Noah Brown - Academia.edu (original) (raw)
Papers by Noah Brown
プレストレストコンクリ-ト技術協会, Oct 1, 1998
Environmental Toxicology and Chemistry
nerve, in such a way, as to provoke contraction of the muscles animated by that nerve. It is beyo... more nerve, in such a way, as to provoke contraction of the muscles animated by that nerve. It is beyond doubt that the faradic current diffuses itself through the tissues, as well as those of the brain skin and muscles, as is proven, moreover, by the galvanometrie experiments of MM. Carville and Duret, and in consequence, we are justified to attribute the effects produced, not to excitation of the gray substance, but to that of the white matter below it. " We may admit'that in the white substance situated below the parts experimented upon, those are excitable fibres in relation, by their deep terminations, with the direct centres of excitation of the muscles smooth and striped, and the glands. These fibres are irritated by the electric current, and they put in action the excitory centres. " But if the excitability of the gray cortical substance is not demon¬ strated by all the experiments, the existence of motor centres for the members, localized in special parts of this substance is no better proven, and needs to be supported by further facts to be put beyond doubt."
European Urology Open Science
We identified urothelial tract biopsy and resection specimens with keratinizing squamous metaplas... more We identified urothelial tract biopsy and resection specimens with keratinizing squamous metaplasia (KSM), nonkeratinizing squamous metaplasia (NKSM), and urothelial and squamous carcinomas over a 20-yr period, focusing on cases with neurogenic lower urinary tract dysfunction (NLUTD) and/or those with spatial or temporal variation in sampling. TERT promoter mutations as assessed via allele-specific polymerase chain reaction were surprisingly common in our testing cohort, identified not only in 15 (94%) invasive cancer foci but also in 13 (68%) examples of KSM and seven (70%) examples of NKSM. TERT promoter mutations were present in 23 foci from NLUTD specimens and 11 foci from bladder diverticula, including in foci of KSM, NKSM, and unremarkable urothelium from cases with no clinical association with previous, concurrent, or subsequent cancer. Our demonstration of temporally and spatially persistent TERT promoter mutation in examples of KSM and NKSM in cases of bladder cancer and in morphologically benign cases with neurogenic dysfunction suggests a molecular mechanism by which such pre-neoplastic lesions can potentially progress and develop into overt carcinoma. Given the interest in TERT promoter mutations as a potential biomarker for the development of bladder cancer, these findings possibly explain the association between conditions with chronic urinary bladder injury (such as the natural history of NLUTD) and higher risk of bladder cancer. TERT promoter mutations may represent an early event in bladder cancer tumorogenesis, and our findings expand on the clinical ramifications and predictive value of TERT promoter mutations in this context. Patient summary Mutations in the TERT gene are the most common genetic changes in bladder cancer. We found that these mutations are also sometimes present in patients with chronic bladder irritation such as neurogenic bladder dysfunction and changes to the lining of the bladder that pathologists would consider “benign.” This finding might explain why such conditions are associated with the development of bladder cancer.
![Research paper thumbnail of [Infectious Disease Reports 2011; 3:e5] [page 15] Diagnosis of Clostridium difficile infection: comparisonof four methods on specimenscollected in Cary-Blair trans-port medium and tcdB PCR on fresh versus frozen samples](https://attachments.academia-assets.com/83339404/thumbnails/1.jpg)
](Clostridium difficile infection (CDI) caused by toxigenic strains of C. difficile is primarily a ... more Clostridium difficile infection (CDI) caused by toxigenic strains of C. difficile is primarily a nosocomial infection with increasing preva-lence. Stool specimens are typically collected in Cary-Blair transport medium to maximize cul-ture-based detection of common stool pathogens. The goal of this study was to estab-lish an analytically accurate and efficient algo-rithm for the detection of CDI in our patient pop-ulation using samples collected in Cary-Blair transport medium. In addition, we wished to determine whether the sensitivity and specifici-ty of PCR was affected by freezing samples before testing. Using 357 specimens, we com-pared four methods: enzyme immunoassay for the antigen glutamate dehydrogenase
International Journal of Surgical Pathology
Fibrin-associated diffuse large B-cell lymphoma (FA-DLBCL) is a provisional entity in the 2017 Re... more Fibrin-associated diffuse large B-cell lymphoma (FA-DLBCL) is a provisional entity in the 2017 Revision of the World Health Organization Classification. This indolent entity, which is frequently discovered incidentally, is currently classified under the category of diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI), an aggressive lymphoma with poor survival. Several authors have proposed that it be classified separately since, in contrast to DLBCL-CI, transformation to aggressive lymphoma has rarely been reported and this entity has distinct clinical and histological features. We describe a rare case of a 62-year-old male with FA-DLBCL associated with atrial myxoma, which was incidentally discovered. In contrast to typically described immunophenotypic features of this entity, that is, activated B-cell phenotype (ABC) and Epstein-Barr virus (EBV) positivity, our case showed germinal center B-cell (GCB) phenotype and was EBV negative. Clinical staging reveal...
