Publications by authors named "Shaolei Lu"

50 Publications

Coexpress of GATA-3 and ER in Anorectal and Head and Neck Squamous Cell Carcinoma Mimicking Metastatic Breast Cancer.

Appl Immunohistochem Mol Morphol 2020 Dec 1. Epub 2020 Dec 1.

Department of Pathology and Lab Medicine, Alpert Medical School of Brown University, Providence, RI.

GATA binding protein 3 (GATA-3) is a sensitive marker for breast and urothelial carcinomas. In combination with the estrogen receptor (ER), it is often used for differential diagnosis of metastatic carcinomas of breast origin. In this study, we sought to characterize GATA-3 and ER expression in squamous cell carcinoma (SqCC) of various origins to compare with breast carcinoma. Sixty-four SqCC of anorectum (35), head and neck (15), lung (11), and breast (3) as well as urothelial carcinoma (31) were included. In anorectal and head and neck SqCC, GATA-3, and ER was observed in 23/50 (46.0%) and 18/50 (36.0%) of the cases, respectively. The expression of GATA-3 and ER were present in both male and female patients without significant sex predominance. In 2 metastatic SqCC, the GATA-3 and ER expressed similar immunoreactivity compatible with their anorectal primary. Progesterone receptor was only expressed in 2 anorectal SqCC and none of head and neck SqCC or urothelial carcinomas. None of the lung SqCC expressed GATA-3 or ER (0/11). p16 was expressed in the majority of head and neck (6/12) and anorectal SqCC (26/27). Our study demonstrated that the combination of GATA-3 and ER positivity is not entirely specific for breast carcinomas, since both stains are expressed in SqCC from anorectal and head and neck origins. Clinical workup for metastatic carcinoma of suspicious breast origin should be cognizant of other tumors with a similar immunohistochemical profile (ie, SqCC).
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http://dx.doi.org/10.1097/PAI.0000000000000887DOI Listing
December 2020

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

Evaluation of a convolutional neural network for ovarian tumor differentiation based on magnetic resonance imaging.

Eur Radiol 2020 Oct 14. Epub 2020 Oct 14.

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

Objectives: There currently lacks a noninvasive and accurate method to distinguish benign and malignant ovarian lesion prior to treatment. This study developed a deep learning algorithm that distinguishes benign from malignant ovarian lesion by applying a convolutional neural network on routine MR imaging.

Methods: Five hundred forty-five lesions (379 benign and 166 malignant) from 451 patients from a single institution were divided into training, validation, and testing set in a 7:2:1 ratio. Model performance was compared with four junior and three senior radiologists on the test set.

Results: Compared with junior radiologists averaged, the final ensemble model combining MR imaging and clinical variables had a higher test accuracy (0.87 vs 0.64, p < 0.001) and specificity (0.92 vs 0.64, p < 0.001) with comparable sensitivity (0.75 vs 0.63, p = 0.407). Against the senior radiologists averaged, the final ensemble model also had a higher test accuracy (0.87 vs 0.74, p = 0.033) and specificity (0.92 vs 0.70, p < 0.001) with comparable sensitivity (0.75 vs 0.83, p = 0.557). Assisted by the model's probabilities, the junior radiologists achieved a higher average test accuracy (0.77 vs 0.64, Δ = 0.13, p < 0.001) and specificity (0.81 vs 0.64, Δ = 0.17, p < 0.001) with unchanged sensitivity (0.69 vs 0.63, Δ = 0.06, p = 0.302). With the AI probabilities, the junior radiologists had higher specificity (0.81 vs 0.70, Δ = 0.11, p = 0.005) but similar accuracy (0.77 vs 0.74, Δ = 0.03, p = 0.409) and sensitivity (0.69 vs 0.83, Δ = -0.146, p = 0.097) when compared with the senior radiologists.

Conclusions: These results demonstrate that artificial intelligence based on deep learning can assist radiologists in assessing the nature of ovarian lesions and improve their performance.

