Publications by authors named "Evgeny Yakirevich"

64 Publications

Immunohistochemical HER2 score correlates with response to neoadjuvant chemotherapy in HER2-positive primary breast cancer.

Breast Cancer Res Treat 2021 Feb 17. Epub 2021 Feb 17.

Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, 593 Eddy St, APC 12, Providence, RI, 02903, USA.

Purpose: The accuracy of biomarker assessment in breast cancer (BC) is paramount for therapy decisions and informs prognosis. We investigated neoadjuvant chemotherapy (NAC) response in HER2-positive BC with respect to immunohistochemistry (IHC) and in situ hybridization (ISH) results. We aimed to determine the role of HER2 protein expression in predicting NAC response and long-term outcome in two HER2-positive groups: IHC 3 + versus IHC 2 + ISH amplified groups.

Methods: This retrospective study included 192 consecutive HER2 + primary BCs diagnosed from 2007 to 2019 treated with NAC and HER2-targeted agent (NACH). There were 158 HER2 3 + and 34 HER2 2 + ISH + cases. Clinicopathological parameters and long-term outcomes were analyzed.

Results: The Pathological Complete Response (pCR) rate was 85.7% (72/84) in ER-/HER2 + BCs and was lower in ER + /HER2 + BCs (42.6%, 46/108). The pCR was 55.1% (86/156) in the HER2 3 + group and was only 17.6% in HER2 2 + ISH + group (p < 0.001). Patients who achieved pCR in HER2 2 + ISH + group did not show a significantly higher HER2/CEP17 ratio or HER2 copy number. The overall survival (OS) and progression-free survival (PFS) were significantly higher in pCR compared to non-pCR cases (p = 0.011 and p = 0.015, respectively).

Conclusions: There is significant heterogeneity in response to the NACH regimens in HER2 + cases. Our findings indicate that HER2 IHC score and ER expression determine NACH response in HER2 + BC. We recommend considering HER2 protein expression and ISH value to better select patients and assess the response for HER2-targeted therapy.
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http://dx.doi.org/10.1007/s10549-021-06124-8DOI Listing
February 2021

Mutations in DNA Repair Genes and Clinical Outcomes of Patients With Metastatic Colorectal Cancer Receiving Oxaliplatin or Irinotecan-containing Regimens.

Am J Clin Oncol 2021 02;44(2):68-73

Division of Hematology/Oncology, Lifespan Cancer Institute.

Objectives: First-line regimens in the treatment of metastatic colorectal cancer (mCRC) combine a fluoropyrimidine with oxaliplatin (FOLFOX/XELOX) or irinotecan (FOLFIRI). There is limited efficacy data to guide the selection of one treatment over the other. This study investigated whether mutations affecting DNA damage response (DDR) could differentially influence the response to oxaliplatin and irinotecan-containing regimens.

Methods: We retrospectively analyzed 49 patients with mCRC for whom treatment outcomes and results of comprehensive genomic profiling of tumors were available. Specimens with at least 1 pathogenic mutation involving BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or RAD54L were classified as DDR-mutated, while those without mutations were DDR-wild-type (WT). We compared the overall survival (OS), disease control rate, and response rate (RR) between the DDR-mutated and DDR-WT groups.

Results: DDR mutations occurred in 11 patients (22%). First-line treatment with an oxaliplatin-containing regimen was administered to 33 patients (31 FOLFOX, 2 XELOX), while 16 patients received FOLFIRI. Among DDR-mutated cases, first-line treatment with FOLFOX/XELOX correlated with a statistically significant improvement in median OS compared with FOLFIRI (3.4 vs.1.8 y; P=0.042) and numerically higher RR (50% vs. 33%; P=0.58). No significant difference in OS (2.4 vs. 2.5 y; P=0.42), RR, disease control rate was observed between the 2 regimens in patients with DDR-WT tumors.

Conclusions: Mutations in DDR genes were present in 22% of patients with mCRC. In patients with DDR-mutated tumors, initial treatment with FOLFOX/XELOX correlated with improved OS and a numerically higher RR compared with FOLFIRI.
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http://dx.doi.org/10.1097/COC.0000000000000785DOI Listing
February 2021

PAX8 Expression in Breast Cancer.

Appl Immunohistochem Mol Morphol 2020 Nov 17. Epub 2020 Nov 17.

Department of Pathology and Laboratory Medicine, Lifespan Medical Center and Brown University Alpert School of Medicine, Providence, RI.

PAX8 expression is frequently detected in renal, thyroidal, and Müllerian carcinomas, and PAX8 immunohistochemistry is often used to confirm the origin of these tumors. Tumors metastatic to the breast may masquerade as primary breast lesions. PAX8 is strongly expressed in tumors of Müllerian origin and largely negative in breast primaries, but an immunohistochemical expression of PAX8 in breast cancer has not been systematically evaluated in a large series. We analyzed 266 cases of invasive carcinoma of the breast on tissue microarrays and whole tissue sections with a PAX8 monoclonal antibody. Both the extent (focal or diffuse) and intensity (weak, moderate, or strong) of nuclear staining were assessed in the tumor cells. In total, 16 cases (6.02%) were positive for PAX8 (12 with weak and 4 with moderate staining). Expression was diffuse in 7 cases and focal in 9 cases. All 16 PAX8-positive tumors were histologic grade III invasive ductal carcinomas, 13 of these were triple-negative, 2 were HER2-positive, only and 1 was progesterone receptor-positive only. Strong PAX8 nuclear expression was not seen in any of the cases. PAX8 was negative in breast tumors with neuroendocrine features. Our study demonstrated a low rate of PAX8 expression in breast cancer. When present, PAX8 expression was only seen in high-grade invasive ductal carcinomas, mostly triple-negative. The presence of PAX8 immunoreactivity alone cannot exclude mammary origin, especially when only weak to moderate staining is observed, so the correlation with available clinical and pathologic data helps to ensure an accurate diagnosis.
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http://dx.doi.org/10.1097/PAI.0000000000000883DOI Listing
November 2020

Characterization of Clinical Cases of Malignant PEComa via Comprehensive Genomic Profiling of DNA and RNA.

Oncology 2020 23;98(12):905-912. Epub 2020 Sep 23.

Foundation Medicine, Cambridge, Massachusetts, USA,

Purpose: Perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal soft tissue neoplasm often linked to mTOR pathway activation via TSC2 mutation. We analyzed a series of 31 consecutive metastatic PEComa (mPEComa) cases using a combined DNA/RNA hybrid capture-based comprehensive genomic profiling (CGP) assay to assess the genomic landscape of mPEComa.

