Faculty Bibliography

PURPOSE/OBJECTIVE:The 2005 diagnostic criteria for Rasmussen encephalitis (RE) are based on seizures, clinical deficits, electroencephalography (EEG), neuroimaging, and pathology (Brain, 128, 2005, 451). We applied these criteria to patients evaluated for RE and epilepsy surgery controls to determine the sensitivity, specificity, and positive and negative predictive values (PPVs, NPVs) using pathology as the gold standard. METHODS:We identified patients evaluated for RE based on medical records from 1993 to 2011. Fifty-two control patients with refractory epilepsy, unilateral magnetic resonance imaging (MRI) changes, and biopsies were selected from an epilepsy surgery database from matching years. Patients meeting all three of group A and/or two of three group B criteria were classified as meeting full criteria (positive). Patients not meeting full criteria were classified as negative. When available, pathology findings were re-reviewed with neuropathologists, and MRI imaging was re-reviewed with a neuroradiologist. KEY FINDINGS/RESULTS:RE was considered in the differential diagnosis for 82 patients, of whom 35 had biopsies. Twenty patients met full criteria (positive) without another explanation, including seven for whom biopsy was required to meet criteria and one in whom another etiology was identified. Two patients met full criteria but had another explanation. Thirty-five met partial criteria (negative), of whom 14 had another etiology identified. Twenty-five met no criteria (negative). The diagnostic criteria had a sensitivity of 81% with four false negatives (criteria-negative, biopsy-positive) when compared to pathology as a gold standard. Five false positives (criteria positive, biopsy negative) had identifiable alternate diagnoses. SIGNIFICANCE/CONCLUSIONS:The 2005 Bien clinical diagnostic criteria for RE have reasonably high sensitivity and specificity and good clinical-pathologic correlation in most cases. We suggest modification of the criteria to allow inclusion of cases with well-described but less common features. Specifically we suggest making the diagnosis in the absence of epilepsia partialis continua (EPC) or clear progression of focal cortical deficits or MRI findings if biopsy is positive and two of the A criteria are met (B3 plus two of three A criteria). This would improve the sensitivity of the criteria.

BACKGROUND:Giant cell reparative granulomas (GCRGs) are rare lesions in the cranial bones. We present a case of this rare lesion emanating from the clivus and replacing the sphenoid sinus, a highly unusual location for this entity. CASE DESCRIPTION/METHODS:The case and clinical course of a 29-year-old female who presented with a large sphenoid mass are described here. The patient presented with symptoms of severe headache and diplopia; imaging demonstrated a large sphenoid mass which was completely resected via an endoscopic endonasal approach. It was based on the clivus and was shown to be a GCRG. CONCLUSION/CONCLUSIONS:GCRGs are benign granulomatous lesions which should be considered in the differential in the setting of a sphenoid mass.

The authors describe the case of a young girl with suprasellar germinoma. Six weeks after this diagnosis, just prior to initiation of therapy, serum and CSF marker analysis revealed sudden and marked elevation of alpha-fetoprotein, indicating transformation of her germinoma to a nongerminomatous germ cell tumor. She underwent chemotherapy and radiation therapy per the national treatment approach for the new diagnosis, with subsequent return of her serum and CSF tumor markers to normal levels. To the authors' knowledge, this is the first case in the English-language literature of a nongerminomatous germ cell tumor resulting from conversion of germinoma at the original site of presentation.

This study evaluated the expression patterns of claudins 1, 3, 4, 7, and 8 in human renal cell carcinomas and oncocytomas and correlated expression with patient prognosis. Tissue microarrays were created from paraffin-embedded tissue samples from 141 patients with renal cell carcinomas or oncocytoma (90 clear cell, 22 papillary, 17 chromophobe renal cell carcinomas, and 12 oncocytomas). The staining pattern for claudins 3, 4, 7, and 8 was membranous and/or cytoplasmic, whereas claudin 1 was predominantly membranous in both nonneoplastic renal tissue and tumors. Negative to weak claudin 3 staining was predominantly detected in Fuhrman's grade 1 and 2 clear cell renal cell carcinomas (78%; P=0.016), suggesting that upregulation of claudin 3 potentially occurs concomitantly with increasing grade of clear cell renal cell carcinomas. In addition, Kaplan-Meier univariate analysis showed a significant inverse correlation between moderate to strong claudin 3 and 4 expression with overall survival in clear cell renal cell carcinomas (P=0.038 and P=0.031). Moderate to strong claudin 7 expression was significantly more common in chromophobe renal cell carcinomas (94%) than in oncocytomas (55%; P=0.041). Claudin 8 staining was moderate to strong in 92% of oncocytomas, which differentiated them from papillary and clear cell renal cell carcinomas (14 and 12%; both P<0.0001). Only negative to weak claudin 8 staining was detected in all chromophobe renal cell carcinomas, whereas there were no claudin 8 negative oncocytomas and 8% exhibited a weak staining pattern (P<0.0001). Due to their distinctive expression patterns, claudins 7 and 8 can be used as useful immunohistochemical markers for the separation of chromophobe renal cell carcinomas from oncocytomas, whereas claudins 3 and 4 may serve as indicators of prognosis in clear cell renal cell carcinomas.