Key Points: • Artificial Intelligence based on deep learning can assess the nature of ovarian lesions on routine MRI with higher accuracy and specificity than radiologists. • Assisted by the deep learning model's probabilities, junior radiologists achieved better performance that matched those of senior radiologists.
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http://dx.doi.org/10.1007/s00330-020-07266-xDOI Listing
October 2020

Convalescent plasma for patients with severe COVID-19: a matched cohort study.

Clin Infect Dis 2020 Oct 10. Epub 2020 Oct 10.

Division of Infectious Diseases, Warren Alpert Medical School of Brown University, Providence, RI, USA.

Background: The efficacy of convalescent plasma (CP) for the treatment of COVID-19 remains unclear.

Methods: In a matched cohort analysis of hospitalized patients with severe COVID-19, the impact of CP treatment on in-hospital mortality was evaluated using univariate and multivariate Cox proportional-hazards models, and the impact of CP treatment on time to hospital discharge was assessed using a stratified log-rank analysis.

Results: 64 patients who received CP a median of 7 days after symptom onset were compared to a matched control group of 177 patients. The incidence of in-hospital mortality was 12.5% and 15.8% in the CP and control groups, respectively (p = 0.52). There was no significant difference in the risk of in-hospital mortality between the two groups (adjusted hazard ratio [aHR] 0.93, 95% confidence interval [CI] 0.39 - 2.20). The overall rate of hospital discharge was not significantly different between the two groups (rate ratio [RR] 1.28, 95% CI 0.91 - 1.81), although there was a significantly increased rate of hospital discharge among patients 65-years-old or greater who received CP (RR 1.86, 95% CI 1.03 - 3.36). There was a greater than expected frequency of transfusion reactions in the CP group (2.8% reaction rate observed per unit transfused).

Conclusions: We did not demonstrate a significant difference in risk of mortality or rate of hospital discharge between the CP and control groups. There was a signal for improved outcomes among the elderly, and further adequately powered randomized studies should target this subgroup when assessing the efficacy of CP treatment.
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http://dx.doi.org/10.1093/cid/ciaa1548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665324PMC
October 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

Testing for SARS-CoV-2 (COVID-19): A General Review.

R I Med J (2013) 2020 Sep 4;103(8):20-23. Epub 2020 Sep 4.

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

The rampant COVID-19 pandemic has strained the testing capabilities of healthcare centers across the country. Several nucleic acid and serologic assays are available or currently being developed to meet the growing demand for large-scale testing. This review summarizes the developments of commonly used testing methods and their strategic use in clinical diagnosis and epidemiologic surveillance. This review will cover the basic virology of SARS-CoV-2, nucleic acid amplification testing, serology, antigen testing, as well as newer testing methods such as CRISPR-based assays.
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September 2020

TET1 promotes malignant progression of cholangiocarcinoma with IDH1 wild-type.

Hepatology 2020 Aug 1. Epub 2020 Aug 1.

Liver Research Center, Division of Gastroenterology & Liver Research Center, Warren Alpert Medical School of Brown University and Rhode Island Hospital, Providence, RI, USA.

Cholangiocarcinoma (CCA) is a highly lethal disease without effective therapeutic approaches. The whole genome sequencing data indicated that there are about 20% of CCA patients having IDH1 mutations which have been suggested to target 2-oxoglutarate (OG) dependent dioxygenases in promoting CCA carcinogenesis. However, the clinical study indicates that the CCA patients with mutant IDH1 have better prognosis than those with wild-type IDH1, further complicating the roles of 2-OG-dependent enzymes. This study aimed to clarify if TET1, which is one of the 2-OG dependent enzymes functioning in regulating 5-hydroxymethylcytosine (5hmC) formation, is involved in CCA progression. By analyzing the Cancer Genome Atlas (TCGA) dataset, TET1 mRNA was found to be substantially up-regulated in CCA patients when compared with non-cancerous bile ducts. Additionally, TET1 protein expression was significantly elevated in human CCA tumors as well. CCA cells were challenged with α-ketoglutarate (α-KG) and dimethyl-α-KG (DM-α-KG) which are co-substrates for TET1 dioxygenase. The treatments of α-KG and DM-α-KG promoted 5hmC formation and malignancy of CCA cells. Molecular and pharmacological approaches were used to inhibit TET1 activity and these treatments substantially suppressed 5hmC and CCA carcinogenesis. Mechanistically, it was found that knockdown of TET1 may suppress CCA progression by targeting cell growth and apoptosis through epigenetic regulation. Consistently, targeting TET1 significantly inhibited CCA malignant progression in a liver orthotopic xenograft model via targeting cell growth and apoptosis. In conclusion, our data suggests that expression of TET1 is highly associated with CCA carcinogenesis. It will be important to evaluate the TET1 expression in CCA tumors before the application of IDH1 mutation inhibitor, since the inhibitor suppresses 2-HG expression which may result in activation of TET, potentially leading to CCA malignancy.
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http://dx.doi.org/10.1002/hep.31486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855500PMC
August 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

