The somatic genomic landscape of glioblastoma.

We describe the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer.

Contemporary diagnosis and management of Warthin's tumor.

OBJECTIVE: Determine if the pathophysiology of Warthin's tumor, clinical presentation, cytology, and frozen section analysis signal an opportunity for less invasive parotid surgery and reduced morbidity. STUDY DESIGN: Retrospective review of 120 human parotidectomies identified 50 consecutive Warthin's tumors. SETTING: Single surgeon, single institutional study. SUBJECTS AND METHODS: Surgeon performed ultrasound guided Fine Needle Aspiration (FNA) and intra-operative frozen section with nerve integrity monitoring were used in all cases. Partial superficial parotidectomy was performed in the initial 25 patients and extracapsular dissection in the subsequent 25 patients. RESULTs: Smoking history was acknowledged in 45/50 (90 percent) of patients. The mean age was 63. Lower parotid pain and cellulitis occurred 23/50 (46 percent) and 11/50 (22 percent), respectively. Tumor in the lower parotid pole occurred in 48/50 (96 percent). Frozen section diagnosis for Warthin's tumor was confirmed by final pathology in all 50/50 (100 percent) patients. Two of 50 patients (8 percent) in the partial superficial parotidectomy group and no patient in the extracapsular dissection group had transient facial nerve dysfunction (p > 0.05). CONCLUSIONS: Warthin's tumor presents with a high rate of symptomatic inflammation, overwhelmingly in the lower parotid pole. Cytology largely excludes malignancy. Frozen section analysis diagnosing Warthin's tumor is highly specific in predicting final diagnosis. Minimally invasive approaches can be performed with confidence with extracapsular dissection or partial superficial parotidectomy resulting in potentially reduced morbidity.

Ruptured extratesticular epidermal inclusion cyst mimicking polyorchidism with torsion on sonography.

The sonographic appearance of epidermal inclusion cysts varies in accordance with the contents of the cyst, ranging from an anechoic lesion to a hyperechoic solid appearing mass. Supernumerary testes are an uncommon congenital abnormality, in which more than two testes are present. We present a rare case of a ruptured scrotal extratesticular epidermal inclusion cyst, which had the sonographic appearance of a supernumerary testicle with torsion.

Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease) of the true vocal cord.

Rosai-Dorfman disease (RDD) is a rare disorder involving massive benign proliferation of histiocytes in the lymph nodes. The etiology is unknown and the disease usually presents as painless lymphadenopathy accompanied with fever, night sweats, and weight loss. Due to its rarity, the disease is still difficult to diagnose when associated with extranodal involvement. We present an unusual case of a 39-year-old African American female with RDD involving the left true vocal cord.

Comparing capsule exposure using extracapsular dissection with partial superficial parotidectomy for pleomorphic adenoma.

UNLABELLED: The aim of this study was to compare capsule exposure using extracapsular dissection (ECD) with partial superficial parotidectomy (PSP) for pleomorphic adenoma. PURPOSE: Long-term favorable results for recurrence and facial nerve function have been reported for ECD and PSP for parotid pleomorphic adenoma. Extracapsular dissection is distinguished from PSP in that the facial nerve is dissected in PSP but not in ECD. This article attempts to answer the following hypothesis: the margin of normal parotid tissue surrounding a parotid pleomorphic adenoma is less for ECD compared with PSP. MATERIAL AND METHODS: This is a retrospective individual case-control study. Twelve consecutive parotidectomy procedures with a final pathology report of pleomorphic adenoma were retrospectively measured for margin (the percent of capsule exposure around the tumor). In 8 highly selected patients, ECD was performed. Four parotid surgical procedures not meeting strict criteria underwent PSP and served as controls. RESULTS: The eight patients with ECD had a mean of 80% (71%-99%) of the capsule exposed. The 4 PSP procedures had 21% (4%-50%) of the capsule exposed (P < .05). CONCLUSIONS: Extracapsular dissection results in higher capsule exposure.

Human epidermal receptor-2 expression in prostate cancer.