Patients And Methods: Formalin-fixed, paraffin-embedded (FFPE) blocks or slides were obtained from tumors from 31 unique patients with mPEC-oma. DNA and RNA were extracted and CGP was performed on 405 genes using a targeted next-generation sequencing (NGS) assay in a CLIA-certified lab.

Results: All cases had locally advanced or metastatic disease, and 58% of patients were female with a median age of 50 years (range 8-76), and 17 and 14 specimens were from primary and metastatic sites, respectively. One hundred genomic alterations were identified in the cohort, with an average of 3.2 genomic alterations/case including alterations in TSC2 32.3% of cases (10), TSC1 9.6% (3), TFE3 16.1% (5, all fusions), and folliculin (FLCN) 6.4% (2), with all occurring in mutually exclusive fashion. Of TSC2 mutant cases, 70% had biallelic inactivation of this locus, as were 100% of TSC1 mutant cases. Two TSC1/2 wildtype cases harbored truncating mutations in FLCN, both of which were under LOH. Five TFE3 fusion cases were identified including the novel 5' fusion partner ZC3H4.

Conclusions: We describe for the first time mPEComa cases with FLCN mutations under LOH, further characterizing dysregulation of the mTOR pathway as a unifying theme in mPEC-oma. Cumulatively, we demonstrate the feasibility and potential utility of segregating mPEComa by TSC, TFE3, and FLCN status via CGP in clinical care.
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http://dx.doi.org/10.1159/000510241DOI Listing
December 2020

NF2 Tumor Suppressor Gene Inactivation in Advanced Papillary Renal Cell Carcinoma.

Am J Surg Pathol 2020 Sep 9. Epub 2020 Sep 9.

Foundation Medicine Inc., Cambridge MA.

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http://dx.doi.org/10.1097/PAS.0000000000001586DOI Listing
September 2020

Validation and performance comparison of three SARS-CoV-2 antibody assays.

J Med Virol 2021 02 13;93(2):916-923. Epub 2020 Aug 13.

Department of Pathology and Laboratory Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island.

Serology testing of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is increasingly being used during the current pandemic of coronavirus disease 2019 (COVID-19), although its clinical and epidemiologic utilities are still debatable. Characterizing these assays provides scientific basis to best use them. The current study assessed one chemiluminescent assay (Abbott COVID-2 IgG) and two lateral flow assays (STANDARD Q [SQ] IgM/IgG Duo and Wondfo total antibody test) using 113 blood samples from 71 PCR-confirmed COVID-19 hospitalized patients, 119 samples with potential cross-reactions, and 1068 negative controls including 942 pre-pandemic samples. SARS-CoV-2 IgM antibodies became detectable 3-4 days post-symptom onset using SQ IgM test and IgG antibodies were first detected 5-6 days post-onset using SQ IgG. Abbott IgG and Wondfo Total were able to detect antibodies 7 to 8 days post-onset. After 14 days post-symptom onset, the SQ IgG, Abbott IgG and Wondfo Total tests were able to detect antibodies from 100% of the PCR-confirmed patients in this series; 87.5% sensitivity for SQ IgM. Overall agreement was 88.5% between SQ IgM/IgG and Wondfo Total and 94.6% between SQ IgG and Abbott IgG. No cross-reaction due to recent sera with three of the endemic coronaviruses was observed. Viral hepatitis and autoimmune samples were the main source of limited cross-reactions. The specificities were 100% for SQ IgG and Wondfo Total, 99.62% for Abbott IgG, and 98.87% for SQ IgM. These findings demonstrated high sensitivity and specificity of appropriately validated SARS-CoV-2 serologic assays with implications for clinical use and epidemiological seroprevalence studies.
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http://dx.doi.org/10.1002/jmv.26341DOI Listing
February 2021

IQGAP1 control of centrosome function defines distinct variants of triple negative breast cancer.

Oncotarget 2020 Jun 30;11(26):2493-2511. Epub 2020 Jun 30.

Department of Pathology and Laboratory Medicine, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI 02903, USA.

Triple negative breast cancer (TNBC) is a heterogenous and lethal disease that lacks diagnostic markers and therapeutic targets; as such common targets are highly sought after. IQGAP1 is a signaling scaffold implicated in TNBC, but its mechanism is unknown. Here we show that IQGAP1 localizes to the centrosome, interacts with and influences the expression level and localization of key centrosome proteins like BRCA1 and thereby impacts centrosome number. Genetic mutant analyses suggest that phosphorylation cycling of IQGAP1 is important to its subcellular localization and centrosome-nuclear shuttling of BRCA1; dysfunction of this process defines two alternate mechanisms associated with cell proliferation. TNBC cell lines and patient tumor tissues differentially phenocopy these mechanisms supporting clinical existence of molecularly distinct variants of TNBC defined by IQGAP1 pathways. These variants are defined, at least in part, by differential mis-localization or stabilization of IQGAP1-BRCA1 and rewiring of a novel Erk1/2-MNK1-JNK-Akt-β-catenin signaling signature. We discuss a model in which IQGAP1 modulates centrosome-nuclear crosstalk to regulate cell division and imparts on cancer. These findings have implications on cancer racial disparities and can provide molecular tools for classification of TNBC, presenting IQGAP1 as a common target amenable to personalized medicine.
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http://dx.doi.org/10.18632/oncotarget.27623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335670PMC
June 2020

Tumor mutational burden and immune signatures interplay in renal cell carcinoma.

Ann Transl Med 2020 Mar;8(6):269

Department of Pathology, Rhode Island Hospital and Alpert Medical School at Brown University, Providence, RI, USA.

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http://dx.doi.org/10.21037/atm.2020.02.81DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186632PMC
March 2020

Cytokeratin 7-negative and GATA binding protein 3-negative breast cancers: Clinicopathological features and prognostic significance.

BMC Cancer 2019 Nov 12;19(1):1085. Epub 2019 Nov 12.

Department of Pathology and Laboratory Medicine, Alpert Medical School of Brown University, 593 Eddy St; APC 12, Providence, RI, 02903, USA.

Background: Cytokeratin 7 (CK7) and GATA binding protein 3 (GATA3) are considered as immunohistochemical hallmarks of breast cancers; however, there are breast tumors lacking these markers. Clinicopathological characterization of CK7 negative breast cancer has not been addressed previously and similar studies on GATA3 negative tumors are limited.

Methods: This study included 196 consecutive cases of Nottingham Grade 3 breast cancers with 159 cases of Grade 1 and Grade 2 tumors for comparison. CK7 and GATA3 expression was correlated with patient's age, histological type, pathological grade and stage, hormone receptor status, molecular subtype and overall survival.

