ABSTRACT
AIMS: MYC rearrangements with or without BCL2 rearrangements have been shown to be associated with poor prognosis and inferior survival in diffuse large B-cell lymphomas (DLBCL). Most of these cases are still diagnosed by fluorescent in situ hybridisation (FISH) testing, which is expensive, requires expertise and is not routinely available in all laboratories. Immunohistochemistry (IHC) is widely available and has the potential to be used as a screening test to identify cases with increased protein expression and select cases that require confirmatory testing. We correlated the expression of MYC and BCL2 by IHC with FISH studies in an attempt to define a cut-off value, which can be used by laboratories to select cases requiring confirmatory FISH testing. The prevalence of MYC-positive DLBCL and double-hit lymphoma (DHL) has also been studied. METHODS: 209 cases comprising of 15 cases of Burkitt lymphoma (BL), 13 cases of intermediate BL/DLBCL and 181 cases of DLBCL were included. IHC and FISH for MYC and BCL2 were performed and the results were correlated. RESULTS: The prevalence of MYC-positive DLBCL and MYC/BCL2DHL was 13.4% and 7.4%, respectively, in our study. Germinal-centre subtype was more common in MYC-positive DLBCL and DHL. MYC-positive DLBCL also showed higher median Ki-67 (>90%) and CD10 positivity as compared with MYC-negative cases. CONCLUSIONS: IHC can be used for screening cases, which require further confirmatory FISH testing. We recommend a cut-off value of ≥30% for MYC by IHC; however, international standardisation of these values is necessary to provide uniformity among laboratories.
Subject(s)
Biomarkers, Tumor/analysis , Burkitt Lymphoma/chemistry , Immunohistochemistry , Lymphoma, Large B-Cell, Diffuse/chemistry , Proto-Oncogene Proteins c-myc/analysis , Aged , Biomarkers, Tumor/genetics , Burkitt Lymphoma/genetics , Burkitt Lymphoma/pathology , Female , Gene Rearrangement , Humans , Immunohistochemistry/standards , In Situ Hybridization, Fluorescence , Ki-67 Antigen/analysis , Lymphoma, Large B-Cell, Diffuse/genetics , Lymphoma, Large B-Cell, Diffuse/pathology , Male , Middle Aged , Neprilysin/analysis , Predictive Value of Tests , Proto-Oncogene Proteins c-bcl-2/analysis , Proto-Oncogene Proteins c-myc/genetics , Reproducibility of ResultsABSTRACT
OBJECTIVE: The isocitrate dehydrogenase 1 (IDH1) R132H mutation is the most common mutation in World Health Organization (WHO) grade II gliomas, reported to be expressed in 70-80%, but only 5-10% of high grade gliomas. Low grade tumors, especially the protoplasmic subtype, have the highest incidence of tumor associated epilepsy (TAE). The IDH1 mutation leads to the accumulation of 2-hydroxyglutarate (2HG), a metabolite that bears a close structural similarity to glutamate, an excitatory neurotransmitter that has been implicated in the pathogenesis of TAE. We hypothesized that expression of mutated IDH1 may play a role in the pathogenesis of TAE in low grade gliomas. METHODS: Thirty consecutive patients with WHO grade II gliomas were analyzed for the presence of the IDH1-R132H mutation using immunohistochemistry. The expression of IDH1 mutation was semiquantified using open-source biologic-imaging analysis software. RESULTS: The percentage of cells positive for the IDH1-R132H mutation was found to be higher in patients with TAE compared to those without TAE (median and interquartile range (IQR) 25.3% [8.6-53.5] vs. 5.2% [0.6-13.4], p = 0.03). In addition, we found a significantly higher median IDH1 mutation expression level in the protoplasmic subtype of low grade glioma (52.2% [IQR 19.9-58.6] vs. 13.8% [IQR 3.9-29.4], p = 0.04). SIGNIFICANCE: Increased expression of the IDH1-R132H mutation is associated with seizures in low grade gliomas and also with the protoplasmic subtype. This supports the hypothesis that this mutation may play a role in the pathogenesis of both TAE and low grade gliomas.
