Somatic mutations in adrenocortical carcinoma with primary aldosteronism or hyperreninemic hyperaldosteronism.

Several somatic mutations specific to aldosterone-producing adenomas (APAs) have been described. A small proportion of adrenocortical carcinomas (ACCs) are associated with hyperaldosteronism, either primary aldosteronism or hyperreninemic hyperaldosteronism. However, it is unknown whether they harbor mutations of the same spectrum as APAs.

Targeted DNA and RNA Sequencing of Paired Urothelial and Squamous Bladder Cancers Reveals Discordant Genomic and Transcriptomic Events and Unique Therapeutic Implications.

Background: Integrated molecular profiling has identified intrinsic expression-based bladder cancer molecular subtypes. Despite frequent histological diversity, robustness of subtypes in paired conventional (urothelial) and squamous components of the same bladder tumor has not been reported.

Objective: To assess the impact of histological heterogeneity on expression-based bladder cancer subtypes.

A five-CpG DNA methylation score to predict metastatic-lethal outcomes in men treated with radical prostatectomy for localized prostate cancer.

Background: Prognostic biomarkers for localized prostate cancer (PCa) could improve personalized medicine. Our group previously identified a panel of differentially methylated CpGs in primary tumor tissue that predict disease aggressiveness, and here we further validate these biomarkers.

Methods: Pyrosequencing was used to assess CpG methylation of eight biomarkers previously identified using the HumanMethylation450 array; CpGs with strongly correlated (r >0.

Solitary Fibrous Tumors of the Head and Neck: A Multi-Institutional Clinicopathologic Study.

Solitary fibrous tumors (SFTs) of the head and neck are uncommon. Lesions previously diagnosed in the head and neck as hemangiopericytomas (HPCs), giant cell angiofibromas (GCAs), and orbital fibrous histiocytomas (OFHs) are now recognized as within the expanded spectrum of SFTs. To better understand the clinicopathologic profile of head and neck SFTs, we performed a multi-institutional study of 88 examples.

Phenotypic diversity of circulating tumour cells in patients with metastatic castration-resistant prostate cancer.

Objectives: To use a non-biased assay for circulating tumour cells (CTCs) in patients with prostate cancer (PCa) in order to identify non-traditional CTC phenotypes potentially excluded by conventional detection methods that are reliant on antigen- and/or size-based enrichment.

Patients And Methods: A total of 41 patients with metastatic castration-resistant PCa (mCRPC) and 20 healthy volunteers were analysed on the Epic CTC platform, via high-throughput imaging of DAPI expression and CD45/cytokeratin (CK) immunofluorescence (IF) on all circulating nucleated cells plated on glass slides. To confirm the PCa origin of CTCs, IF was used for androgen receptor (AR) expression and fluorescence in situ hybridization was used for PTEN and ERG assessment.

Comprehensive genomic profiling of orbital and ocular adnexal lymphomas identifies frequent alterations in MYD88 and chromatin modifiers: new routes to targeted therapies.

Non-Hodgkin lymphoma of the orbit and ocular adnexa is the most common primary orbital malignancy. Treatments for low- (extra-nodal marginal zone and follicular lymphomas) and high-grade (diffuse large B-cell lymphoma) are associated with local and vision-threatening toxicities. High-grade lymphomas relapse frequently and exhibit poor survival rates.

Expression of PDL1 (B7-H1) Before and After Neoadjuvant Chemotherapy in Urothelial Carcinoma.

Unlabelled: Expression of the costimulatory ligand PDL1 (B7-H1) on tumors allows escape from antitumor immunity. PDL1 expression has been reported in urothelial carcinoma (UC), suggesting it could be used as an immunotherapy target. We investigated the impact of cytotoxic neoadjuvant chemotherapy (NAC) on PDL1 expression in UC.

Clonal evaluation of prostate cancer foci in biopsies with discontinuous tumor involvement by dual ERG/SPINK1 immunohistochemistry.

The presence of two or more prostate cancer foci separated by intervening benign tissue in a single core is a well-recognized finding on prostate biopsy. Cancer involvement can be measured by including intervening benign tissue or only including the actual cancer involved area. Importantly, this parameter is a common enrollment criterion for active surveillance protocols.