Results: CK7 negativity was seen in 13% of Grade 3, 9% of Grade 2, and 2% of Grade 1 cases (P = 0.0457). Similarly, 28% of Grade 3, 5% of Grade 2 and 2% of Grade 1 cases were GATA3 negative (P < 0.0001). CK7 negative tumors did not show association with other clinicopathological parameters. GATA3 negative tumors were enriched in the basal-like molecular subgroup and were associated with negative estrogen receptor (ER) and negative progesterone receptor (PR) statuses. Both CK7 and GATA3 expression showed no association with overall survival in patients with Grade 3 tumor.

Conclusions: This is the first study to characterize CK7 negative breast tumors in the context of clinicopathology. Profiling the CK7 negative and GATA3 negative breast cancers helps to understand the biology of these specific tumor subgroups and may aid in their diagnosis.
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http://dx.doi.org/10.1186/s12885-019-6295-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849242PMC
November 2019

TKI-resistant -rearranged lung adenocarcinoma with secondary CTNNB1 p.S45V and tertiary ALK p.I1171N mutations.

Lung Cancer (Auckl) 2019 15;10:81-86. Epub 2019 Aug 15.

Department of Pathology, Rhode Island Hospital and Alpert Medical School at Brown University, Providence, RI 02903, USA.

Anaplastic lymphoma kinase ()-rearranged non-small cell lung cancer (NSCLC) is an important molecular subgroup of tumors that are typically sensitive to tyrosine kinase inhibitors (TKIs). Although a substantial portion of patients benefit from TKIs, this approach is complicated by intrinsic and acquired resistance. We report a patient with -rearranged NSCLC who showed an initial response to targeted therapy, but developed resistance to multiple TKIs. Serial comprehensive genomic profiling (CGP) was performed at four independent points during the clinical course. We review the pathology and clonal progression of the tumor, with CGP identifying a secondary CTNNB1 p.S45V mutation after the initiation of targeted therapy, followed by tertiary ALK p.I1171N. The presence of an alteration in a second oncogenic driver gene suggests a possible mechanism for resistance, and a secondary therapeutic target. Due to the involvement of Wnt signaling in the pathogenesis of many tumors and its association with immune evasion, a variety of therapeutic strategies are being developed to target this pathway. This case exemplifies the challenges of targeted therapeutics in the face of tumor progression, as well as the increasing role of genomics in understanding tumor biology.
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http://dx.doi.org/10.2147/LCTT.S212406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699522PMC
August 2019

A Novel Next-Generation Sequencing Approach to Detecting Microsatellite Instability and Pan-Tumor Characterization of 1000 Microsatellite Instability-High Cases in 67,000 Patient Samples.

J Mol Diagn 2019 11 22;21(6):1053-1066. Epub 2019 Aug 22.

Department of Research and Development, Foundation Medicine, Inc., Cambridge, Massachusetts.

Microsatellite instability (MSI) is an important biomarker for predicting response to immune checkpoint inhibitor therapy, as emphasized by the recent checkpoint inhibitor approval for MSI-high (MSI-H) solid tumors. Herein, we describe and validate a novel method for determining MSI status from a next-generation sequencing comprehensive genomic profiling assay using formalin-fixed, paraffin-embedded samples. This method is 97% (65/67) concordant with current standards, PCR and immunohistochemistry. We further apply this method to >67,000 patient tumor samples to identify genes and pathways that are enriched in MSI-stable or MSI-H tumor groups. Data show that although rare in tumors other than colorectal and endometrial carcinomas, MSI-H samples are present in many tumor types. Furthermore, the large sample set revealed that MSI-H tumors selectively share alterations in genes across multiple common pathways, including WNT, phosphatidylinositol 3-kinase, and NOTCH. Last, MSI is sufficient, but not necessary, for a tumor to have elevated tumor mutation burden. Therefore, MSI can be determined from comprehensive genomic profiling with high accuracy, allowing for efficient MSI-H detection across all tumor types, especially those in which routine use of immunohistochemistry or PCR-based assays would be impractical because of a rare incidence of MSI. MSI-H tumors are enriched in alterations in specific signaling pathways, providing a rationale for investigating directed immune checkpoint inhibitor therapies in combination with pathway-targeted therapies.
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http://dx.doi.org/10.1016/j.jmoldx.2019.06.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807551PMC
November 2019

Comprehensive Genomic Profiling of Adult Renal Sarcomas Provides Insight into Disease Biology and Opportunities for Targeted Therapies.

Eur Urol Oncol 2019 Apr 22. Epub 2019 Apr 22.

Foundation Medicine Inc., Cambridge, MA, USA.

Background: Primary adult renal sarcomas (RSs) are rare aggressive neoplasms. Clinical outcomes are extremely poor, and optimal treatment remains challenging.

Objective: To identify genomic alterations (GAs) in patients with RSs.

Design, Setting, And Participants: Comprehensive genomic profiling (CGP) was conducted on DNA/RNA extracted from formalin-fixed paraffin-embedded tissue using the FoundationOne Heme/Sarcoma assay in 13 adult, locally advanced or metastatic RSs of various histologic types.

Outcome Measurements And Statistical Analysis: All classes of GAs, including base substitutions, small indels, rearrangements, copy number alterations, tumor mutational burden (TMB), and microsatellite instability (MSI), were analyzed.

Results And Limitations: CGP revealed 55 GAs (4.2 per tumor), 29 of which were clinically relevant genomic alterations (CRGAs; 2.2 per tumor). At least one CRGA was detected in nine (69%) cases. High-level amplifications (more than six copies) involving 4q12 amplicon of the KIT and PDGFRA genes were identified in four (31%) cases (two undifferentiated pleomorphic sarcomas [UPSs], one sarcomatoid renal cell carcinoma, and one myxofibrosarcoma). Both UPSs also had KDR gene amplification in addition to KIT and PDGFRA. Additional CRGAs were found in CDKN2A/B (23%), NF1 (23%), and MET (8%). All RSs were MSI stable, the mean TMB was 3.5 mutations/megabase (Mb), and none (0%) featured TMB >10 mutations/Mb. Limitations include the small sample size.

Conclusions: RSs are characterized by diverse histology and genomic profiles including 31% of cases with 4q12 amplification harboring the KIT/PDGFRA/KDR genes. Of the tumors, 69% carry CRGAs, which could lead to potential benefit from targeted therapies; however, a low TMB also suggests that these cases are unlikely to respond to checkpoint inhibitors.

