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  • 1
    Keywords: CLASSIFICATION ; BRAF ; uveal melanoma ; NEVI ; SOMATIC MUTATIONS ; MORPHOLOGIC FEATURES ; SPITZ TUMORS
    Abstract: Recently a group of spitzoid melanocytic proliferations with loss of BAP1 expression has been reported. The lesions may occur sporadically or as part of a familial cancer syndrome. They have distinct histopathologic features characterized by a nevus-like silhouette and cytologic composition of large epithelioid melanocytes with oval vesicular nuclei, distinct nucleoli, and abundant cytoplasm with well-defined cytoplasmic borders. A characteristic immunohistochemical finding is loss of nuclear labeling for BAP1. In contrast to classic Spitz nevi, the lesions carry the BRAF(V600E) mutation. They may present as a pure large epithelioid cell proliferation or as a combined lesion in association with a conventional nevus. Here we report a series of 8 combined melanocytic lesions, in which a dominant large epithelioid cell proliferation with loss of BAP1 expression was associated and intimately admixed with a BAP1-positive conventional nevus. These biphenotypic lesions were from 6 patients, 3 female and 3 male, ranging in age from 16 to 59 years. Immunohistochemical analysis for BAP1 showed loss of nuclear labeling confined to the large epithelioid melanocyte sub-population. The conventional melanocytes retained BAP1 expression. Both large epithelioid and conventional melanocytes were immunoreactive with the monoclonal antibody VE1, which recognizes the protein encoded by mutant BRAF(V600E). In 6 cases the conventional nevus component was a compound nevus of small "type B" melanocytes. In 2 cases, the nevus remnant was entirely intradermal. The lesions described herein may represent a peculiar combined melanocytic nevus variant. However, longer follow-up and more studies are needed to determine the biological potential of the BAP1-negative melanocyte proliferations.
    Type of Publication: Journal article published
    PubMed ID: 23026932
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  • 2
    Keywords: CLASSIFICATION ; MALIGNANT-MELANOMA ; uveal melanoma ; NEVI ; VEMURAFENIB ; BRAF V600E MUTATION ; RAF INHIBITOR RESISTANCE ; NRAS MUTATIONS
    Abstract: BRAF(V600E) is the most common mutation in cutaneous melanoma and has become the target of treatment for patients with metastatic melanoma. A number of methods are currently available to determine mutation status. Recently, a monoclonal antibody (VE1) against mutant BRAF(V600E) was generated. Its use permits assessment of the mutant protein expression throughout a tumor sample and may allow faster and cheaper determination of the mutation status in selected cases. However, for BRAF(V600E) protein expression analysis to be of clinical value, high sensitivity and specificity of the antibody is a prerequisite. In this study we analyzed 44 metastatic melanoma samples with a known BRAF(V600E) mutation status with immunohistochemical expression of the BRAF(V600E) protein. None of the 22 tumors that lacked the BRAF(V600E) mutation labeled with the antibody VE1. This set of VE1-immunonegative tumors included 4 metastatic lesions with the BRAF(V600E) mutation. All 22 tumor samples that were known to carry the BRAF(V600E) mutation were immunoreactive with VE1. Sixteen of them stained strongly and homogenously throughout the tumor sample. However, 6 tumor samples contained both BRAF(V600E) immunopositive and BRAF(V600E)-immunonegative cell populations. When the BRAF status was compared with immunoreactivity for melanocyte differentiation antigens, no significant difference in the expression of melan-A, microphthalmia transcription factor, gp100, or tyrosinase was found between mutant and wild-type tumors. In addition to metastatic lesions, we also examined 20 primary melanomas for the expression of BRAF(V600E). Seven of 10 superficial spreading melanomas were immunoreactive with the antibody VE1. Five tumors were strongly and homogenously immunoreactive. In 2 primary tumors the staining was focal, involving only a sub-population of the tumor. None of the nonsuperficial spreading melanomas was immunoreactive. In 7 primary tumors the mutation status could be analyzed: only tumors carrying the BRAF(V600E) mutation were immunoreactive with VE1. The high specificity and sensitivity of VE1 for the detection of mutant BRAF(V600E) suggests a valuable reagent for clinical purposes. Heterogeneity in BRAF expression may be relevant for treatment response to BRAF inhibitors.