Genomic Profiling of Penile Squamous Cell Carcinoma Reveals New Opportunities for Targeted Therapy.

Penile squamous cell carcinoma (PeSCCA) is a rare malignancy for which there are limited treatment options due to a poor understanding of the molecular alterations underlying disease development and progression. Therefore, we performed comprehensive, targeted next-generation sequencing to identify relevant somatic genomic alterations in a retrospective cohort of 60 fixed tumor samples from 43 PeSCCA cases (including 14 matched primary/metastasis pairs). We identified a median of two relevant somatic mutations and one high-level copy-number alteration per sample (range, 0-5 and 0-6, respectively).

A subset of solitary fibrous tumors express nuclear PAX8 and PAX2: a potential diagnostic pitfall.

Solitary fibrous tumor (SFT), a mesenchymal neoplasm with widespread anatomic distribution, can be diagnostically challenging in limited samples. We recently encountered an aspirate of a pancreatic mass, incorrectly interpreted as metastatic renal cell carcinoma based on strong PAX8 expression by immunohistochemistry (IHC). After resection, morphologic features with additional IHC (CD34 positivity) correctly identified this lesion as a SFT.

Next-Generation Sequencing of Tubal Intraepithelial Carcinomas.

Importance: High-grade serous carcinoma (HGSC) is the most prevalent and lethal form of ovarian cancer. HGSCs frequently arise in the distal fallopian tubes rather than the ovary, developing from small precursor lesions called serous tubal intraepithelial carcinomas (TICs, or more specifically, STICs). While STICs have been reported to harbor TP53 mutations, detailed molecular characterizations of these lesions are lacking.

Development and validation of a scalable next-generation sequencing system for assessing relevant somatic variants in solid tumors.

Next-generation sequencing (NGS) has enabled genome-wide personalized oncology efforts at centers and companies with the specialty expertise and infrastructure required to identify and prioritize actionable variants. Such approaches are not scalable, preventing widespread adoption. Likewise, most targeted NGS approaches fail to assess key relevant genomic alteration classes.

Next-Gen Sequencing Exposes Frequent MED12 Mutations and Actionable Therapeutic Targets in Phyllodes Tumors.

Unlabelled: Phyllodes tumors are rare fibroepithelial tumors with variable clinical behavior accounting for a small subset of all breast neoplasms, yet little is known about the genetic alterations that drive tumor initiation and/or progression. Here, targeted next-generation sequencing (NGS) was used to identify somatic alterations in formalin-fixed paraffin-embedded (FFPE) patient specimens from malignant, borderline, and benign cases. NGS revealed mutations in mediator complex subunit 12 (MED12) affecting the G44 hotspot residue in the majority (67%) of cases spanning all three histologic grades.

Tumor evolution and progression in multifocal and paired non-invasive/invasive urothelial carcinoma.

Although multifocal tumors and non-invasive/invasive components are commonly encountered in surgical pathology, their genetic relationship is often poorly characterized. We used next-generation sequencing (NGS) to characterize somatic alterations in a patient with five spatially distinct, high-grade papillary urothelial carcinomas (UCs), with one tumor harboring an underlying invasive component. NGS of 409 cancer-related genes was performed on DNA isolated from formalin-fixed paraffin-embedded (FFPE) blocks representing each papillary tumor (n = 5), the invasive component of one tumor, and matched normal tissue.

HRAS mutations are frequent in inverted urothelial neoplasms.

Inverted urothelial papilloma (IUP) is an uncommon neoplasm of the urinary bladder with distinct morphologic features. Studies regarding the role of human papillomavirus (HPV) in the etiology of IUP have provided conflicting evidence of HPV infection. In addition, little is known regarding the molecular alterations present in IUP or other urothelial neoplasms, which might demonstrate inverted growth pattern like low-grade or high-grade urothelial carcinoma (UCA).

Immunohistochemical staining characteristics of nephrogenic adenoma using the PIN-4 cocktail (p63, AMACR, and CK903) and GATA-3.