Journal of Cutaneous Pathology, 2021
Primary cutaneous T‐cell lymphoma (CTCL) comprises a heterogeneous group of neoplasms with variab... more Primary cutaneous T‐cell lymphoma (CTCL) comprises a heterogeneous group of neoplasms with variable clinical behavior. Immunophenotypic switch (IS) is a phenomenon that occurs during lymphoma progression and is defined by an alteration in the immunophenotypic expression of a tumor with retention of its genotypic signature. This has been well‐recognized in hematopoietic neoplasms; however, it has been rarely reported in CTCL and its clinical implications are not well understood. We present the clinical, histopathologic, immunophenotypic, and genetic findings of three cases of CTCL that demonstrated IS post treatment with variable outcomes. We add our cases to the small number previously reported to increase awareness of this phenomenon and its diagnostic challenge.
Design is difficult to teach in traditional ways of lecturing and testing. One defined learning m... more Design is difficult to teach in traditional ways of lecturing and testing. One defined learning methodology that applies well to design education is project-based learning. In an attempt to better understand the patterns of project-based learning in different design-related programs, we studied three small groups of teachers and students at an innovative academy based out of Shanghai Institute of Visual Art, entitled De Tao Master’s Academy, and compared their education style to that of subjects in regular programs at Shanghai Institute of Visual Art. Our goal was to seek patterns of cognitive apprenticeship in our subjects’ education, and find out (a) if it’s more effective than the traditional approach, and (b) can modelling (i.e. direct replication of learned material) be excluded from a design curriculum. The information gathered through surveys, interviews and observation were segmented into six categories: (1) self-regulation, (2) creative thinking and thinking styles, (3) inc...
Journal of Cutaneous Pathology, 2020
Follicle center lymphomas, including primary cutaneous follicle center lymphoma (PCFCL), may rare... more Follicle center lymphomas, including primary cutaneous follicle center lymphoma (PCFCL), may rarely show plasmacytic differentiation. Such cases can pose a diagnostic challenge and can be mistaken for other lymphomas that more commonly include plasma cells. Here, we report four cases of PCFCL and one case of systemic follicular lymphoma involving the skin with associated monotypic plasma cells, including the clinical, morphologic and immunophenotypic features.
International journal of surgical pathology, 2021
Fibrin-associated diffuse large B-cell lymphoma (FA-DLBCL) is a provisional entity in the 2017 Re... more Fibrin-associated diffuse large B-cell lymphoma (FA-DLBCL) is a provisional entity in the 2017 Revision of the World Health Organization Classification. This indolent entity, which is frequently discovered incidentally, is currently classified under the category of diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI), an aggressive lymphoma with poor survival. Several authors have proposed that it be classified separately since, in contrast to DLBCL-CI, transformation to aggressive lymphoma has rarely been reported and this entity has distinct clinical and histological features. We describe a rare case of a 62-year-old male with FA-DLBCL associated with atrial myxoma, which was incidentally discovered. In contrast to typically described immunophenotypic features of this entity, that is, activated B-cell phenotype (ABC) and Epstein-Barr virus (EBV) positivity, our case showed germinal center B-cell (GCB) phenotype and was EBV negative. Clinical staging reveal...
Human Pathology
MYC rearrangement is a relatively rare genetic abnormality in follicular lymphoma (FL). In this s... more MYC rearrangement is a relatively rare genetic abnormality in follicular lymphoma (FL). In this study, we evaluated the relative frequency of MYC rearrangement in 522 cases of FL and studied their clinicopathologic, cytogenetic and molecular characteristics. FISH studies for MYC (break-apart probe), MYC/IGH, IGH/BCL2, and BCL6 rearrangements were performed on tissue microarrays. Immunohistochemical stains for CD10, BCL2, BCL6, and MYC were performed and scored on MYC-rearranged cases. On 4 FL cases, a custom targeted panel of 356 genes was used for mutation analysis. Ten cases (1.9%) were positive for MYC rearrangement. Histologically, 6/10 cases were grade 1-2, and 4 cases were grade 3A. By immunohistochemistry, 9/9 tested cases were CD10+, all cases were BCL6+, and 9/10 cases were BCL2+. MYC protein staining was low in all cases tested. IGH/BCL2 rearrangement was detected in 5/9 cases, whereas BCL6 rearrangement was detected in 3/7 tested cases and 4/10 cases showed MYC/IGH rearrangement. The most commonly detected mutations in the MYC-positive cases included HLA-B, TNFRSF14 and KMT2D. MYC and/or B2M abnormalities were detected in 2 cases. In conclusion, MYC rearrangement is uncommon in FL and these cases do not appear to have specific histologic characteristics. Molecular analysis showed abnormalities in genes associated with transformation, namely MYC and B2M. Larger studies are needed to evaluate if MYC-rearrangement in FL has prognostic significance.