PURPOSE: Efforts to conclusively establish that human epidermal receptor (HER)-2 overexpression is important to androgen-dependent carcinoma of the prostate (AD-CaP) or to progression to androgen independence (AI-CaP) have failed because of variability in tissue procurement, antibodies, immunostaining procedures, and assessment methods. However, because some in vitro and animal model data correlate HER-2 overexpression with progression to androgen independence, trials of agents that target the HER-2 receptor are under way. To clarify human tumor findings, we studied HER-2 expression at the gene (DNA), mRNA, and protein levels in well-characterized CaP specimens. EXPERIMENTAL DESIGN: Fifty AD-CaP and 25 AI-CaP specimens from similar numbers of Caucasian and African Americans were immunostained for HER-2 receptor. HER-2 mRNA levels were measured using real-time fluorescence quantitative PCR in patients for whom frozen specimens were available. HER-2 amplification was evaluated using fluorescent in situ hybridization. RESULTS: HER-2 receptor immunostained in 52% of androgen-dependent and one (4%) androgen-independent tumor. HER-2 immunostaining was not related to age, race, serum prostate-specific antigen levels, or pathologic stage and Gleason grade. HER-2 overexpression was not detected in AI-CaP at the mRNA or gene level. Mean HER-2 mRNA expression was higher (P < 0.05) in AD-CaP than AI-CaP (22,080 versus 15,496 HER-2 copies). HER-2 was not amplified in any of 20 AD-CaP or 19 AI-CaP specimens. CONCLUSIONS: HER-2 protein and message overexpression and HER-2 amplification were not found in AI-CaP.

Cytokeratin immunohistochemical validation of the sentinel node hypothesis in patients with breast cancer.

No standard method for handling and histopathologic examination of the sentinel node (SN) exists. We hypothesized that a focused examination of all nodes with serial sectioning and cytokeratin immunohistochemical staining would confirm the SN as the node most likely to harbor metastasis. Intraoperative lymphatic mapping and sentinel lymphadenectomy using blue dye and (99m)technetium-labeled sulfur colloid were performed. All nodes were stained with H&E. All tumor-free nodes underwent additional sectioning and staining with H&E and an immunohistochemical stain. Routine H&E examination detected SN metastases in 27.6% of cases. Occult SN metastases were identified in 12.7% of cases. None of the 724 non-SNs examined contained occult metastases. The SN false-negative rate was zero. This study confirms histopathologically that the SN has biologic significance as the axillary node most likely to harbor metastatic tumor Standardization of the handling, sectioning, and staining of the SN is necessary as lymphatic mapping and sentinel lymphadenectomy become integrated into the care of patients with breast cancer

High focal adhesion kinase expression in invasive breast carcinomas is associated with an aggressive phenotype.

Focal adhesion kinase (FAK) is a protein tyrosine kinase expressed in invasive breast cancer that regulates antiapoptotic signaling. We have examined FAK expression by immunohistochemistry using anti-FAK 4.47 in breast tumor samples from a large population-based, case-control study of women participating in the University of North Carolina Breast Specialized Programs of Research Excellence (SPORE), Carolina Breast Cancer Study. In this population, 629 formalin-fixed, paraffin-embedded tissue sections were stained for FAK and scored as high (3+ or 4+ intensity and > or = 90% positive cells) or otherwise. High FAK expression was associated with poor prognostic indicators including high mitotic index (>10 mitoses per 10 consecutive high-power fields), nuclear grade 3, architectural grade 3, estrogen and progesterone receptor negative, and HER-2/neu overexpressed using CB11 antibody. The association of high FAK expression with HER-2/neu overexpression lends further support that HER-2/neu and FAK collaborate to promote tumorigenesis. The presence of strong FAK expression in many high grade, estrogen- and progesterone-negative breast carcinomas indicates that FAK may be an attractive target for therapeutic intervention.

HER2 codon 655 polymorphism and risk of breast cancer in African Americans and whites.

BACKGROUND: Several recent epidemiologic studies examined the association between breast cancer risk and an inherited, single-nucleotide polymorphism in the HER2 gene, codon 655 G to A, which leads to an amino acid substitution of Ile to Val. Results of previous studies have been mixed, with most studies showing no association but some suggesting an association in younger women or women with a family history of breast cancer. METHODS: We conducted an association study of HER2 codon 655 genotype and breast cancer within the Carolina Breast Cancer study, a population-based, case-control study of in situ and invasive breast cancer in African American and white women in North Carolina. A total of 2015 cases and 1808 controls were genotyped. RESULTS: We observed no overall association between HER2 genotype and breast cancer. However, a modest positive association (OR = 2.3, 95% CI 1.0-5.3) was observed for Val/Val + Ile/Val versus Ile/Ile genotypes in women age 45 or younger with a family history of breast cancer. Val/Val homozygotes were more common among cases with in situ versus invasive disease (P = 0.002). Breast tumors from women with Val/Val genotype were more likely to exhibit HER2 overexpression, but the results were not statistically significant (P = 0.17). CONCLUSIONS: The HER2 codon 655 polymorphism may be one of many low-penetrant genes that make a minor contribution to breast cancer, particularly in subgroups of women. Additional large studies, as well as data pooling, will be needed to estimate the contribution of such genes to breast cancer risk.