The kidney is an important target for mineralocorticoids. Aldosterone, the major endogenously secreted mineralocorticoid, acts by binding to mineralocorticoid receptor (MR) in the distal renal tubule. The enzyme 11beta-hydroxysteroid dehydrogenase type II (11beta-HSD2) prevents the binding of glucocorticoids to the MR by inactivating cortisol to cortisone. Our goal was to determine whether MR and 11beta-HSD2 expression could be used to characterize the major types of renal cell neoplasms. Using immunohistochemistry we analyzed tissue microarray specimens from 132 patients with renal cell neoplasms, stratified into 84 clear cell renal cell carcinomas (CRCC), including 9 cases clear cell carcinoma with predominantly granular cytoplasm; 14 papillary RCC (PRCC); 20 chromophobe RCC (CHRCC); and 14 oncocytomas (OCs). MR and 11beta-HSD2 expression were also quantitated by real-time reverse transcription-polymerase chain reaction. Expression of both MR and 11-betaHSD2 was detected in the distal nephrons of normal kidneys. The CHRCC group stained for 11-betaHSD2 in a membranous and cytoplasmic pattern whereas diffuse cytoplasmic reactivity was seen in OCs. MR and 11beta-HSD2 were coexpressed in most of CHRCC (90% and 95%) and oncocytomas (93% and 100%). No MR staining was detected in CRCC, including clear cell carcinoma with predominantly granular cytoplasm, or in PRCC. Only 2 cases of CRCC (2.6%) showed focal positivity for 11beta-HSD2, whereas all PRCCs were negative. CHRCC and OC demonstrated significantly higher levels of MR and 11beta-HSD2 expression than CRCC and PRCC by real-time polymerase chain reaction. Moreover, CHRCC showed higher expression of MR and 11beta-HSD2, as compared with OC. Our study indicates MR and 11beta-HSD2 are both sensitive and specific markers of the distal nephron and its related neoplasms (CHRCC and OC). Additionally, the staining pattern and the level of MR and 11beta-HSD2 expression seems to be useful in the distinction of CHRCC from OC. MR and 11beta-HSD2 should be considered in the immunohistochemical panel to more accurately subtype renal cell tumors.

PURPOSE/OBJECTIVE:Renal cancer response to interleukin 2 (IL-2) therapy and patient survival has been correlated with tumor histology and carbonic anhydrase IX (CAIX) expression. In an effort to confirm and expand these observations, we examined CAIX expression in pathology specimens from renal cancer patients who had previously received IL-2 therapy. EXPERIMENTAL DESIGN/METHODS:Paraffin-embedded tissue sections of renal cancer were immunostained with the MN-75 monoclonal antibody to CAIX and expression levels were correlated with histologic findings and clinical outcome. RESULTS:Tissue specimens were obtained from 66 patients; 27 of whom (41%) had responded to IL-2-based therapy. Fifty-eight specimens were assessed as clear cell, with 56, 33, and 4 having alveolar, granular, and papillary features, respectively. Twenty-four (36%), 31 (47%), and 11 (17%) were classified into good, intermediate, and poor prognosis groups according to the Upton pathology model. Forty-one specimens (62%) had high CAIX expression. Twenty-one of 27 (78%) responding patients had high CAIX expressing tumors compared with 20 of 39 (51%) nonresponders (odds ratio, 3.3; P = 0.04). Median survival was prolonged (P = 0.04) and survival >5 years was only seen in high CAIX expressers. In patients with intermediate pathologic prognosis, all nine responders had high CAIX expression versus 11 of 22 nonresponders. A resultant group with good pathologic prognosis alone or with intermediate pathologic prognosis and high CAIX contained 26 of 27 (96%) responders compared with 18 of 39 (46%) nonresponders (odds ratio, 30; P < 0.01) and exhibited longer median survival (P < 0.01). CONCLUSIONS:CAIX expression seems to be an important predictor of outcome in renal cell carcinoma patients receiving IL-2-based therapy and may enhance prognostic information obtained from pathology specimens.