Evaluation of BioPlex 2200 Syphilis Total With Automated Rapid Plasma Reagin: Experience From a Tertiary Medical Center.

Sex Transm Dis 2020 05;47(5):301-305

From the Departments of Pathology and Laboratory Medicine.

Background: Treponema-specific assays are widely adopted in the first step of the reverse algorithm of serologic syphilis screening. The new BioPlex 2200 Syphilis Total and rapid plasma reagin (RPR) test is designed to perform the first 2 steps of the algorithm simultaneously. However, limited data regarding the BioPlex Syphilis Total and RPR in clinical practice exist.

Methods: A total of 293 random samples at a tertiary medical center were tested by BioPlex Syphilis Total and RPR, BioPlex Syphilis IgG, Architect Syphilis TP, and BD Macro-Vue RPR card. Treponema pallidum particle agglutination (TP-PA) assay and clinical chart review were used to resolve discrepancies. Comparisons were performed among treponemal-specific assays and between 2 RPR tests.

Results: Good overall agreements (>91%) were achieved between BioPlex Syphilis Total, BioPlex Syphilis IgG, and Architect Syphilis TP. Overall agreement between BioPlex RPR and BD RPR was 86.8% with positive percent agreement of 66.7% and negative percent agreement of 96.3%. There were 37 discordant samples including 30 with BD RPR+/BioPlex RPR- and 7 with BD RPR-/BioPlex RPR+. Negative BioPlex RPR results were observed in samples with reactive BD RPR: 10 (91%) of 11 for BD RPR 1:1, 13 (65%) of 20 for BD RPR 1:2, 6 (35%) of 17 for BD RPR 1:4, and 1 (7%) of 14 for BD RPR 1:8. The discordant samples were predominantly from patients with high-risk of syphilis reinfection and included 9 patients with an early reinfection.

Conclusions: Our results demonstrated that BioPlex Syphilis Total and Architect Syphilis TP performed similarly. The BioPlex RPR missed a small number of early syphilis reinfections, and its implementation should depend on the patient population that the laboratory serves.
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http://dx.doi.org/10.1097/OLQ.0000000000001153DOI Listing
May 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

Stromal ColXα1 expression correlates with tumor-infiltrating lymphocytes and predicts adjuvant therapy outcome in ER-positive/HER2-positive breast cancer.

BMC Cancer 2019 Nov 1;19(1):1036. Epub 2019 Nov 1.

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.

Background: The breast cancer microenvironment contributes to tumor progression and response to chemotherapy. Previously, we reported that increased stromal Type X collagen α1 (ColXα1) and low TILs correlated with poor pathologic response to neoadjuvant therapy in estrogen receptor and HER2-positive (ER+/HER2+) breast cancer. Here, we investigate the relationship of ColXα1 and long-term outcome of ER+/HER2+ breast cancer patients in an adjuvant setting.

Methods: A total of 164 cases with at least 5-year follow-up were included. Immunohistochemistry for ColXα1 was performed on whole tumor sections. Associations between ColXα1expression, clinical pathological features, and outcomes were analyzed.