Patient Summary: This study provides insights into molecular biology of renal sarcoma, a rare aggressive subtype of kidney tumors. We demonstrated that renal sarcomas harbor unique, recurrent, clinically relevant molecular abnormalities that provide new opportunities for targeted therapies.
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http://dx.doi.org/10.1016/j.euo.2019.04.002DOI Listing
April 2019

: a novel gene fusion in hepatic angiosarcoma.

Oncotarget 2019 Jan 4;10(2):245-251. Epub 2019 Jan 4.

Division of Hematology-Oncology, Lifespan Cancer Institute, Warren-Alpert Medical School of Brown University, Providence, RI, USA.

Hepatic angiosarcoma (HAS) is a rare and highly lethal malignancy with few effective systemic treatments. Relatively little is known about the genetic abnormalities that drive this disease. As a result, there has been minimal progress towards applying targeted therapies to the treatment of HAS. We describe the first reported case of a patient with HAS that harbored a fusion of with . Similar to other rearrangements involving , the resulting fusion protein is believed to act as a major driver of carcinogenesis and may be subject to inhibition by drugs that target such as crizotinib. We then queried the MSK-IMPACT clinical sequencing cohort and cBioportal datasets, demonstrating the previously unknown prevalence of fusions in soft tissue sarcomas and hepatobiliary cancers. Amplification of these genes was also found to correlate with reduced overall survival. This is followed by a review of the role played by rearrangements in cancer, as well as the evidence supporting the use of targeted therapies against the resulting fusion protein. We suggest that testing for ROS1 fusion and, if positive, treatment with a targeted therapy could be considered at the time of diagnosis for patients with angiosarcoma. This report also highlights the need for further investigation into the molecular pathophysiology of this deadly disease.
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http://dx.doi.org/10.18632/oncotarget.26521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349438PMC
January 2019

Clinicopathologic Features of a Series of Primary Renal CIC-rearranged Sarcomas With Comprehensive Molecular Analysis.

Am J Surg Pathol 2018 10;42(10):1360-1369

Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI.

CIC-rearranged sarcomas rarely occur in visceral organs including the kidney. The most common fusion partner with CIC is the DUX4 gene, but variant fusion partners have also been reported. Herein, we describe the clinicopathologic features and comprehensive molecular profiling of 4 cases of primary renal CIC-rearranged sarcomas. All cases occurred in females, age range 13 to 82 years and included 3 resections and 1 needle biopsy specimen. There was a tendency for development of metastatic disease predominantly to the lungs and poor disease outcome despite different treatment strategies. Histologically, variable round cell (20% to 100%), spindle cell (0% to 80%), and rhabdoid morphologies (0% to 20%) were seen. By immunohistochemistry diffuse WT1 nuclear (2 to 3+, ∼90%) labeling was present in 1 case, with cytoplasmic staining in the others (3+, 40% to 75%). CD99 was focally positive in all 4 cases (≤10%); 1 case each was diffusely positive for c-myc (2 to 3+, ∼90%) and ETV4 (3+, ∼90%); 1 case was focally positive for c-myc (2+, ∼5%) and calretinin (2+, ∼5%); and all cases were negative for cytokeratin and NKX2.2. CIC rearrangement by fluorescence in situ hybridization was present in the 3 cases tested. Comprehensive genomic profiling (CGP) of 3 cases revealed a CIC-DUX4 fusion in 2 cases, and 1 CIC-NUTM1 fusion. All 4 CIC-rearranged renal sarcomas had low mutation burden, and except HLA-A and MLL mutations lacked genomic alterations in other oncogenic drivers. Material from the needle biopsy was insufficient for CGP but that case was positive with the DUX4 immunohistochemical stain as were the 2 CIC-DUX4 tumors. In conclusion, CIC-rearranged sarcomas rarely occur in the kidney with a tendency for poor outcome and in this series we illustrate an example with CIC-NUTM1 fusion, an emerging variant, at a visceral site. Testing by fluorescence in situ hybridization or CGP is optimal to avoid missing cases that harbor variant fusion partners.
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http://dx.doi.org/10.1097/PAS.0000000000001098DOI Listing
October 2018

Alanine-glyoxylate aminotransferase 1 (AGXT1) is a novel marker for hepatocellular carcinomas.

Hum Pathol 2018 10 5;80:76-81. Epub 2018 Jun 5.

Department of Pathology and Laboratory Medicine, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI 02903. Electronic address:

Arginase-1 has been demonstrated as a marker for hepatocellular carcinoma (HCC) with higher sensitivity and specificity than HepPar-1 and glypican-3. However, its sensitivity is diminished in moderately and poorly differentiated HCCs. In the current study, we evaluated the utility of AGXT1 as a diagnostic marker. Immunostains for AGXT1 and arginase-1 were performed in tissue microarrays of 139 HCCs and 374 gastrointestinal and nongastrointestinal carcinomas. AGXT1 exhibited granular cytoplasmic immunoreactivity in contrast to the diffuse cytoplasmic staining characteristic of arginase-1 in nonneoplastic and neoplastic hepatocytes. Sensitivities of AGXT1 for all HCCs were 90.0% compared to 87.8% for arginase-1. A small number of tumors expressed only 1 of the 2 markers. Sensitivity increased to 92.1% when the presence of either marker was considered positive. Excepting 5 cases of cholangiocarcinoma, both AGXT1 and arginase-1 were negative in all non-HCC tumors with specificities of 98.7%. Our data support the consideration of AGXT1 as a novel hepatocellular marker with equally high specificity and slightly higher sensitivity as compared to arginase-1. AGXT1 may aid in diagnostic workup especially in conjunction with arginase-1 for HCCs that may otherwise defy conventional immunostaining patterns.
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http://dx.doi.org/10.1016/j.humpath.2018.05.025DOI Listing
October 2018

Spectrum of findings in orchiectomy specimens of persons undergoing gender confirmation surgery.

Hum Pathol 2018 06 17;76:91-99. Epub 2018 Mar 17.

Department of Pathology and Laboratory Medicine, Rhode Island Hospital, Providence, RI 02903, USA.