    Type of Publication: Journal article published
    PubMed ID: 23211290
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  • 3
    Keywords: CANCER ; SURVIVAL ; TUMORS ; TRIAL ; ASSAY ; metastases ; STAGE-II ; BRAF(V600E) MUTATION ; COPY NUMBER ANALYSIS ; POLYCLONALITY
    Abstract: This study investigated the sensitivity and specificity of immunohistochemical (IHC) analysis using an anti-BRAF antibody to detect the presence of the BRAF V600E mutation in patients with metastatic melanoma. A total of 100 patients with American Joint Committee on Cancer stage IIIC unresectable or stage IV melanoma and who underwent tumor DNA BRAF mutation testing were selected. Paraffin-embedded, formalin-fixed melanoma biopsies were analyzed for the BRAF mutation status by independent, blinded observers using both conventional DNA molecular techniques and IHC with the novel BRAF V600E mutant-specific antibody, VE1. The antibody had a sensitivity of 97% (37/38) and a specificity of 98% (58/59) for detecting the presence of a BRAF V600E mutation. Of the BRAF-mutated cases, none of the non-V600E cases (including V600K) stained positive with the antibody (0/11). There were 5 cases with discordant BRAF mutation results. Additional molecular analysis confirmed the immunohistochemically obtained BRAF result in 3 cases, suggesting that the initial molecular testing results were incorrect. Two of these patients would not have received a BRAF inhibitor on the basis of the initial false-negative mutation testing result. Two cases remained discordant. The reported IHC method is an accurate, rapid, and cost-effective method for detecting V600E BRAF mutations in melanoma patients. Clinical use of the V600E BRAF antibody should be a valuable supplement to conventional mutation testing and allow V600E mutant metastatic melanoma patients to be triaged rapidly into appropriate treatment pathways.
    Type of Publication: Journal article published
    PubMed ID: 23026937
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  • 4
    Keywords: CANCER ; PROTEIN ; TRIAL ; colorectal cancer ; metastases ; COLON-CANCER ; INSTABILITY ; microsatellite instability ; BRAF MUTATIONS ; MISMATCH REPAIR DEFICIENCY ; POOR SURVIVAL ; Lynch syndrome ; FAMILY REGISTRY ; ISLAND METHYLATOR PHENOTYPE ; PAPILLARY THYROID-CARCINOMA ; BRAFV600E ; MMR ; MSI ; VE1 immunohistochemistry
    Abstract: BRAFV600E mutation in microsatellite-unstable (MSI) colorectal carcinomas (CRCs) virtually excludes Lynch syndrome (LS). In microsatellite-stable (MSS) CRCs it predicts poor prognosis. We propose a universal CRC LS screening algorithm using concurrent reflex immunohistochemistry (IHC) for BRAFV600E and mismatch-repair (MMR) proteins. We compared BRAFV600E IHC with multiplex polymerase chain reaction (PCR) and matrix-assisted laser desorption/ionization-time of flight mass spectrometry in 216 consecutive CRCs from 2011. Discordant cases were resolved with real-time PCR. BRAFV600E IHC was performed on 51 CRCs from the Australasian Colorectal Cancer Family Registry (ACCFR), which were fully characterized for BRAF mutation by allele-specific PCR, MMR status (MMR IHC and MSI), MLH1 promoter methylation, and germline MLH1 mutation. We then assessed MMR and BRAFV600E IHC on 1403 consecutive CRCs. By matrix-assisted laser desorption/ionization-time of flight mass spectrometry 15 cases did not yield a BRAF result, whereas 38/201 (19%) were positive. By IHC 45/216 (20%) were positive. Of the 7 discordant cases, real-time PCR confirmed the IHC result in 6. In the 51 CRCs from the ACCFR, IHC was concordant with allele-specific PCR in 50 cases. BRAFV600E and MSI IHC on 1403 CRCs demonstrated the following phenotypes: BRAF/MSS (1029 cases, 73%), BRAF/MSS (98, 7%), BRAF/MSI (183, 13%), and BRAF/MSI (93, 7%). All 11/1403 cancers associated with proven LS were BRAF/MSI. We conclude that BRAF IHC is highly concordant with 2 commonly used PCR-based BRAFV600E assays; it performed well in identifying MLH1 mutation carriers from the ACCFR and identified all cases of proven LS among the 1403 CRCs. Reflex BRAFV600E and MMR IHC are simple cheap tests that facilitate universal LS screening and identify the poor prognosis of the BRAFV600E-mutant MSS CRC phenotype.