Journal of Cutaneous Pathology
Primary cutaneous follicle center lymphoma (PCFCL) is the most common cutaneous B‐cell lymphoma. ... more Primary cutaneous follicle center lymphoma (PCFCL) is the most common cutaneous B‐cell lymphoma. The typical immunophenotype includes expression of both CD20 and BCL6, with the majority of cases lacking expression of CD10, BCL2, and the characteristic t(14;18)/IGH‐BCL2 rearrangement seen in systemic follicular lymphoma (FL). Plasmacytic differentiation (PD) is an uncommon finding in both systemic and cutaneous FLs and presents a diagnostic challenge when present, leading to the potential for misdiagnosis as marginal zone lymphoma (MZL). Limited reports have described light chain restriction in the plasma cell component of FLs with PD, and rare cases of PCFCL with PD have been described. While the IGH‐BCL2 translocation has been identified in a subset of FLs with PD, the presence of the BCL2 translocation in monotypic plasma cells of PCFCL has not been previously described to our knowledge. Here, we report a case of PCFCL with extensive PD in a 77‐year‐old woman that was favored to represent primary cutaneous MZL on an initial punch biopsy. Excisional biopsy, however, revealed that the atypical lymphocytes expressed CD10, BCL6, and BCL2, while the plasma cell component demonstrated light‐chain lambda restriction. FISH studies showed the presence of an IGH‐BCL2 translocation in both the lymphocytic and plasmacytic components.
Modern Pathology
Sinonasal papillomas are benign epithelial tumors of the sinonasal tract that are associated with... more Sinonasal papillomas are benign epithelial tumors of the sinonasal tract that are associated with a synchronous or metachronous sinonasal carcinoma in a subset of cases. Our group recently identified mutually exclusive EGFR mutations and human papillomavirus (HPV) infection in inverted sinonasal papillomas and frequent KRAS mutations in oncocytic sinonasal papillomas. We also demonstrated concordant mutational and HPV infection status in sinonasal papilloma-associated sinonasal carcinomas, confirming a clonal relationship between these tumors. Despite our emerging understanding of the oncogenic mechanisms driving formation of sinonasal papillomas, little is currently known about the molecular mechanisms of malignant progression to sinonasal carcinoma. In the present study, we utilized targeted next-generation DNA sequencing to characterize the molecular landscape of a large cohort of sinonasal papilloma-associated sinonasal carcinomas. As expected, EGFR or KRAS mutations were present in the vast majority of tumors. In addition, highly recurrent TP53 mutations, CDKN2A mutations, and/or CDKN2A copy-number losses were detected; overall, nearly all tumors (n = 28/29; 96.6%) harbored at least one TP53 or CDKN2A alteration. TERT copy-number gains also occurred frequently (27.6%); however, no TERT promoter mutations were identified. Other recurrent molecular alterations included NFE2L2 and PIK3CA mutations and SOX2, CCND1, MYC, FGFR1, and EGFR copy-number gains. Importantly, TP53 mutations and CDKN2A alterations were not detected in matched sinonasal papillomas, suggesting that these molecular events are associated with malignant transformation. Compared to aerodigestive tract squamous cell carcinomas from The Cancer Genome Atlas (TCGA) project, sinonasal papilloma-associated sinonasal carcinomas have a distinct molecular phenotype, including more frequent EGFR, KRAS, and CDKN2A mutations, TERT copy-number gains, and low-risk human papillomavirus (HPV) infection. These findings shed light on the molecular mechanisms of malignant progression of sinonasal papillomas and may have important diagnostic and therapeutic implications for patients with advanced sinonasal cancer.