Results: ColXα1 expression was directly proportional to the amount of tumor associated stroma (p = 0.024) and inversely proportional to TILs. Increased ColXα1 was significantly associated with shorter disease free survival and overall survival by univariate analysis. In multivariate analysis, OS was lower in ColXα1 expressing (HR = 2.1; 95% CI = 1.2-3.9) tumors of older patients (> = 58 years) (HR = 5.3; 95% CI = 1.7-17) with higher stage (HR = 2.6; 95% CI = 1.3-5.2). Similarly, DFS was lower in ColXα1 expressing (HR = 1.8; 95% CI = 1.6-5.7) tumors of older patients (HR = 3.2; 95% CI = 1.3-7.8) with higher stage (HR = 2.7; 95% CI = 1.6-5.7) and low TILs. In low PR+ tumors, higher ColXα1 expression was associated with poorer prognosis.

Conclusion: ColXα1 expression is associated with poor disease free survival and overall survival in ER+/HER2+ breast cancer. This study provides further support for the prognostic utility of ColXα1 as a breast cancer associated stromal factor that predicts response to chemotherapy.
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http://dx.doi.org/10.1186/s12885-019-6134-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825361PMC
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

High Rates of Indeterminate TB Tests Among Hospitalized Patients: Can We Optimize Use of Gamma Interferon Release Assays in Tuberculosis?

R I Med J (2013) 2019 Aug 1;102(6):27-30. Epub 2019 Aug 1.

Division of Pulmonary, Critical Care and Sleep Medicine, Warren Alpert Medical School of Brown University, Providence, RI.

In the United States, high concern for iatrogenic reactivation to tuberculosis (TB) disease secondary to prescribed immunosuppression has resulted in increased use of the QuantiFERON-TB Gold In-Tube test (QFT-GIT) to screen for Mycobacterium tuberculosis (Mtb) infection. The aim of our study was to determine indications for QFT-GIT testing and risk factors for indeterminate QFT-GIT results. We retrospectively identified patients with QFT-GIT testing over a six-month period in a tertiary care academic health care system and performed a record review. Inpatients were 11 times more likely to have an indeterminate QFT-GIT result than outpatients (95% CI 7.6-16.2). 61.5% inpatient QFT-GITs were ordered during workup of active TB. Providers treating exogenously or endogenously immunosuppressed patients ordered the most QFT-GITs. We highlight the significant limitations of TB screening tests in the inpatient setting and the need to test earlier in those requiring immunosuppressive therapy to avoid indeterminate results.
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August 2019

Expression of Indoleamine 2, 3-dioxygenase 1 (IDO1) and Tryptophanyl-tRNA Synthetase (WARS) in Gastric Cancer Molecular Subtypes.

Appl Immunohistochem Mol Morphol 2020 May/Jun;28(5):360-368

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

Aims: Developments in genomic pathology have led to novel molecular classification schemes in gastric cancers. Two of these new subtypes, Epstein-Barr virus (EBV)-associated and microsatellite instability-high (MSI-H), are associated with a dominant T-cell-mediated immune response. The roles of the immune modulators, indoleamine 2, 3-dioxygenase 1 (IDO1) and tryptophanyl-tRNA synthetase (WARS), have not been investigated in the context of this classification.

Methods And Results: Using in situ hybridization and immunohistochemistry we subclassified 421 primary gastric adenocarcinomas into 5 subtypes, EBV-associated, epithelial to mesenchymal transition, MSI-H, p53-aberrant, and p53-wildtype tumors. Tumor-infiltrative lymphocytes were counted and protein expression of IDO1 and WARS was graded on tissue microarrays of these 421 tumors. High tumor-infiltrative lymphocytes as well as high expression of both IDO1 and WARS was found in EBV and MSI-H tumors. The prognostic effects of IDO1 and WARS expression were tumor subtype dependent. Although high expression levels of IDO1 and WARS were associated with poor prognosis in p53-aberrant, p53-wildtype, and all cancers combined, WARS expression was associated with better prognosis in MSI tumors.

Conclusions: The immunomodulators, IDO1 and WARs, are upregulated and have prognostic significance in EBV-associated and MSI-H tumors. Novel therapies targeting these proteins should be considered in the treatment of these patients.
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http://dx.doi.org/10.1097/PAI.0000000000000761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6813876PMC
May 2021

Utility of 15(S)-HETE as a Serological Marker for Eosinophilic Esophagitis.