Subject(s)
Astrocytoma/complications , Astrocytoma/genetics , Brain Neoplasms/genetics , Isocitrate Dehydrogenase/genetics , Mutation/genetics , Adolescent , Adult , Aged , Arginine/genetics , Cohort Studies , Epilepsy/etiology , Female , Genetic Association Studies , Histidine/genetics , Humans , Male , Middle Aged , Seizures/complications , Seizures/genetics , Young AdultABSTRACT
Overexpression of the prosurvival protein BCL-2 is common in breast cancer. Here we have explored its role as a potential therapeutic target in this disease. BCL-2, its anti-apoptotic relatives MCL-1 and BCL-XL, and the proapoptotic BH3-only ligand BIM were found to be coexpressed at relatively high levels in a substantial proportion of heterogeneous breast tumors, including clinically aggressive basal-like cancers. To determine whether the BH3 mimetic ABT-737 that neutralizes BCL-2, BCL-XL, and BCL-W had potential efficacy in targeting BCL-2-expressing basal-like triple-negative tumors, we generated a panel of primary breast tumor xenografts in immunocompromised mice and treated recipients with either ABT-737, docetaxel, or a combination. Tumor response and overall survival were significantly improved by combination therapy, but only for tumor xenografts that expressed elevated levels of BCL-2. Treatment with ABT-737 alone was ineffective, suggesting that ABT-737 sensitizes the tumor cells to docetaxel. Combination therapy was accompanied by a marked increase in apoptosis and dissociation of BIM from BCL-2. Notably, BH3 mimetics also appeared effective in BCL-2-expressing xenograft lines that harbored p53 mutations. Our findings provide in vivo evidence that BH3 mimetics can be used to sensitize primary breast tumors to chemotherapy and further suggest that elevated BCL-2 expression constitutes a predictive response marker in breast cancer.
Subject(s)
Biphenyl Compounds/therapeutic use , Breast Neoplasms/drug therapy , Nitrophenols/therapeutic use , Proto-Oncogene Proteins c-bcl-2/metabolism , Sulfonamides/therapeutic use , Xenograft Model Antitumor Assays , Animals , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Apoptosis/drug effects , Apoptosis Regulatory Proteins/metabolism , Bcl-2-Like Protein 11 , Biphenyl Compounds/pharmacology , Breast Neoplasms/classification , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Line, Tumor , Docetaxel , Female , Humans , Membrane Proteins/metabolism , Mice , Myeloid Cell Leukemia Sequence 1 Protein , Nitrophenols/pharmacology , Piperazines/pharmacology , Piperazines/therapeutic use , Proto-Oncogene Proteins/metabolism , Remission Induction , Sulfonamides/pharmacology , Taxoids/pharmacology , Taxoids/therapeutic use , bcl-X Protein/metabolismABSTRACT
Basal-like breast cancers arising in women carrying mutations in the BRCA1 gene, encoding the tumor suppressor protein BRCA1, are thought to develop from the mammary stem cell. To explore early cellular changes that occur in BRCA1 mutation carriers, we have prospectively isolated distinct epithelial subpopulations from normal mammary tissue and preneoplastic specimens from individuals heterozygous for a BRCA1 mutation. We describe three epithelial subsets including basal stem/progenitor, luminal progenitor and mature luminal cells. Unexpectedly, we found that breast tissue from BRCA1 mutation carriers harbors an expanded luminal progenitor population that shows factor-independent growth in vitro. Moreover, gene expression profiling revealed that breast tissue heterozygous for a BRCA1 mutation and basal breast tumors were more similar to normal luminal progenitor cells than any other subset, including the stem cell-enriched population. The c-KIT tyrosine kinase receptor (encoded by KIT) emerged as a key marker of luminal progenitor cells and was more highly expressed in BRCA1-associated preneoplastic tissue and tumors. Our findings suggest that an aberrant luminal progenitor population is a target for transformation in BRCA1-associated basal tumors .