Archives of Pathology & Laboratory Medicine
Context.— Quantification and detection of the t(9;22) (BCR-ABL1) translocation in chronic myeloge... more Context.— Quantification and detection of the t(9;22) (BCR-ABL1) translocation in chronic myelogenous leukemia and B-lymphoblastic leukemia are important for directing treatment protocols and monitoring disease relapse. However, quantification using traditional reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) is dependent on a calibration curve and is prone to laboratory-to-laboratory variation. Droplet digital polymerase chain reaction (ddPCR) is a novel method that allows for highly sensitive absolute quantification of transcript copy number. As such, ddPCR is a good candidate for disease monitoring, an assay requiring reproducible measurements with high specificity and sensitivity. Objective.— To compare results of ddPCR and RT-qPCR BCR-ABL1 fusion transcript measurements of patient samples and determine if either method is superior. Design.— We optimized and standardized a 1-step multiplexed ddPCR assay to detect BCR-ABL1 p190 and ABL1 e10 transcripts. The ...
Drug Resistance Updates
Multidrug resistance (MDR) remains a major obstacle towards curative treatment of cancer. Despite... more Multidrug resistance (MDR) remains a major obstacle towards curative treatment of cancer. Despite considerable progress in delineating the basis of intrinsic and acquired MDR, the underlying molecular mechanisms remain to be elucidated. Emerging evidences suggest that dysregulation in endolysosomal compartments is involved in mediating MDR through multiple mechanisms, such as alterations in endosomes, lysosomes and autophagosomes, that traffic and biodegrade the molecular cargo through macropinocytosis, autophagy and endocytosis. For example, altered lysosomal pH, in combination with transcription factor EB (TFEB)-mediated lysosomal biogenesis, increases the sequestration of hydrophobic anti-cancer drugs that are weak bases, thereby producing an insufficient and off-target accumulation of anti-cancer drugs in MDR cancer cells. Thus, the use of well-tolerated, alkalinizing compounds that selectively block Vacuolar H⁺-ATPase (V-ATPase) may be an important strategy to overcome MDR in cancer cells and increase chemotherapeutic efficacy. Other mechanisms of endolysosomal-mediated drug resistance include increases in the expression of lysosomal proteases and cathepsins that are involved in mediating carcinogenesis and chemoresistance. Therefore, blocking the trafficking and maturation of lysosomal proteases or direct inhibition of cathepsin activity in the cytosol may represent novel therapeutic modalities to overcome MDR. Furthermore, endolysosomal compartments involved in catabolic pathways, such as macropinocytosis and autophagy, are also shown to be involved in the development of MDR. Here, we review the role of endolysosomal trafficking in MDR development and discuss how targeting endolysosomal pathways could emerge as a new therapeutic strategy to overcome chemoresistance in cancer.
Modern Pathology
Microphthalmia-associated transcription factor (MiT) family aberration-associated renal cell carc... more Microphthalmia-associated transcription factor (MiT) family aberration-associated renal cell carcinoma (MiTF-RCC) is a subtype of renal cell carcinoma harboring recurrent chromosomal rearrangements involving TFE3 or TFEB genes. MiTF-RCC is morphologically diverse, can histologically resemble common RCC subtypes like clear cell RCC and papillary RCC, and often poses a diagnostic challenge in genitourinary clinical and pathology practice. To characterize the MiTF-RCC at the molecular level and identify biomarker signatures associated with MiTF-RCC, we analyzed RNAseq data from MiTF-RCC, other RCC subtypes and benign kidney. Upon identifying TRIM63 as a cancer-specific biomarker in MiTF-RCC, we evaluated its expression independently by RNA in situ hybridization (RNA-ISH) in whole tissue sections from 177 RCC cases. We specifically included 31 cytogenetically confirmed MiTF-RCC cases and 70 RCC cases suspicious for MiTF-RCC in terms of clinical and morphological features, to evaluate and compare TRIM63 RNA-ISH results with the results from TFE3/TFEB fluorescence in situ hybridization (FISH), which is the current clinical standard. We confirmed that TRIM63 mRNA was highly expressed in all classes of MiTF-RCC compared to other renal tumor categories, where it was mostly absent to low. While the TRIM63 RNA-ISH and TFE3/TFEB FISH results were largely concordant, importantly, TRIM63 RNA-ISH was strongly positive in TFE3 FISH false-negative cases with RBM10-TFE3 inversion. In conclusion, TRIM63 can serve as a diagnostic marker to distinguish MiTF-RCC from other renal tumor subtypes with overlapping morphology. We suggest a combination of TFE3/TFEB FISH and TRIM63 RNA-ISH assays to improve the accuracy and efficiency of MiTF-RCC diagnosis. Accurate diagnosis of MiTF-RCC and other RCC subtypes would enable effective targeted therapy and avoid poor therapeutic response due to tumor misclassification.
Acta Cytologica
Fine needle aspiration (FNA) has become increasingly popular in the evaluation of lymph nodes for... more Fine needle aspiration (FNA) has become increasingly popular in the evaluation of lymph nodes for lymphoproliferative disorders, but there are limitations to accurate subclassification of lymphoma using morphology alone. This case aims to expand diagnostic considerations of large B-cell populations identified on FNA material. We also address the significance of Epstein-Barr virus (EBV) DNA in the workup of patients with suspected lymphoma by FNA.