    Type of Publication: Journal article published
    PubMed ID: 23797718
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  • 5
  • 6
    Keywords: RECEPTOR ; CANCER ; EXPRESSION ; GROWTH ; proliferation ; tumor ; CELL ; Germany ; MICROSCOPY ; THERAPY ; CLASSIFICATION ; FOLLOW-UP ; SUPPORT ; HISTORY ; DISTINCT ; GENE ; HYBRIDIZATION ; PROTEIN ; DIFFERENTIATION ; TUMORS ; SURGERY ; TIME ; PATIENT ; COMPARATIVE GENOMIC HYBRIDIZATION ; COPY NUMBER ; MALIGNANCIES ; MEMBRANE ; NUMBER ; AGE ; RECURRENCE ; vimentin ; pathology ; IMBALANCES ; MOLECULAR-CLONING ; LACKING ; FEATURES ; MALIGNANCY ; ELECTRON-MICROSCOPY ; HIGH-RESOLUTION ; GLIOMA ; analysis ; TUMOR-CELL ; USA ; LOSSES ; PHOSPHATASE ; epilepsy ; genomic ; RARE ; NECROSIS ; IMMUNOREACTIVITY ; CHROMOSOME-6 ; angiocentric ; NEUROFIBRILLARY TANGLES ; TANYCYTIC EPENDYMOMA
    Abstract: Angiocentric glioma has recently been described as a novel epilepsy associated tumor with distinct clinico-pathologic features. We report the clinical and pathologic findings in 8 additional cases of this rare tumor type and extend its characterization by genomic profiling. Almost all patients had a history of long-standing drug-resistant epilepsy. Cortico-subcortical tumors were located in the temporal and parietal lobes. Seizures began at 3 to 14 years of age and surgery was performed at 6 to 70 years. Histologically, the tumors were characterized by diffuse growth and prominent perivascular tumor cell arrangements with features of astrocytic/ependymal differentiation, but lacking neoplastic neuronal features. Necrosis and vascular proliferation were not observed and mitoses were sparse or absent. M1B-1 proliferation indices ranged from 〈 1% to 5%. Immunohistochemically, all cases stained positively for glial fibrillary acidic protein, vimentin, protein S100B, variably for podoplanin, and showed epithelial membrane antigen-positive cytoplasmic dots. Electron microscopy showed ependymal characteristics in 2 of 3 cases investigated. An analysis of genomic imbalances by chromosomal comparative genomic hybridization revealed loss of chromosomal bands 6q24 to q25 as the only alteration in I of 8 cases. In I of 3 cases, a high-resolution screen by array-comparative genomic hybridization identified a copy number gain of 2 adjacent clones from chromosomal band 11p11.2 containing the protein-tyrosine phosphatase receptor type J (PTPRJ) gene. All patients are seizure free and without evidence of tumor recurrence at follow-up times ranging from 1/2 to 6.9 years. Our findings support 2 previous reports proposing that angiocentric glioma is a novel glial tumor entity of low-grade malignancy
    Type of Publication: Journal article published
    PubMed ID: 18059228
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  • 7
    Keywords: CANCER ; FOLLOW-UP ; GENE ; FREQUENCY ; METASTASIS ; PREVALENCE ; BRAF ; Nodules ; V600E mutation ; Papillary thyroid carcinoma ; BRAF(V600E) MUTATION ; MICROCARCINOMA ; SOLID VARIANT
    Abstract: The V600E mutation of the B-type Raf kinase (BRAF) gene is a common event in papillary thyroid carcinoma (PTC) and seems to play a key role in the development and progression of this disease. We evaluated the expression of the mutated BRAF V600E protein in 144 cases of PTC using a novel mutation- specific antibody. Seventy-six PTCs (52.8%) showed unequivocal diffuse cytoplasmic expression of the mutated BRAF protein, and the T1799A point mutation was confirmed by sequencing analysis in selected cases. No statistical difference in V600E BRAF protein expression was seen between microcarcinomas and macrocarcinomas. Further, no significant correlation of V600E expression with clinicopathologic parameters of aggressiveness such as lymph node metastasis, peritumoral infiltration, or perithyroidal infiltration was found. BRAF V600E protein expression was significantly more common in tumors with tall cell or oncocytic features but was less common in tumors with follicular growth pattern. Diffuse sclerosing, solid and follicular variants did not show the mutated BRAF protein. Immunohistochemical detection of the mutated V600E BRAF protein in PTC may facilitate mutational analysis in the clinical setting. Our data show that the expression of the mutated BRAF V600 protein and thus the corresponding BRAF mutation seems not to be per se a marker of aggressiveness but is already seen in clinically indolent microcarcinomas. Nevertheless, the investigation of BRAF V600E protein expression might be of clinical interest especially in therapy-resistant disease, as new therapeutics inhibiting the mutated protein are clinically available