Nephrogenic adenoma (NA) is a benign lesion of the urinary tract associated with injury to the urothelium. The varied morphologic patterns of NA make it a potential diagnostic pitfall, because it can mimic closely prostatic adenocarcinoma and urothelial carcinoma. In current practice, an antibody cocktail comprising p63, CK903, and AMACR (PIN-4 cocktail) is frequently utilized to evaluate foci suspicious for prostatic adenocarcinoma.

An immunohistochemical panel for reliable differentiation of salivary duct carcinoma and mucoepidermoid carcinoma.

Salivary duct carcinoma is a highly aggressive salivary gland malignancy that may be misdiagnosed as high-grade mucoepidermoid carcinoma. We utilized tissue microarrays with 78 examples of mucoepidermoid carcinoma and 47 salivary duct carcinomas to evaluate the utility of an immunohistochemical panel consisting of androgen receptor, Her2/neu, p63, and cytokeratin 5/6 in distinguishing these entities. Among all cases in the cohorts, androgen receptor was highly specific for salivary duct carcinoma, while cytokeratin 5/6 and p63 were specific for mucoepidermoid carcinoma.

Funding anatomic pathology research: a retrospective analysis of an intramural funding mechanism.

Context: In 2006, the department of pathology at our institution established an intramural research funding mechanism to support anatomic pathology research projects for faculty and trainee development. A review committee consisting of faculty members with diverse academic interests evaluated applications; proposals were eligible for a maximum award amount of $30 000 per project with a maximum program cost of $150 000 annually.

Objective: To report our experience based on a retrospective review of the research proposals submitted to the committee since the inception of the Anatomic Pathology Research Fund and evaluate the outcomes of the funded projects.

Hematopoiesis and leukemogenesis in mice expressing oncogenic NrasG12D from the endogenous locus.

NRAS is frequently mutated in hematologic malignancies. We generated Mx1-Cre, Lox-STOP-Lox (LSL)-Nras(G12D) mice to comprehensively analyze the phenotypic, cellular, and biochemical consequences of endogenous oncogenic Nras expression in hematopoietic cells. Here we show that Mx1-Cre, LSL-Nras(G12D) mice develop an indolent myeloproliferative disorder but ultimately die of a diverse spectrum of hematologic cancers.

Nf1-/- Schwann cell-conditioned medium modulates mast cell degranulation by c-Kit-mediated hyperactivation of phosphatidylinositol 3-kinase.

Neurofibromatosis type 1 (NF1) is a common genetic disorder and is characterized by both malignant and nonmalignant neurofibromas, which are composed of Schwann cells, degranulating mast cells, fibroblasts, and extracellular matrix. We and others have previously shown that hyperactivation of the c-Kit pathway in an Nf1 haploinsufficient microenvironment is required for both tumor formation and progression. Mast cells play a key role in both tumorigenesis and neoangiogenesis via the production of matrix metalloproteinases, heparin, and a range of different growth factors.

Mutant Ikzf1, KrasG12D, and Notch1 cooperate in T lineage leukemogenesis and modulate responses to targeted agents.

Mice that accurately model the genetic diversity found in human cancer are valuable tools for interrogating disease mechanisms and investigating novel therapeutic strategies. We performed insertional mutagenesis with the MOL4070LTR retrovirus in Mx1-Cre, Kras(G12D) mice and generated a large cohort of T lineage acute lymphoblastic leukemias (T-ALLs). Molecular analysis infers that retroviral integration within Ikzf1 is an early event in leukemogenesis that precedes Kras(G12D) expression and later acquisition of somatic Notch1 mutations.

p21-activated kinase regulates mast cell degranulation via effects on calcium mobilization and cytoskeletal dynamics.

Mast cells are key participants in allergic diseases via activation of high-affinity IgE receptors (FcepsilonRI) resulting in release of proinflammatory mediators. The biochemical pathways linking IgE activation to calcium influx and cytoskeletal changes required for intracellular granule release are incompletely understood. We demonstrate, genetically, that Pak1 is required for this process.