プレストレストコンクリ-ト技術協会, Oct 1, 1998
Environmental Toxicology and Chemistry
nerve, in such a way, as to provoke contraction of the muscles animated by that nerve. It is beyo... more nerve, in such a way, as to provoke contraction of the muscles animated by that nerve. It is beyond doubt that the faradic current diffuses itself through the tissues, as well as those of the brain skin and muscles, as is proven, moreover, by the galvanometrie experiments of MM. Carville and Duret, and in consequence, we are justified to attribute the effects produced, not to excitation of the gray substance, but to that of the white matter below it. " We may admit'that in the white substance situated below the parts experimented upon, those are excitable fibres in relation, by their deep terminations, with the direct centres of excitation of the muscles smooth and striped, and the glands. These fibres are irritated by the electric current, and they put in action the excitory centres. " But if the excitability of the gray cortical substance is not demon¬ strated by all the experiments, the existence of motor centres for the members, localized in special parts of this substance is no better proven, and needs to be supported by further facts to be put beyond doubt."
European Urology Open Science
We identified urothelial tract biopsy and resection specimens with keratinizing squamous metaplas... more We identified urothelial tract biopsy and resection specimens with keratinizing squamous metaplasia (KSM), nonkeratinizing squamous metaplasia (NKSM), and urothelial and squamous carcinomas over a 20-yr period, focusing on cases with neurogenic lower urinary tract dysfunction (NLUTD) and/or those with spatial or temporal variation in sampling. TERT promoter mutations as assessed via allele-specific polymerase chain reaction were surprisingly common in our testing cohort, identified not only in 15 (94%) invasive cancer foci but also in 13 (68%) examples of KSM and seven (70%) examples of NKSM. TERT promoter mutations were present in 23 foci from NLUTD specimens and 11 foci from bladder diverticula, including in foci of KSM, NKSM, and unremarkable urothelium from cases with no clinical association with previous, concurrent, or subsequent cancer. Our demonstration of temporally and spatially persistent TERT promoter mutation in examples of KSM and NKSM in cases of bladder cancer and in morphologically benign cases with neurogenic dysfunction suggests a molecular mechanism by which such pre-neoplastic lesions can potentially progress and develop into overt carcinoma. Given the interest in TERT promoter mutations as a potential biomarker for the development of bladder cancer, these findings possibly explain the association between conditions with chronic urinary bladder injury (such as the natural history of NLUTD) and higher risk of bladder cancer. TERT promoter mutations may represent an early event in bladder cancer tumorogenesis, and our findings expand on the clinical ramifications and predictive value of TERT promoter mutations in this context. Patient summary Mutations in the TERT gene are the most common genetic changes in bladder cancer. We found that these mutations are also sometimes present in patients with chronic bladder irritation such as neurogenic bladder dysfunction and changes to the lining of the bladder that pathologists would consider “benign.” This finding might explain why such conditions are associated with the development of bladder cancer.
Clostridium difficile infection (CDI) caused by toxigenic strains of C. difficile is primarily a ... more Clostridium difficile infection (CDI) caused by toxigenic strains of C. difficile is primarily a nosocomial infection with increasing preva-lence. Stool specimens are typically collected in Cary-Blair transport medium to maximize cul-ture-based detection of common stool pathogens. The goal of this study was to estab-lish an analytically accurate and efficient algo-rithm for the detection of CDI in our patient pop-ulation using samples collected in Cary-Blair transport medium. In addition, we wished to determine whether the sensitivity and specifici-ty of PCR was affected by freezing samples before testing. Using 357 specimens, we com-pared four methods: enzyme immunoassay for the antigen glutamate dehydrogenase
International Journal of Surgical Pathology
Fibrin-associated diffuse large B-cell lymphoma (FA-DLBCL) is a provisional entity in the 2017 Re... more Fibrin-associated diffuse large B-cell lymphoma (FA-DLBCL) is a provisional entity in the 2017 Revision of the World Health Organization Classification. This indolent entity, which is frequently discovered incidentally, is currently classified under the category of diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI), an aggressive lymphoma with poor survival. Several authors have proposed that it be classified separately since, in contrast to DLBCL-CI, transformation to aggressive lymphoma has rarely been reported and this entity has distinct clinical and histological features. We describe a rare case of a 62-year-old male with FA-DLBCL associated with atrial myxoma, which was incidentally discovered. In contrast to typically described immunophenotypic features of this entity, that is, activated B-cell phenotype (ABC) and Epstein-Barr virus (EBV) positivity, our case showed germinal center B-cell (GCB) phenotype and was EBV negative. Clinical staging reveal...