Sci Rep 2018 09 28;8(1):14498. Epub 2018 Sep 28.

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

The pathogenesis of eosinophilic esophagitis (EoE) involves Th2-mediated eosinophil recruitment and degranulation into the esophagus. However, measuring serum Th2 cytokines, eosinophils, and eosinophil-derived products does not reliably distinguish EoE from control populations. Non-invasive methods to diagnose EoE are lacking. We evaluated the diagnostic value of a novel candidate biomarker of EoE: 15(S)-hydroxyeicosatetraenoic acid (HETE). We used immunoassay to measure 15(S)-HETE and cytokine profiles in patients undergoing endoscopy with known or suspected EoE. 31 subjects were enrolled, 16 with EoE, and 15 with an alternate diagnosis. 15(S)-HETE was elevated in the EoE group compared to non-EoE group. The sensitivity and specificity of 15(S)-HETE to be used as a non-invasive marker is 50% and 80%, respectively. 15(S)-HETE may aid in the diagnosis of EoE.
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http://dx.doi.org/10.1038/s41598-018-32944-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162315PMC
September 2018

ColXα1 is a stromal component that colocalizes with elastin in the breast tumor extracellular matrix.

J Pathol Clin Res 2019 01 1;5(1):40-52. Epub 2018 Nov 1.

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

The tumor microenvironment regulates tissue development and homeostasis, and its dysregulation contributes to neoplastic progression. Increased expression of type X collagen α-1 (ColXα1) in tumor-associated stroma correlates with poor pathologic response to neoadjuvant chemotherapy in estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2)-positive breast cancers. Evaluation of ColXα1 expression patterns suggests a potential connection with elastin fibers. To investigate the possible interaction between ColXα1 and elastin, we evaluated the expression of ColXα1 in relation to elastin fibers in normal breast tissue, ductal carcinoma in situ, and invasive breast carcinomas at cellular and subcellular levels. Our findings demonstrate that ColXα1 colocalizes with elastin in invasive breast cancer-associated stroma by immunohistochemistry, immunofluorescence, and electron microscopy. In 212 invasive breast carcinomas, this complex was aberrantly and selectively expressed in tumor extracellular matrix in 79% of ER+/HER2-, 80% of ER+/HER2+, 76% of ER-/HER2+, and 58% of triple negative breast cancers. In contrast, ColXα1 was generally absent, while elastin was present perivascularly in normal breast tissue. ColXα1 and elastin were coexpressed in 58% of ductal carcinoma in situ (DCIS) in periductal areas. In mass-forming DCIS with desmoplastic stroma, the complex was intensely expressed in periductal areas as well as within the tumor-associated stroma in all cases. Our data suggest that the breast carcinoma neoplastic process may involve aberrant expression of ColXα1 and elastin in the tumor microenvironment emerging early at the DCIS stage. Enrichment of these complexes in tumor-associated stroma may represent a stromal signature indicative of intrinsic differences between breast cancers. These findings shed light on investigation into the role of aberrant collagen complex expression in tumorigenesis and tumor progression which may be leveraged in therapeutic and theranostic applications.
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http://dx.doi.org/10.1002/cjp2.115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6317058PMC
January 2019

Chronic ethanol-mediated hepatocyte apoptosis links to decreased TET1 and 5-hydroxymethylcytosine formation.

FASEB J 2019 02 6;33(2):1824-1835. Epub 2018 Sep 6.

Division of Gastroenterology and Liver Research Center, Rhode Island Hospital, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA.