Gender confirmation surgery is increasingly common in persons with gender dysphoria. We describe changes seen in gonads from individuals seeking male-to-female physical adaptation. We studied 99 orchiectomies from 50 persons. The average age was 33 years (range, 21-63 years). Eighty-six (86.8%) of 99 testes were normal in size with an average size of 3.87 cm (range, 3.0-5.5 cm). Thirteen (13.1%) of 99 testes were hypotrophic and measured up to 2.5 cm. Seminiferous tubules were reduced in diameter compared with controls (0.137 mm versus 0.237 mm; P < .001) and showed peritubular fibrosis in 41 (82%) of 50 persons. In 40 (80%) of 50 persons, there was maturation arrest at the spermatogonia level. In 10 (20%) of 50 persons, the seminiferous tubules showed focal spermatids/spermatozoa up to 7 per 10 tubules mixed with partial maturation arrest at primary spermatocytes. Twenty-six (26%) of 99 testes showed seminiferous tubules with rare cells with large nuclei (3× size of Sertoli cells nuclei) and degenerative chromatin (cytomegaly). Leydig cells were absent in 50 (50%), markedly reduced in 30 (30%), and similar to controls (mean, 33/high-power field) in 20 (20%). A subset (20/99; 20%) of testes had epithelial hyperplasia of the proximal epididymis with stratification and micropapillae. There was no germ cell tumor, sex cord stromal tumors, or germ cell neoplasia in situ. In summary, the histologic changes include (1) decreased diameter of seminiferous tubules and expansion of the interstitium, (2) marked hypoplasia of germ cells, (3) rare cytomegaly, (4) hypoplasia or absence of Leydig cells, and (5) epididymal hyperplasia.
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http://dx.doi.org/10.1016/j.humpath.2018.03.007DOI Listing
June 2018

Loss of Expression of a Novel Chromatin Remodeler SMARCA1 in Soft Tissue Sarcoma.

J Cytol Histol 2018 23;9(6). Epub 2018 Nov 23.

Department of Pathology, Warren Alpert Medical School of Brown University, Lifespan Academic Medical Center, Providence, Rhode Island, USA.

Introduction: Vital cellular processes such as proliferation and differentiation are regulated by chromatin remodeling complexes. A variety of neoplasms have been discovered to have genomic alterations (GAs) and loss of immunohistochemical (IHC) expression of chromatin remodelers and is another member of the chromatin remodelers, and has not yet been studied in neoplasia. As is located on chromosome X, could be potentially inactivated by a single hit. We aimed to evaluate GAs and protein expression of in soft tissue tumors.

Method: The publically available cBioPortal.32e34 platform was queried to analyze data on soft tissue tumors from The Cancer Genome Atlas project (TCGA) related to GAs. Our institutional archives were queried to collect 26 cases of soft tissue tumors including 10 undifferentiated sarcomas, 5 leiomyosarcomas, 6 liposarcomas, and 5 malignant peripheral sheath tumors (MPNST). IHC for SMARCA1 with an SNF 2C4 monoclonal antibody was performed on whole tissue sections.

Results: GAs were present in 8/261 soft tissue sarcomas (3%) in the TCGA dataset. Leiomyosarcomas had most common GAs in 6/99 cases. deletions existed in 1/56 dedifferentiated liposarcomas and 1/48 undifferentiated sarcomas. No GAs occurred in other sarcoma subtypes. SMARCA1 IHC was studied in the sarcoma subtypes with potential alterations in our institutional cases. SMARCA1 nuclear expression was lost in 3/10 cases (30%) of undifferentiated sarcoma, and 2/5 cases of MPNST (40%). SMARCA1 expression was intact in all cases of leiomyosarcoma and liposarcoma.

Conclusion: This is the first study to demonstrate loss of expression of SMARCA1 in soft tissue sarcomas subtypes, including undifferentiated sarcoma. Our study highlights merit for further investigation on the role of in the differentiation process and molecular mechanisms of inactivation.
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http://dx.doi.org/10.4172/2157-7099.1000524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513346PMC
November 2018

T-complex-associated-testis-expressed 3 (TCTE3) is a novel marker for pancreatobiliary carcinomas.

Hum Pathol 2017 12 24;70:62-69. Epub 2017 Oct 24.

Department of Pathology and Laboratory Medicine, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI 02903. Electronic address:

Several markers of pancreatobiliary lineage have been described in the literature. However, none have demonstrated sufficient specificity and sensitivity to warrant diagnostic use. We evaluated the utility of T-complex-associated-testis-expressed 3 (TCTE3) as a pancreatobiliary marker. A set of 247 adenocarcinomas from the gastrointestinal (GI) tract was identified including 18 from the gastroesophageal junction (GEJ), 29 stomach, 17 ampullary, 62 pancreatic, and 16 common bile duct and gallbladder (CBD/GB), 13 non-ampullary small intestine, 32 colon, and 24 rectum. The remainder consisted of 16 cholangiocarcinomas and 20 hepatocellular carcinomas (HCC). Additionally, 163 adenocarcinomas from the breast, gynecologic tract, prostate, urothelium, kidney, and lung were stained for comparison. Immunohistochemistry for TCTE3 and other gastrointestinal markers was performed. Positive expression of TCTE3 was characterized by a strong, well-defined membranous pattern with or without weak cytoplasmic staining. Expression was identified in the normal epithelial cells of pancreatobiliary tree, but staining was absent in normal epithelial cells of esophagus, stomach, and intestine. Hepatocytes, pancreatic acini and islets and other non-epithelial cells were also negative for staining. TCTE3 was expressed in 93.5% of pancreatic ductal adenocarcinomas, 37.5% of CBD/GB adenocarcinomas, 50% of cholangiocarcinomas, 76.4% of ampullary adenocarcinomas, and 33.3% of GEJ adenocarcinomas. Only 3.5% of the gastric, 7.7% of non-ampullary small intestinal and 6.25% of colonic tumors exhibited positive staining. Expression was absent in rectal carcinomas and HCCs. These results suggest that TCTE3 is a useful marker of pancreatobiliary differentiation and may aid in distinguishing these tumors from gastric and intestinal primary tumors.
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http://dx.doi.org/10.1016/j.humpath.2017.10.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5757622PMC
December 2017

Prognostic significance of IgG4+ plasma cell infiltrates following neoadjuvant chemoradiation therapy for esophageal adenocarcinoma.

Hum Pathol 2017 08 28;66:126-135. Epub 2017 Jun 28.

Department of Pathology, Rhode Island Hospital, and Alpert Medical School at Brown University, Providence, RI 02903.