Journal of Cutaneous Pathology, 2021
Primary cutaneous T‐cell lymphoma (CTCL) comprises a heterogeneous group of neoplasms with variab... more Primary cutaneous T‐cell lymphoma (CTCL) comprises a heterogeneous group of neoplasms with variable clinical behavior. Immunophenotypic switch (IS) is a phenomenon that occurs during lymphoma progression and is defined by an alteration in the immunophenotypic expression of a tumor with retention of its genotypic signature. This has been well‐recognized in hematopoietic neoplasms; however, it has been rarely reported in CTCL and its clinical implications are not well understood. We present the clinical, histopathologic, immunophenotypic, and genetic findings of three cases of CTCL that demonstrated IS post treatment with variable outcomes. We add our cases to the small number previously reported to increase awareness of this phenomenon and its diagnostic challenge.
Design is difficult to teach in traditional ways of lecturing and testing. One defined learning m... more Design is difficult to teach in traditional ways of lecturing and testing. One defined learning methodology that applies well to design education is project-based learning. In an attempt to better understand the patterns of project-based learning in different design-related programs, we studied three small groups of teachers and students at an innovative academy based out of Shanghai Institute of Visual Art, entitled De Tao Master’s Academy, and compared their education style to that of subjects in regular programs at Shanghai Institute of Visual Art. Our goal was to seek patterns of cognitive apprenticeship in our subjects’ education, and find out (a) if it’s more effective than the traditional approach, and (b) can modelling (i.e. direct replication of learned material) be excluded from a design curriculum. The information gathered through surveys, interviews and observation were segmented into six categories: (1) self-regulation, (2) creative thinking and thinking styles, (3) inc...
Journal of Cutaneous Pathology, 2020
Follicle center lymphomas, including primary cutaneous follicle center lymphoma (PCFCL), may rare... more Follicle center lymphomas, including primary cutaneous follicle center lymphoma (PCFCL), may rarely show plasmacytic differentiation. Such cases can pose a diagnostic challenge and can be mistaken for other lymphomas that more commonly include plasma cells. Here, we report four cases of PCFCL and one case of systemic follicular lymphoma involving the skin with associated monotypic plasma cells, including the clinical, morphologic and immunophenotypic features.
International journal of surgical pathology, 2021
Fibrin-associated diffuse large B-cell lymphoma (FA-DLBCL) is a provisional entity in the 2017 Re... more Fibrin-associated diffuse large B-cell lymphoma (FA-DLBCL) is a provisional entity in the 2017 Revision of the World Health Organization Classification. This indolent entity, which is frequently discovered incidentally, is currently classified under the category of diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI), an aggressive lymphoma with poor survival. Several authors have proposed that it be classified separately since, in contrast to DLBCL-CI, transformation to aggressive lymphoma has rarely been reported and this entity has distinct clinical and histological features. We describe a rare case of a 62-year-old male with FA-DLBCL associated with atrial myxoma, which was incidentally discovered. In contrast to typically described immunophenotypic features of this entity, that is, activated B-cell phenotype (ABC) and Epstein-Barr virus (EBV) positivity, our case showed germinal center B-cell (GCB) phenotype and was EBV negative. Clinical staging reveal...
Human Pathology
MYC rearrangement is a relatively rare genetic abnormality in follicular lymphoma (FL). In this s... more MYC rearrangement is a relatively rare genetic abnormality in follicular lymphoma (FL). In this study, we evaluated the relative frequency of MYC rearrangement in 522 cases of FL and studied their clinicopathologic, cytogenetic and molecular characteristics. FISH studies for MYC (break-apart probe), MYC/IGH, IGH/BCL2, and BCL6 rearrangements were performed on tissue microarrays. Immunohistochemical stains for CD10, BCL2, BCL6, and MYC were performed and scored on MYC-rearranged cases. On 4 FL cases, a custom targeted panel of 356 genes was used for mutation analysis. Ten cases (1.9%) were positive for MYC rearrangement. Histologically, 6/10 cases were grade 1-2, and 4 cases were grade 3A. By immunohistochemistry, 9/9 tested cases were CD10+, all cases were BCL6+, and 9/10 cases were BCL2+. MYC protein staining was low in all cases tested. IGH/BCL2 rearrangement was detected in 5/9 cases, whereas BCL6 rearrangement was detected in 3/7 tested cases and 4/10 cases showed MYC/IGH rearrangement. The most commonly detected mutations in the MYC-positive cases included HLA-B, TNFRSF14 and KMT2D. MYC and/or B2M abnormalities were detected in 2 cases. In conclusion, MYC rearrangement is uncommon in FL and these cases do not appear to have specific histologic characteristics. Molecular analysis showed abnormalities in genes associated with transformation, namely MYC and B2M. Larger studies are needed to evaluate if MYC-rearrangement in FL has prognostic significance.
