas: association with poor outcome.

PURPOSE: Annexin A1 (ANXA1) is a calcium-binding protein involved in arachidonic acid metabolism and epidermal growth factor receptor tyrosine kinase pathway. ANXA1 has been implicated in early squamous cell carcinogenesis of esophagus and correlates with degree of tumor differentiation. However, the role of ANXA1 in esophageal adenocarcinoma is unclear. Our goal was to evaluate ANXA1 expression and determine its prognostic significance in adenocarcinoma of the esophagus and esophagogastric junction. EXPERIMENTAL DESIGN: This study included 104 consecutive patients with primary resected esophageal and esophagogastric junction adenocarcinomas (11 stage I, 24 stage II, 53 stage III, and 16 stage IV). ANXA1 protein expression in each tumor was assessed by immunohistochemical staining of tissue microarrays. ANAX1 expression level was classified as high (>/=25% of tumor cells with cytoplasmic staining), low (<25% of tumor cells with cytoplasmic staining), or negative; and was correlated with clinicopathologic features and patients' outcomes. RESULTS: High ANXA1 expression was present in 39% (41 of 104) of tumors and was associated with higher pathologic T stage (P = 0.03) and distant metastasis (P = 0.04). High ANXA1 expression correlated with increased recurrence rate (P = 0.004) and decreased overall survival (P = 0.003) in univariate analysis. In multivariate analysis, ANXA1 expression and pN stage significantly correlated with recurrence rate (P = 0.008 and P < 0.001, respectively) and overall survival (P = 0.02 and P < 0.001, respectively) independent of T stage. CONCLUSION: Our results indicate that high ANXA1 expression is frequent in esophageal and esophagogastric junction adenocarcinomas, correlates with more advanced pathologic T stage and the presence of distant metastasis, and is an independent prognostic factor for patient survival.

A molecular classification of papillary renal cell carcinoma.

Despite the moderate incidence of papillary renal cell carcinoma (PRCC), there is a disproportionately limited understanding of its underlying genetic programs. There is no effective therapy for metastatic PRCC, and patients are often excluded from kidney cancer trials. A morphologic classification of PRCC into type 1 and 2 tumors has been recently proposed, but its biological relevance remains uncertain. We studied the gene expression profiles of 34 cases of PRCC using Affymetrix HGU133 Plus 2.0 arrays (54,675 probe sets) using both unsupervised and supervised analyses. Comparative genomic microarray analysis was used to infer cytogenetic aberrations, and pathways were ranked with a curated database. Expression of selected genes was validated by immunohistochemistry in 34 samples with 15 independent tumors. We identified two highly distinct molecular PRCC subclasses with morphologic correlation. The first class, with excellent survival, corresponded to three histologic subtypes: type 1, low-grade type 2, and mixed type 1/low-grade type 2 tumors. The second class, with poor survival, corresponded to high-grade type 2 tumors (n = 11). Dysregulation of G1-S and G2-M checkpoint genes were found in class 1 and 2 tumors, respectively, alongside characteristic chromosomal aberrations. We identified a seven-transcript predictor that classified samples on cross-validation with 97% accuracy. Immunohistochemistry confirmed high expression of cytokeratin 7 in class 1 tumors and of topoisomerase IIalpha in class 2 tumors. We report two molecular subclasses of PRCC, which are biologically and clinically distinct and may be readily distinguished in a clinical setting.

Overexpression of glutathione s-transferase alpha in clear cell renal cell carcinoma.

To determine its diagnostic value, we evaluated glutathione S-transferase alpha (GST-alpha) expression in a large number of renal cell carcinomas (RCCs). GST-alpha messenger RNA (mRNA) levels from 70 renal neoplasms were analyzed with complementary DNA (cDNA) microarray chips containing 21,632 cDNA clones. Furthermore, 348 primary renal tumors and 24 metastatic RCCs were subjected to immunohistochemical analysis with a GST-alpha-specific antibody. GST-alpha mRNA was elevated significantly (11.4-fold) in a majority of clear cell RCCs (28/43 [65.1%]; 28/39 [71.8%] with adjustments for informative spots) compared with other kidney tumors (1/27 [3.7%]). Strong and diffuse GST-alpha immunoreactivity was demonstrated in a majority of clear cell (166/202 [82.2%]; mean intensity, 2.41) and metastatic clear cell RCCs (17/24 [70.8%]; mean intensity, 2.62). Other renal tumor types did not exhibit significant GST-alpha immunoreactivity, confirming mRNA results. Through cDNA microarrays and immunohistochemical analysis, we demonstrated GST-alpha as a biomarker for clear cell RCCs.

General anesthesia for pediatric dermatologic procedures: risks and complications.