Lymphoplasmacytic infiltrates in esophageal adenocarcinoma (EAC) tissue following chemoradiotherapy (CRT) reflect alterations in the tumor immunoenvironment. The presence and role of plasma cells in this process are poorly understood. Our aim was to characterize the IgG4+ plasma cell population in EAC following CRT. Seventy-one esophagectomy specimens post-CRT were compared with a surgery-only group of 31 EACs. The distribution, density, and ratio of IgG4+ and IgG+ plasma cells were evaluated by immunohistochemistry and correlated with clinicopathologic features, treatment response, and survival. In the CRT group, the presence of higher numbers of IgG4+ (≥ median of 94/high-power field) and IgG+ (≥ median of 225/high-power field) plasma cells and increased IgG4+/IgG+ ratio (≥ median of 41%) within ulcers was associated with complete or near-complete treatment response (P = .0077, P = .0503, and P = .0063, respectively). Lower tumor grade, smaller tumor size, and higher levels of IgG4+ plasma cells in posttherapy ulcers significantly correlated with better overall survival, whereas pretherapy clinical stage, posttherapy pathologic stage, smaller tumor size, and lower tumor grade were associated with longer recurrence-free survival. Multivariate analysis revealed that both posttherapy pathologic stage and high IgG4+ plasma cells in ulcers were independent predictors of overall survival (P = .05 and P = .01), whereas only posttherapy pathologic stage was associated with recurrence-free survival (P < .01). This is the first study describing a dense IgG4+ plasma cell infiltrate in EAC following CRT. The presence of increased IgG4+ plasma cells may be a novel reliable factor to predict prognosis of EAC patients following CRT.
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http://dx.doi.org/10.1016/j.humpath.2017.06.009DOI Listing
August 2017

Characterization of Clinical Cases of Advanced Papillary Renal Cell Carcinoma via Comprehensive Genomic Profiling.

Eur Urol 2018 01 4;73(1):71-78. Epub 2017 Jun 4.

Foundation Medicine, Cambridge, MA, USA.

Background: Papillary renal cell carcinoma (PRCC) is a rare subset of RCC. The Cancer Genome Atlas (TCGA) data largely reflect localized disease, and there are limited data for advanced PRCC.

Objective: To characterize the frequency of genomic alterations (GAs) in patients with advanced PRCC for whom comprehensive genomic profiling (CGP) was performed in the context of routine clinical care.

Design, Setting, And Participants: Formalin-fixed, paraffin-embedded tissue was obtained for 169 consecutive patients with confirmed PRCC. DNA was extracted and comprehensive genomic profiling was performed in a certified central laboratory.

Measurements: Hybrid-capture, adaptor ligation-based libraries of up to 315 genes were sequenced to a median coverage of 648×. All classes of GAs were identified, including substitutions, insertions/deletions, copy number alterations, and rearrangements.

Results And Limitations: From 169 patients, either primary tumor tissue (102 patients, 60%) or metastatic tissue (67 patients, 40%) was collected. In patients with type 1 PRCC, commonly altered genes were MET (33%; 8 activating mutations, 5 amplifications at >6 copies), TERT (30%), CDKN2A/B (13%), and EGFR (8%). In patients with type 2 PRCC, commonly altered genes were CDKN2A/B (18%), TERT (18%), NF2 (13%), and FH (13%); MET GAs (5 mutations, 3 amplifications) were observed in 7% of type 2 cases. Notable differences from TCGA data include higher frequencies of MET, NF2, and CDKN2A/B GAs, association of alterations in SWI/SNF complex genes with type 2 PRCC, and observation of frequent CDKN2A/B alterations in both type 1 and type 2 disease.

Conclusions: Both the current study and the TCGA experience represent similarly sized cohorts of patients with PRCC. Key differences in GA frequency probably underscore the marked difference in stage distribution between these data sets. These results may inform planned precision medicine trials for metastatic PRCC.

Patient Summary: Papillary renal cell carcinoma (PRCC) is a rare subtype of kidney cancer, and understanding of the biology of advanced PRCC is limited. This report highlights some of the unique biologic features of PRCC that may inform on future use of targeted therapies for the treatment of metastatic disease.
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http://dx.doi.org/10.1016/j.eururo.2017.05.033DOI Listing
January 2018

Detection of an Fusion in Colorectal Carcinoma by Hybrid Capture-Based Assay of Circulating Tumor DNA.

Oncologist 2017 07 15;22(7):774-779. Epub 2017 May 15.

Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada, USA.

rearrangements have been observed in 0.05%-2.5% of patients with colorectal cancers (CRCs) and are predicted to be oncogenic drivers largely mutually exclusive of or alterations. Here we present the case of a patient with metastatic CRC who was treatment naïve at the time of molecular testing. Initial ALK immunohistochemistry (IHC) staining was negative, but parallel genomic profiling of both circulating tumor DNA (ctDNA) and tissue using similar hybrid capture-based assays each identified an identical fusion. Subsequent ALK IHC staining of the same specimens was positive, suggesting that the initial result was a false negative. This report is the first instance of an fusion in CRC detected using a ctDNA assay.

Key Points: Current guidelines for colorectal cancer (CRC) only recommend genomic assessment of and microsatellite instability (MSI) status. rearrangements are rare in CRC, but patients with activating fusions have responded to targeted therapies rearrangements can be detected by genomic profiling of ctDNA from blood or tissue, and this methodology may be informative in cases where immunohistochemistry (IHC) or other standard testing is negative.
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http://dx.doi.org/10.1634/theoncologist.2016-0376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5507649PMC
July 2017

Primary Spinal Epidural CIC-DUX4 Undifferentiated Sarcoma in a Child.

Pediatr Dev Pathol 2018 Jul-Aug;21(4):411-417. Epub 2017 May 5.

1 Department of Pathology, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, Rhode Island.

Primitive round- or spindle-cell EWSR1-negative undifferentiated sarcomas harboring CIC-DUX4 gene fusion are the most common form of Ewing-like sarcomas. These tumors primarily occur in peripheral soft tissues, but examples have been described within viscera and the brain. As far as we are aware, CIC-DUX4 positive primary epidural spinal sarcoma has not been reported. Herein, we describe a T5-T6 epidural tumor in a 15-year-old girl in which many neoplastic cells had moderate and focally abundant cytoplasm, including plasmacytoid or rhabdoid cells, rather than the more common Ewing-like morphology described in the majority of such tumors. The diagnosis was confirmed by fluorescent in situ hybridization after the tumor was found to be WT-1 positive, and comprehensive genomic profiling demonstrated breakpoints in exon 20 and exon 1 of the CIC and DUX4 genes, respectively. After treatment with local radiation and systemic chemotherapy, resected recurrent tumor demonstrated more pleomorphic neoplastic cells as well as intracytoplasmic eosinophilic globules and nuclear pseudoinclusions which may reflect therapy-related changes. Unfortunately, there was further progression of tumor including the development of intracranial lesions, and the patient succumbed to her tumor 22 months after the original resection.
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http://dx.doi.org/10.1177/1093526617707856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5575979PMC
May 2019

Differentiating tumor heterogeneity in formalin-fixed paraffin-embedded (FFPE) prostate adenocarcinoma tissues using principal component analysis of matrix-assisted laser desorption/ionization imaging mass spectral data.