Journal of Cutaneous Pathology
Primary cutaneous follicle center lymphoma (PCFCL) is the most common cutaneous B‐cell lymphoma. ... more Primary cutaneous follicle center lymphoma (PCFCL) is the most common cutaneous B‐cell lymphoma. The typical immunophenotype includes expression of both CD20 and BCL6, with the majority of cases lacking expression of CD10, BCL2, and the characteristic t(14;18)/IGH‐BCL2 rearrangement seen in systemic follicular lymphoma (FL). Plasmacytic differentiation (PD) is an uncommon finding in both systemic and cutaneous FLs and presents a diagnostic challenge when present, leading to the potential for misdiagnosis as marginal zone lymphoma (MZL). Limited reports have described light chain restriction in the plasma cell component of FLs with PD, and rare cases of PCFCL with PD have been described. While the IGH‐BCL2 translocation has been identified in a subset of FLs with PD, the presence of the BCL2 translocation in monotypic plasma cells of PCFCL has not been previously described to our knowledge. Here, we report a case of PCFCL with extensive PD in a 77‐year‐old woman that was favored to represent primary cutaneous MZL on an initial punch biopsy. Excisional biopsy, however, revealed that the atypical lymphocytes expressed CD10, BCL6, and BCL2, while the plasma cell component demonstrated light‐chain lambda restriction. FISH studies showed the presence of an IGH‐BCL2 translocation in both the lymphocytic and plasmacytic components.
Modern Pathology
Sinonasal papillomas are benign epithelial tumors of the sinonasal tract that are associated with... more Sinonasal papillomas are benign epithelial tumors of the sinonasal tract that are associated with a synchronous or metachronous sinonasal carcinoma in a subset of cases. Our group recently identified mutually exclusive EGFR mutations and human papillomavirus (HPV) infection in inverted sinonasal papillomas and frequent KRAS mutations in oncocytic sinonasal papillomas. We also demonstrated concordant mutational and HPV infection status in sinonasal papilloma-associated sinonasal carcinomas, confirming a clonal relationship between these tumors. Despite our emerging understanding of the oncogenic mechanisms driving formation of sinonasal papillomas, little is currently known about the molecular mechanisms of malignant progression to sinonasal carcinoma. In the present study, we utilized targeted next-generation DNA sequencing to characterize the molecular landscape of a large cohort of sinonasal papilloma-associated sinonasal carcinomas. As expected, EGFR or KRAS mutations were present in the vast majority of tumors. In addition, highly recurrent TP53 mutations, CDKN2A mutations, and/or CDKN2A copy-number losses were detected; overall, nearly all tumors (n = 28/29; 96.6%) harbored at least one TP53 or CDKN2A alteration. TERT copy-number gains also occurred frequently (27.6%); however, no TERT promoter mutations were identified. Other recurrent molecular alterations included NFE2L2 and PIK3CA mutations and SOX2, CCND1, MYC, FGFR1, and EGFR copy-number gains. Importantly, TP53 mutations and CDKN2A alterations were not detected in matched sinonasal papillomas, suggesting that these molecular events are associated with malignant transformation. Compared to aerodigestive tract squamous cell carcinomas from The Cancer Genome Atlas (TCGA) project, sinonasal papilloma-associated sinonasal carcinomas have a distinct molecular phenotype, including more frequent EGFR, KRAS, and CDKN2A mutations, TERT copy-number gains, and low-risk human papillomavirus (HPV) infection. These findings shed light on the molecular mechanisms of malignant progression of sinonasal papillomas and may have important diagnostic and therapeutic implications for patients with advanced sinonasal cancer.
Archives of Pathology & Laboratory Medicine
Context.— Quantification and detection of the t(9;22) (BCR-ABL1) translocation in chronic myeloge... more Context.— Quantification and detection of the t(9;22) (BCR-ABL1) translocation in chronic myelogenous leukemia and B-lymphoblastic leukemia are important for directing treatment protocols and monitoring disease relapse. However, quantification using traditional reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) is dependent on a calibration curve and is prone to laboratory-to-laboratory variation. Droplet digital polymerase chain reaction (ddPCR) is a novel method that allows for highly sensitive absolute quantification of transcript copy number. As such, ddPCR is a good candidate for disease monitoring, an assay requiring reproducible measurements with high specificity and sensitivity. Objective.— To compare results of ddPCR and RT-qPCR BCR-ABL1 fusion transcript measurements of patient samples and determine if either method is superior. Design.— We optimized and standardized a 1-step multiplexed ddPCR assay to detect BCR-ABL1 p190 and ABL1 e10 transcripts. The ...