OBJECTIVE: To assess the safety and adverse events associated with the use of general anesthesia in children undergoing elective dermatologic procedures. DESIGN: A multicenter retrospective review. SETTING: Children's Hospital and Health Center, San Diego, Calif, and Northwestern University School of Medicine, Chicago, Ill. PATIENTS: The study population comprised 269 children and adolescents ranging in age from 2 months to 18 years (881 procedures performed by 6 pediatric dermatologic and laser surgeons). MAIN OUTCOME MEASURES: The risk of an adverse event occurring during general anesthesia for pediatric dermatologic procedures. RESULTS: The risk of general anesthesia in elective pediatric dermatologic procedures was low: 90% of patients experienced no clinically relevant complications. The most common clinically relevant adverse effect of general anesthesia was perioperative nausea and emesis, which was noted in 4% of patients. There were no serious life-threatening events noted, and the mortality rate was 0%. CONCLUSION: The use of general anesthesia for dermatologic procedures in a children's hospital setting appears safe, with a low rate of complications.

Signet-ring cell change versus signet-ring cell carcinoma: a comparative analysis.

Signet-ring cell change (SCC) is a nonneoplastic condition that morphologically simulates signet-ring cell carcinoma (SRCA). The few case reports on SCC have focused on morphologic characteristics in distinguishing benign from malignant. In biopsy specimens, however, SCC can be easily confused with SRCA, which often demonstrates innocuous cytologic features. The object of this study is twofold: 1) to report 14 additional cases of SCC, comparing their morphologic and phenotypic features with that of SRCA; and 2) to evaluate the incidence of SCC in pseudomembranous colitis. Paraffin sections of biopsy or resection specimens containing focal or extensive SCC and 5 cases of colonic SRCA were stained with hematoxylin and eosin, periodic-acid Schiff stain with and without diastase digestion, and by standard ABC immunoperoxidase procedure using antibodies to E-cadherin, p53, and Ki-67. Both cells in SCC and SRCA were strongly positive for neutral mucins. Cells in SCC were strongly positive for E-cadherin and negative for p53 and Ki-67. In contrast, cells in SRCA were strongly positive for p53, exhibited high proliferation, and demonstrated absent or weak positivity for E-cadherin. Although SCC is not well recognized in pseudomembranous colitis, the incidence is fairly high: 14 of 50 (28%) cases showed variable numbers of signet-ring cells. Extensive SCC, although rare, can occur in different clinical conditions and can be easily mistaken for SRCA. When in doubt, routine immunohistochemical stains such as p53, Ki-67, and E-cadherin can help to differentiate SCC from SRCA.

Multifocal presentation of gangliocytic paraganglioma in the mediastinum and esophagus.

Gangliocytic paraganglioma (GP) is a rare, typically benign tumor that shows neuroectodermal (neurosustentacular or Schwannian and neuronal) and neuroendocrine differentiation. Once thought to arise exclusively in the periampullary region as a solitary lesion, recent reports have documented both origin of GP in a variety of extra-duodenal sites as well as synchronous multifocal presentation of the tumor. Herein, we describe the first reported case of simultaneous occurrence of GP in the superior mediastinum and esophagus. A mass in the mid-distal esophagus and a separate mass in the superior mediastinum at the thoracic inlet were found in a 58-year-old woman by computed tomography scan. Subsequent biopsy of the superior mediastinal mass showed nests of epithelioid tumor cells coexisting with ganglioneuromatous elements, whereas biopsy of the esophageal mass showed nests of epithelioid cells with interspersed ganglion cells. The epithelioid tumor cells showed diffuse immunohistochemical expression of keratin (CAM 5.2), chromogranin, and synaptophysin supporting true neuroendocrine differentiation; ganglion cells expressed S-100 protein and neurofilament protein; and the spindled elements expressed S-100 protein, neurofilament protein, and glial fibrillary acidic protein indicating Schwannian differentiation. The finding of another GP occurring outside the periampullary region bolsters the argument for a stem cell origin of this unusual tumor.

Comparative analysis of cell adhesion molecules, cell cycle regulatory proteins, mismatch repair genes, cyclooxygenase-2, and DPC4 in carcinomas arising in inflammatory bowel disease and sporadic colon cancer.

Colon carcinoma arising in inflammatory bowel disease often exhibits aggressive behavior compared to sporadic carcinomas. The rationale for the different biological behaviors of these two groups of tumors is not fully understood. In this study, we have examined carcinomas arising in inflammatory bowel disease (IBD) and sporadic carcinomas (SCA) for molecular differences that may provide clues for the behavioral disparity of these tumors. Thirty-eight colon carcinomas (12 from ulcerative colitis, 5 from Crohn's disease, and 21 SCA) were analyzed by immunohistochemistry for cell adhesion molecules (E-cadherin, beta-catenin, CD44), cell cycle regulatory proteins (cyclin D1, p27, p21), mismatch repair proteins (hMLH1, hMSH2), cyclooxygenase-2 and DPC4. Carcinomas arising in IBD showed significant decrease in expression of cell adhesion molecules, the cell cycle inhibitor protein, p21, and increased expression of cyclooxygenase-2 compared to sporadic carcinomas. No differences were observed in the expression of cell cycle regulatory proteins p27, cyclin D1, DPC4 and mismatch repair proteins between these two groups of tumors. Decreased expression of p21 as well as adhesion molecules may provide increased impetus for the aggressive behavior of tumors arising in inflammatory bowel disease.