Subject(s)
Breast Neoplasms/genetics , Cell Transformation, Neoplastic/genetics , Genes, BRCA1 , Heterozygote , Stem Cells/pathology , Breast Neoplasms/etiology , Cells, Cultured , Female , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Humans , Mammary Glands, Human/cytology , Mammary Glands, Human/metabolism , Mammary Glands, Human/pathology , Models, Biological , Mutation/physiology , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Precancerous Conditions/genetics , Precancerous Conditions/metabolism , Precancerous Conditions/pathology , Receptors, Progesterone/metabolism , Stem Cells/metabolismABSTRACT
Accurate quantification of plasma cells in bone marrow samples is essential for the diagnosis, classification and prognosis of plasma-cell dyscrasias. Published comparisons between aspirate/trephine morphology, flow cytometry and immunohistochemistry are lacking. Bone marrow plasma cells from 100 patients with plasma cell myeloma or monoclonal gammopathy of undetermined significance were quantified by a 500-cell differential count on Romanowsky-stained aspirate slides, flow-cytometry gating of CD38bright+/CD138+ cells, hematoxylin and eosin trephine section examination and CD138 trephine immunohistology. The results of quantification by the different methods were compared. Compared to other methods, CD138 trephine immunohistology consistently demonstrated greater plasma-cell infiltration. Immunohistology is the most sensitive method for assessment of plasma-cell infiltration at diagnosis or post-therapy, especially in patients with minimal bone marrow involvement.
Subject(s)
ADP-ribosyl Cyclase 1/analysis , Multiple Myeloma/diagnosis , Paraproteinemias/diagnosis , ADP-ribosyl Cyclase 1/immunology , Bone Marrow Examination/methods , Bone Marrow Examination/standards , Coloring Agents/standards , Flow Cytometry/standards , Humans , Immunohistochemistry/standards , Plasma Cells/pathology , Retrospective Studies , Sensitivity and SpecificityABSTRACT
Plasma cell microaggregates detected by CD138 immunohistology were demonstrated in 22% of patients achieving morphologic remission 3 months after high-dose therapy for myeloma. Microaggregates were predictive of earlier disease progression, indicating that immunohistology may represent a useful tool in the assessment of minimal disease in patients after high-dose therapy for myeloma.
Subject(s)
Bone Marrow Cells/pathology , Multiple Myeloma/drug therapy , Multiple Myeloma/pathology , Neoplasm, Residual/pathology , Humans , Immunohistochemistry , Multiple Myeloma/therapy , Plasma Cells/pathology , Predictive Value of Tests , Recurrence , Stem Cell TransplantationABSTRACT
PURPOSE: To assess the concordance of breast cancer immunohistochemical receptor assays on core biopsy and surgical specimens. PATIENTS AND METHODS: We identified 100 patients whose core biopsy and definitive surgical specimens were processed in our hospital. New sections, with core and surgical specimens on the same slides, were stained for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) immunohistochemistry (IHC). Two pathologists assessed the sections independently. Raw scores and clinically significant groupings were compared. RESULTS: Concordance for ER, PR, overall hormone receptor (HR), and HER-2 status was seen in 86%, 83%, 90%, and 80% of patients, respectively. The core was positive, while the surgical specimen was negative in 13%, 11%, 9%, and 1% of patients, respectively. Using a log-linear model, differences in ER, PR, and HER-2 staining were all in the direction of stronger staining in the cores, and were statistically significant. Nine percent (95% CI, 4.2% to 16.4%) of women in this group would have had endocrine therapy inappropriately withheld if management decisions were based on surgical specimen results alone. CONCLUSION: ER and PR assays on core biopsy specimens are more reliable than assays on surgical specimens. Receptor IHC should be performed on core biopsy specimens to avoid patients with HR positive cancers not receiving appropriate hormonal therapy and being overtreated with systemic chemotherapy. Biopsy should be considered in patients with "receptor negative" cancer and recurrent disease.