Drug Resistance Updates
Multidrug resistance (MDR) remains a major obstacle towards curative treatment of cancer. Despite... more Multidrug resistance (MDR) remains a major obstacle towards curative treatment of cancer. Despite considerable progress in delineating the basis of intrinsic and acquired MDR, the underlying molecular mechanisms remain to be elucidated. Emerging evidences suggest that dysregulation in endolysosomal compartments is involved in mediating MDR through multiple mechanisms, such as alterations in endosomes, lysosomes and autophagosomes, that traffic and biodegrade the molecular cargo through macropinocytosis, autophagy and endocytosis. For example, altered lysosomal pH, in combination with transcription factor EB (TFEB)-mediated lysosomal biogenesis, increases the sequestration of hydrophobic anti-cancer drugs that are weak bases, thereby producing an insufficient and off-target accumulation of anti-cancer drugs in MDR cancer cells. Thus, the use of well-tolerated, alkalinizing compounds that selectively block Vacuolar H⁺-ATPase (V-ATPase) may be an important strategy to overcome MDR in cancer cells and increase chemotherapeutic efficacy. Other mechanisms of endolysosomal-mediated drug resistance include increases in the expression of lysosomal proteases and cathepsins that are involved in mediating carcinogenesis and chemoresistance. Therefore, blocking the trafficking and maturation of lysosomal proteases or direct inhibition of cathepsin activity in the cytosol may represent novel therapeutic modalities to overcome MDR. Furthermore, endolysosomal compartments involved in catabolic pathways, such as macropinocytosis and autophagy, are also shown to be involved in the development of MDR. Here, we review the role of endolysosomal trafficking in MDR development and discuss how targeting endolysosomal pathways could emerge as a new therapeutic strategy to overcome chemoresistance in cancer.
Modern Pathology
Microphthalmia-associated transcription factor (MiT) family aberration-associated renal cell carc... more Microphthalmia-associated transcription factor (MiT) family aberration-associated renal cell carcinoma (MiTF-RCC) is a subtype of renal cell carcinoma harboring recurrent chromosomal rearrangements involving TFE3 or TFEB genes. MiTF-RCC is morphologically diverse, can histologically resemble common RCC subtypes like clear cell RCC and papillary RCC, and often poses a diagnostic challenge in genitourinary clinical and pathology practice. To characterize the MiTF-RCC at the molecular level and identify biomarker signatures associated with MiTF-RCC, we analyzed RNAseq data from MiTF-RCC, other RCC subtypes and benign kidney. Upon identifying TRIM63 as a cancer-specific biomarker in MiTF-RCC, we evaluated its expression independently by RNA in situ hybridization (RNA-ISH) in whole tissue sections from 177 RCC cases. We specifically included 31 cytogenetically confirmed MiTF-RCC cases and 70 RCC cases suspicious for MiTF-RCC in terms of clinical and morphological features, to evaluate and compare TRIM63 RNA-ISH results with the results from TFE3/TFEB fluorescence in situ hybridization (FISH), which is the current clinical standard. We confirmed that TRIM63 mRNA was highly expressed in all classes of MiTF-RCC compared to other renal tumor categories, where it was mostly absent to low. While the TRIM63 RNA-ISH and TFE3/TFEB FISH results were largely concordant, importantly, TRIM63 RNA-ISH was strongly positive in TFE3 FISH false-negative cases with RBM10-TFE3 inversion. In conclusion, TRIM63 can serve as a diagnostic marker to distinguish MiTF-RCC from other renal tumor subtypes with overlapping morphology. We suggest a combination of TFE3/TFEB FISH and TRIM63 RNA-ISH assays to improve the accuracy and efficiency of MiTF-RCC diagnosis. Accurate diagnosis of MiTF-RCC and other RCC subtypes would enable effective targeted therapy and avoid poor therapeutic response due to tumor misclassification.
Acta Cytologica
Fine needle aspiration (FNA) has become increasingly popular in the evaluation of lymph nodes for... more Fine needle aspiration (FNA) has become increasingly popular in the evaluation of lymph nodes for lymphoproliferative disorders, but there are limitations to accurate subclassification of lymphoma using morphology alone. This case aims to expand diagnostic considerations of large B-cell populations identified on FNA material. We also address the significance of Epstein-Barr virus (EBV) DNA in the workup of patients with suspected lymphoma by FNA.