Expression of epidermal growth factor receptor in esophageal and esophagogastric junction adenocarcinomas: association with poor outcome.

BACKGROUND: The prognosis for patients with esophageal and esophagogastric junction (EGJ) adenocarcinoma remains poor, even after surgical resection. Pathologic assessment of depth of invasion and lymph node status are the primary prognostic factors in these patients. In patients with esophageal squamous cell carcinoma, increased epidermal growth factor receptor (EGFR) expression has been associated with a worse prognosis. It is not known whether EGFR plays a similar role in esophageal and EGJ adenocarcinomas. METHODS: To address this issue, the authors studied tumor specimens from 103 patients with surgically resected esophageal and EGJ adenocarcinomas (9 patients with stage I disease, 23 patients with stage II disease, 57 patients with stage III disease, and 14 patients with stage IV disease). The expression of EGFR was assessed by immunohistochemical analysis of tissue microarrays. Tumors were considered positive for EGFR expression when >5% of tumor cells were stained and negative when

The significance of neuroendocrine differentiation in adenocarcinoma of the esophagus and esophagogastric junction after preoperative chemoradiation.

BACKGROUND: Esophageal and esophagogastric junction (EGJ) adenocarcinomas frequently have neuroendocrine (NE) differentiation, but the significance of NE differentiation in patients who have undergone preoperative chemoradiation and resection remains unclear. METHODS: The authors evaluated the presence of NE differentiation in esophageal and EGJ adenocarcinomas by immunohistochemistry for chromogranin A and synaptophysin and evaluated the clinical significance of NE differentiation in 83 patients (10 patients who had a complete tumor response and 73 patients who had residual tumor in resection specimens) who received preoperative chemoradiation. RESULTS: Of 73 patients who had residual tumor after preoperative treatment, 52% showed NE differentiation. The proportion of tumor cells with NE differentiation had increased from 6% +/- 18% in pretreatment biopsy specimens to 47% +/- 42% (P = .00003) in posttreatment resection specimens in 30 patients who had paired pretreatment biopsy and resection specimens available. Disease-free survival (P = .002) and overall survival (P = .006) were significantly better in patients who had a complete tumor response than in patients who had residual tumor. Among patients who had residual tumor after preoperative chemoradiation, disease-free survival (P = .03) and overall survival (P = .045) were significantly better in patients who had residual tumor without NE differentiation than in patients who had residual tumor with NE differentiation. In multivariate analysis, the presence of NE differentiation in residual tumor was a prognostic factor for worse disease-free survival (P = .02) independent of pathologic stage and extent of residual tumor. CONCLUSIONS: The results from this study suggested that tumor cells with NE differentiation were more resistant to neoadjuvant chemoradiation in patients with esophageal and EGJ adenocarcinomas. The presence of NE differentiation in residual tumor was associated with poor survival after preoperative neoadjuvant therapy.

Immunohistochemical expression of matrix metalloproteinases 1, 2, 9, and 14 in dermatofibrosarcoma protuberans and common fibrous histiocytoma (dermatofibroma).

CONTEXT: Common fibrous histiocytoma (cFH) or dermatofibroma and dermatofibrosarcoma protuberans (DFSP) are 2 spindle cell mesenchymal tumors that are distinguished in part by their microscopic growth patterns and clinically by the greater propensity for DFSP to recur. Matrix metalloproteinases (MMPs) potentially play a role in modulating the growth patterns of cFH and DFSP by remodeling the extracellular matrix. OBJECTIVE: To evaluate the immunohistochemical (IHC) expression of MMP-1, MMP-2, MMP-9, and MMP-14 in DFSP and cFH, because (1) MMP-1, MMP-2, MMP-9, and MMP-14 are synthesized by dermal fibroblasts, the major constituent of DFSP and cFH; and (2) platelet-derived growth factor B, which is overexpressed in most examples of DFSP because of t(17;22), activates ets-1, a transcription factor that regulates molecules associated with tumor invasion and metastasis, including MMP-1, MMP-3, and MMP-9. DESIGN: Immunohistochemical studies were performed on archived, formalin-fixed, paraffin-embedded tissue of DFSP (n = 48) and cFH (n = 47).Results.-Significant IHC expression (>10% of tumor cells) in cFH included MMP-14 (27 [59%] of 46 tumors positive), MMP-2 (21 [47%] of 45 tumors positive), MMP-9 (9 [20%] of 45 tumors positive), and MMP-1 (6 [13%] of 46 tumors positive). No DFSPs showed significant IHC expression of any of the MMPs evaluated. However, anti- MMP-2 highlighted a rich microvascular element within deep tumor tissue present in 81% of DFSPs with a prominent subcutaneous component. CONCLUSION: Our IHC results indicate that MMP-1 and MMP-9 are not up-regulated in DFSP. Convincing expression of MMP-14 in cFH suggests that this MMP may affect the growth pattern of the lesion, perhaps by activating MMP-2 expression in tumor cells. In DFSP, MMP-2 may play a role in tumor angiogenesis.