Rapid Commun Mass Spectrom 2017 Jan;31(2):160-170

Brown University, Warren Alpert Medical School, COBRE Center for Cancer Research, Rhode Island Hospital, Providence, RI, USA.

Rationale: Many patients with adenocarcinoma of the prostate present with advanced and metastatic cancer at the time of diagnosis. There is an urgent need to detect biomarkers that will improve the diagnosis and prognosis of this disease. Matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) is playing a key role in cancer research and it can be useful to unravel the molecular profile of prostate cancer biopsies.

Methods: MALDI imaging data sets are highly complex and their interpretation requires the use of multivariate statistical methods. In this study, MALDI-IMS technology, sequential principal component analysis (PCA) and two-dimensional (2-D) peak distribution tests were employed to investigate tumor heterogeneity in formalin-fixed paraffin-embedded (FFPE) prostate cancer biopsies.

Results: Multivariate statistics revealed a number of mass ion peaks obtained from different tumor regions that were distinguishable from the adjacent normal regions within a given specimen. These ion peaks have been used to generate ion images and visualize the difference between tumor and normal regions. Mass peaks at m/z 3370, 3441, 3447 and 3707 exhibited stronger ion signals in the tumor regions.

Conclusions: This study reports statistically significant mass ion peaks unique to tumor regions in adenocarcinoma of the prostate and adds to the clinical utility of MALDI-IMS for analysis of FFPE tissue at a molecular level that supersedes all other standard histopathologic techniques for diagnostic purposes used in the current clinical practice. Copyright © 2016 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/rcm.7776DOI Listing
January 2017

Collagen type III α1 as a useful diagnostic immunohistochemical marker for fibroepithelial lesions of the breast.

Hum Pathol 2016 11 3;57:176-181. Epub 2016 Aug 3.

Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, RI 02903.

Phyllodes tumors (PTs) of the breast constitute an uncommon group of fibroepithelial neoplasms that are classified into benign, borderline, and malignant categories based on a constellation of histologic characteristics including cytologic atypia, mitotic count, degree of stromal cellularity, stromal overgrowth, and microscopic margins. Accurately and reproducibly differentiating these tumors is a long-standing diagnostic challenge. In addition, the distinction between benign PT from cellular fibroadenoma (FA) is especially difficult because of overlapping microscopic features. We have previously shown differential expression of various collagens, including collagen type III α1 (Col3A) in breast carcinomas. In this study, we evaluated clinicopathological characteristics of 95 cases of fibroepithelial lesions including 56 PTs and 39 FAs (25 cellular FA, 14 typical FA) and correlated them with the immunohistochemical staining pattern for Col3A. We found that stromal Col3A expression was significantly increased in PTs when compared with FAs (P < .0001). Among the PT groups, there was significantly increased expression from benign tumors through borderline to malignant tumors. High Col3A expression was associated with PT type, irregular margin status, and high mitotic activity. A distinct periductal cuffing pattern of Col3A staining was unique to PTs and absent in FAs. These findings suggest that Col3A can be a potential adjunct marker for both differentiating FA from PT and assessing malignant potential in PTs.
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http://dx.doi.org/10.1016/j.humpath.2016.07.017DOI Listing
November 2016

Fatal Sepsis in a Patient With Celiac Disease-Associated Hyposplenism.

ACG Case Rep J 2016 Aug 12;3(4):e140. Epub 2016 Oct 12.

Department of Pathology and Laboratory Medicine, Alpert Medical School of Brown University and Rhode Island Hospital, Providence, RI.

We present a 59-year-old male with poorly controlled celiac disease (CD) and fatal sepsis, describe the morphologic findings, and stress the need for monitoring splenic function and pneumococcal vaccination in these patients.
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http://dx.doi.org/10.14309/crj.2016.113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5064423PMC
August 2016

Can Sentinel Lymph Node Biopsy Be Spared in Papillary Carcinoma of the Breast?

Clin Breast Cancer 2017 04 8;17(2):127-133. Epub 2016 Sep 8.

Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, The Warren Alpert Medical School of Brown University, Providence, RI.

Background: Papillary carcinoma (PC) of the breast represents ∼0.5% of all newly diagnosed cases of breast cancer and usually has an indolent course. The current data suggest lack of a consensus in the surgical management of this disease. Because patients can occasionally develop metastatic disease, sentinel lymph node (SLN) biopsy is often performed during surgery.

Materials And Methods: In the present study, we retrospectively evaluated the histologic characteristics of 99 cases of PC with or without associated frank invasive carcinoma, including 43 encapsulated or intracystic PCs, 24 solid PCs, and 32 intraductal PCs, and correlated these with the incidence of nodal metastasis.

Results: Of the 99 cases, 64 were tumor stage Tis (noninvasive), 5 were T1 microinvasive, 17 T1a, 5 T1b, 5 T1c, and 3 were T2. A total of 37 patients (37%) underwent axillary staging, including 31 SLN biopsies and 6 axillary dissections. Only 1 patient (2.7%) with noninvasive solid PC had evidence of nodal metastasis. Follow-up information was available for 81 patients, with a mean follow-up period of 4.9 years (range, 1-13 years). Two local recurrences, no distant metastases, and no disease-related deaths were recorded.

Conclusion: PC rarely involves the lymph nodes even in tumors with an associated frank invasive component, and the overall prognosis and long-term survival is excellent. We propose that evaluation of the SLN should not be routinely indicated for patients with PC treated by local control lumpectomy.
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http://dx.doi.org/10.1016/j.clbc.2016.08.009DOI Listing
April 2017

Succinate Dehydrogenase B (SDHB) Immunohistochemistry for the Evaluation of Muscle Biopsies.

Appl Immunohistochem Mol Morphol 2017 Oct;25(9):645-650

*Department of Pathology and Laboratory Medicine, Rhode Island Hospital †Warren Alpert Medical School of Brown University, Providence, RI.