The cyclin-dependent kinase (cdk) inhibitor p27 preferentially inactivates cdk complexes required for progression through the G1/S transition. Loss of p27 is associated with aggressive behavior in a variety of tumors, including Barrett's associated adenocarcinoma (BAA). We have previously shown that gastroduodenal-esophageal reflux (GDER) together with N-methyl-N-benzylnitrosamine (MBN) induces Barrett's esophagus (BE) and malignant transformation of the esophageal mucosa in mice. This process is enhanced in a p27 null background. Here, we show that chronic flavopiridol administration sharply reduced the prevalence of BE in GDER/MBN-treated p27 knockout mice when compared to animals treated with diluent only (7 vs 26%, P=0.0079). Similarly, flavopiridol reduced the prevalence of BAA (11 vs 32%, P=0.0098) and overall cancer prevalence (15 vs 60%, P<0.0001). In addition, appropriate molecular targeting by flavopiridol in tumor cells was confirmed by downregulation of cyclin D1, a known target of this pan-cdk inhibitor. The results of this study represent the experimental basis for chemoprevention with cdk inhibitors in human BE and BAA.

Prostate tumor cells preferentially adhere to bone marrow endothelial cells (BMECs) compared with endothelial linings from other tissue microvessels, implicating the importance of BMEC adhesion in the predilection of prostate tumor metastasis to bone. E (endothelial)-selectin, which functions as an initiator of leukocyte adhesion to target tissue endothelium, is constitutively expressed on BMECs, suggesting that prostate tumor cells could use this adhesive mechanism to initiate their migration into bone. In this report, we demonstrate for the first time that human bone-metastatic prostate tumor cells roll on human BMECs under physiological flow conditions. We show that these dynamic adhesive interactions are dependent on the expression of BMEC E-selectin and sialylated glycoconjugates on bone-metastatic prostate tumor cells. We also establish the importance of both glycoprotein(s) and glycosphingolipid structures displaying sialyl Lewis X epitopes as potential E-selectin ligands on bone-metastatic prostate tumor cells. Coexpression of sialylated glycoproteins and glycolipids on bone-metastatic prostate tumor cells triggers robust E-selectin binding activity, which is identical to that observed on human hematopoietic progenitor cells. By Western blot analysis, we identify candidate E-selectin glycoprotein ligand(s); distinct sialyl Lewis X (or HECA-452 antigen)-bearing membrane proteins were resolved at M(r) 130,000 and M(r) 220,000 as well as others ranging from M(r) 100,000 to M(r) 220,000. Immunohistochemical analysis of HECA-452 antigen expression on normal prostate tissue and on low- and high-grade prostate adenocarcinoma shows that HECA-452 antigen expression is directly associated with prostate tumor progression and may indicate acquisition of E-selectin ligand expression. These findings provide novel insight into potential adhesive mechanisms promoting hematogenous dissemination of prostate tumor cells into bone.

Cellular levels of key regulatory proteins are controlled via ubiquitination and subsequent degradation. Deubiquitinating enzymes or isopeptidases can potentially prevent targeted destruction of protein substrates through deubiquitination prior to proteasomal degradation. However, only one deubiquitinating enzyme to date has been matched to a specific substrate in mammalian cells and shown to functionally modify it. Here we show that the isopeptidase USP2a (ubiquitin-specific protease-2a) interacts with and stabilizes fatty acid synthase (FAS), which is often overexpressed in biologically aggressive human tumors. Further, USP2a is androgen-regulated and overexpressed in prostate cancer, and its functional inactivation results in decreased FAS protein and enhanced apoptosis. Thus, the isopeptidase USP2a plays a critical role in prostate cancer cell survival through FAS stabilization and represents a therapeutic target in prostate cancer.