    Type of Publication: Journal article published
    PubMed ID: 22592144
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  • 8
  • 9
    Keywords: GENOME ; INSTABILITY ; EVOLUTION ; SELECTION ; RECTAL-CANCER ; CONSEQUENCES ; TARGETED THERAPY ; HUMAN COLON ; INTRATUMOR HETEROGENEITY ; MATCHED PRIMARY
    Abstract: A multistep model of disease progression and genomic landscape has been firmly established for colorectal cancer (CRC) primaries, but the genetic makeup of related metastases and the dynamics of genetic changes during metastatic progression are scarcely known. To address these issues, we used multigene high-coverage next-generation sequencing of 24 microsatellite-stable CRC primaries, matched normal tissue, and related multiple metastases to nodes, liver, lung, and brain with a CRC-specific gene panel to infer the degree of clonal evolution during metastatic progression of the disease. Somatic mutations were detected in 40% of CRC-related genes, and we observed a striking 100% genetic concordance between primary and multiple secondary sites for APC, KRAS, FBXW7, PIK3CA, BRAF, SMAD4, and ACVR2A. Except for true de novo mutations in 4 cases (affecting SYNE1, CTNNB1, TP53, and PTEN), all remaining cases (84.4%) shared the genetic lesions of the primary tumors with all investigated metastases irrespective of the site of metastasis or time lapse between primary tumor resection and the occurrence of metastatic spread. Putative biomarkers and druggable targets were identified in 25% of the cases. Our data proves that genetic alterations occurring early in CRC carcinogenesis are remarkably stable during metastatic progression, indicating (i) a very low degree of genetic heterogeneity between primary and multiple secondary sites with respect to CRC driver mutations and (ii) that genetic interrogation of archived primary tumor samples appears to be sufficient for the application of cancer precision medicine in the metastatic setting.
    Type of Publication: Journal article published
    PubMed ID: 25786087
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  • 10
    Abstract: Infantile myofibroma (MF) is an uncommon benign myofibroblastic tumor of infancy and childhood. Solitary adult MF shares similar features with infantile MF. The lesions occur in 3 clinicopathologic settings: solitary, multicentric, and generalized and can be either sporadic or familial. Traditionally, infantile MF has been included in the spectrum of infantile hemangiopericytoma. The recent World Health Organization classification listed MF, angioleiomyoma, and myopericytoma under the general heading of perivascular tumors in the sense of a morphologic spectrum of perivascular myoid cell neoplasms. Although activating germline PDGFRB mutations have recently been linked to familial infantile MF, the molecular pathogenesis of sporadic infantile and adult solitary MF remained unclear. In this study, we analyzed 25 solitary MFs without evidence of familial disease (9 infantile and 16 adult MFs) to address the question whether somatic PDGFRB mutations might be responsible for the sporadic form of the disease. Given the presumed histogenetic link of MF to myopericytoma and angioleiomyoma, we additionally analyzed a control group of 6 myopericytomas and 9 angioleiomyomas for PDGFRB mutations. We detected PDGFRB mutations in 6/8 (75%) analyzable infantile and in 11/16 (69%) adult MFs but in none of the angioleiomyomas or myopericytomas. In 2 infantile MFs, additional sequencing of the germline confirmed the somatic nature of PDGFRB mutations. To our knowledge, this is the first study reporting apparently somatic recurrent PDGFRB mutations as molecular driver events in the majority of sporadic infantile and adult solitary MFs. Our results suggest molecular distinctness of MF as compared with angioleiomyoma/myopericytoma. Investigation of more cases including those with atypical and worrisome features, as well as other mimickers in the heterogenous morphologic spectrum of MF, is mandatory for validating the potential diagnostic value of PDGFRB mutation testing as a possible surrogate in difficult-to-classify lesions.
    Type of Publication: Journal article published
    PubMed ID: 27776010
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