Succinate dehydrogenase (SDH) is a key mitochondrial enzyme complex composed of 4 subunits. SDH histochemistry is routinely utilized in the assessment of muscle biopsies to reveal underlying pathology such as subsarcolemmal mitochondrial aggregates. In this study, we evaluated the utility of succinate dehydrogenase B (SDHB) immunohistochemistry (IHC) in 27 muscle biopsies, including 13 mitochondrial myopathies (MMs), 9 inflammatory myopathies, and 5 controls. SDHB IHC was performed on formalin-fixed, paraffin-embedded tissue sections with a mouse monoclonal antibody (Abcam 21A11AE7) in parallel with histochemical SDH stains on a fresh-frozen tissue. In all muscle biopsies, SDHB IHC exhibited granular immunoreactivity and highlighted the dark type 1 and lighter type 2 staining pattern observed by histochemistry. In all cases of MM, SDHB IHC showed subsarcolemmal granular aggregates involving the entire periphery of the fibers that were more distinct than those seen by SDH histochemistry. In 3 extraocular muscle biopsies, SDHB immunoreactive speckles of various sizes were distributed throughout the entire sarcoplasm that were more prominent than those seen on SDH histochemistry. Subsarcolemmal and cytoplasmic granular aggregates seen on SDHB IHC correlated with mitochondrial pathology on electron microscopy. In cases of inflammatory myopathy, there was diffuse sarcoplasmic SDHB immunoreactivity in degenerating fibers, but no evidence of subsarcolemmal aggregates. This study demonstrates that SDHB IHC is highly sensitive and specific in the identification of MM. The automation, reproducibility, and cost efficiency of SDHB IHC offer advantages over the labor-intensive histochemical method requiring frozen sections. As this technique is performed on formalin-fixed, paraffin-embedded tissues, it can be easily applied for retrospective studies.
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http://dx.doi.org/10.1097/PAI.0000000000000432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5323393PMC
October 2017

Primary Undifferentiated Sarcoma of the Kidney Harboring a Novel Variant of CIC-DUX4 Gene Fusion.

Am J Surg Pathol 2016 09;40(9):1298-301

*Department of Pathology, Rhode Island Hospital & Alpert Medical School of Brown University, Providence, RI †Department of Pathology, The Hospital for Sick Children & University of Toronto, Toronto, ON, Canada ‡Foundation Medicine Inc. Cambridge, MA.

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http://dx.doi.org/10.1097/PAS.0000000000000688DOI Listing
September 2016

Activating KRAS mutations are characteristic of oncocytic sinonasal papilloma and associated sinonasal squamous cell carcinoma.

J Pathol 2016 08 1;239(4):394-8. Epub 2016 Jul 1.

Department of Pathology, University of Michigan Health System, Ann Arbor, MI, USA.

Oncocytic sinonasal papillomas (OSPs) are benign tumours of the sinonasal tract, a subset of which are associated with synchronous or metachronous sinonasal squamous cell carcinoma (SNSCC). Activating EGFR mutations were recently identified in nearly 90% of inverted sinonasal papillomas (ISPs) - a related tumour with distinct morphology. EGFR mutations were, however, not found in OSP, suggesting that different molecular alterations drive the oncogenesis of these tumours. In this study, tissue from 51 cases of OSP and five cases of OSP-associated SNSCC was obtained retrospectively from six institutions. Tissue was also obtained from 50 cases of ISP, 22 cases of ISP-associated SNSCC, ten cases of exophytic sinonasal papilloma (ESP), and 19 cases of SNSCC with no known papilloma association. Using targeted next-generation and conventional Sanger sequencing, we identified KRAS mutations in 51/51 (100%) OSPs and 5/5 (100%) OSP-associated SNSCCs. The somatic nature of KRAS mutations was confirmed in a subset of cases with matched germline DNA, and four matched pairs of OSP and concurrent associated SNSCC had concordant KRAS genotypes. In contrast, KRAS mutations were present in only one (5%) SNSCC with no known papilloma association and none of the ISPs, ISP-associated SNSCCs, or ESPs. This is the first report of somatic KRAS mutations in OSP and OSP-associated SNSCC. The presence of identical mutations in OSP and concurrent associated SNSCC supports the putative role of OSP as a precursor to SNSCC, and the high frequency and specificity of KRAS mutations suggest that OSP and OSP-associated SNSCC are biologically distinct from other similar sinonasal tumours. The identification of KRAS mutations in all studied OSP cases represents an important development in our understanding of the pathogenesis of this disease and may have implications for diagnosis and therapy. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.4750DOI Listing
August 2016

Oncogenic ALK Fusion in Rare and Aggressive Subtype of Colorectal Adenocarcinoma as a Potential Therapeutic Target.

Clin Cancer Res 2016 08 1;22(15):3831-40. Epub 2016 Mar 1.

Oncology Division, Department of Internal Medicine, Rhode Island Hospital, and Alpert Medical School at Brown University, Providence, Rhode Island.

Purpose: Chromosomal translocations in the anaplastic lymphoma kinase (ALK) gene have been identified as oncogenic drivers in lung adenocarcinomas and other tumors, recently including rare cases of colorectal carcinoma. We identified a patient with refractory metastatic colorectal carcinoma harboring a STRN-ALK gene fusion who achieved an exceptional clinical benefit to the ALK inhibitor ceritinib. Our goal was to further define the clinicopathologic features of ALK-rearranged colorectal carcinoma in a large cohort.

Experimental Design: Clinical cases of colorectal carcinoma evaluated by comprehensive genomic profiling (CGP) or by ALK immunohistochemistry (IHC) were reviewed retrospectively. FISH and microsatellite instability (MSI) analyses were performed.

Results: Nine colorectal carcinoma cases harbored ALK gene fusions. Six cases were identified by CGP of 3,157 colorectal carcinoma (0.2%) and three by IHC of 2,980 colorectal carcinoma (0.1%). The ALK fusions involved known ALK partners EML4, C2orf44, CAD, and the novel STRN, PPP1R21, SENPF, MAPRE3, and PRKAP1B partners. These advanced-stage colorectal carcinomas lacked mutations in other oncogenic drivers, predominantly involved the proximal colon, and often exhibited MSI and mucinous phenotype. The index patient was treated with the ALK inhibitor ceritinib, resulting in a marked decrease in size of a skin metastasis, and resolution by computerized tomography of all contrast enhancing tumor. After 9 months of treatment, biopsy of progressive disease demonstrated a KRAS mutation, consistent with acquired resistance to ceritinib.

Conclusions: Colorectal carcinoma harboring ALK fusions represent a rare aggressive subtype of colorectal carcinoma with distinct clinicopathologic features. This report provides the first clinical evidence that such patients may benefit from targeted monotherapy with ALK inhibitors. Clin Cancer Res; 22(15); 3831-40. ©2016 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-3000DOI Listing
August 2016