The 5-hydroxymethylcytosine (5hmc) is a newly identified epigenetic modification thought to be regulated by the TET family of proteins. Little information is available about how ethanol consumption may modulate 5hmC formation and alcoholic liver disease (ALD) progression. A rat ALD model was used to study 5hmC in relationship to hepatocyte apoptosis. Human ALD liver samples were also used to validate these findings. It was found that chronic ethanol feeding significantly reduced 5hmC formation in a rat ALD model. There were no significant changes in TET2 and TET3 between the control- and ethanol-fed animals. In contrast, methylcytosine dioxygenase TET1 (TET1) expression was substantially reduced in the ethanol-fed rats and was accompanied by increased hepatocyte apoptosis. Similarly, knockdown of TET1 in human hepatocyte-like cells also significantly promoted apoptosis. Down-regulation of TET1 resulted in elevated expression of the DNA damage marker, suggesting a role for 5hmc in hepatocyte DNA damage as well. Mechanistic studies revealed that inhibition of TET1 promoted apoptotic gene expression. Similarly, targeting TET1 activity by removing cosubstrate promoted apoptosis and DNA damage. Furthermore, treatment with 5-azacitidine significantly mimics these effects, suggesting that chronic ethanol consumption promotes hepatocyte apoptosis and DNA damage by diminishing TET1-mediated 5hmC formation and DNA methylation. In summary, the current study provides a novel molecular insight that TET1-mediated 5hmC is involved in hepatocyte apoptosis in ALD progression.-Ji, C., Nagaoka, K., Zou, J., Casulli, S., Lu, S., Cao, K. Y., Zhang, H., Iwagami, Y., Carlson, R. I., Brooks, K., Lawrence, J., Mueller, W., Wands, J. R., Huang, C.-K. Chronic ethanol-mediated hepatocyte apoptosis links to decreased TET1 and 5-hydroxymethylcytosine formation.
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http://dx.doi.org/10.1096/fj.201800736RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338639PMC
February 2019

Immune environment in serrated lesions of the colon: intraepithelial lymphocyte density, PD-1, and PD-L1 expression correlate with serrated neoplasia pathway progression.

Hum Pathol 2019 01 31;83:115-123. Epub 2018 Aug 31.

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

The serrated neoplasia pathway accounts for approximately 20% of colorectal carcinomas (CRCs). Sessile serrated adenomas (SSAs), the main precursor lesion of the serrated pathway, are molecularly driven by MLH1 promoter methylation and microsatellite instability (MSI) in their progression to CRC. MSI-high (MSI-H) lesions are highly immunogenic and associated with a high density of tumor-infiltrating lymphocytes. Our study's aim was to determine how the kinetics of this immune environment relates to SSAs in their progression through low-grade (SSA-LD) to high-grade dysplasia (SSA-HD) and CRC. We analyzed 74 cases (16 CRCs, 14 SSAs-HD, and 44 SSAs-LD). Cases of hyperplastic polyp and SSA without dysplasia were analyzed for comparison. MSI status, intraepithelial lymphocyte (IEL) density, and immune checkpoint expression were assessed by immunohistochemistry for mismatch repair proteins, CD3, and PD-1/PD-L1, respectively. Average IEL density was 12, 18.6, 21.6, and 31 for SSA, SSA-LD, SSA-HD, and CRC, respectively, as opposed to 8.1 in normal colon (P < .0001). Average PD-1/PD-L1 lymphocytic expression was 1.1/1.0, 1.2/2.9, 4.8/6.9, and 12.4/15.2 in SSA, SSA-LD, SSA-HD, and CRC, respectively, compared with 0.5/0 in normal crypts (P < .0001). IEL and PD-1/PD-L1 lymphocytic expression values of MSI-H lesions were 22.6, 27.7, and 36.8, and 3/6.5, 6.2/10.6, and 18.3/17.6 in MSI-H SSA-LD, SSA-HD, and CRCs, respectively (P ranged from .0478 to .3529). PD-L1 epithelial expression was positive in 40% of SSAs, 59.1% of SSAs-LD, 100% of SSAs-HD, and 60% of CRCs (P < .0001). Increased IELs and PD-1/PD-L1 expression correlate with sequential progression of SSAs, through development of cytologic dysplasia, to CRC and MSI-H status.
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http://dx.doi.org/10.1016/j.humpath.2018.08.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365194PMC
January 2019

Discordant HER2 immunohistochemical expression and gene amplification in ductal carcinoma in situ - evaluating HER2 in synchronous in-situ and invasive carcinoma.

Histopathology 2019 01 29;74(2):358-362. Epub 2018 Oct 29.

Department of Pathology, Rhode Island Hospital and Lifespan Medical Center, Providence, RI, USA.

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http://dx.doi.org/10.1111/his.13731DOI Listing
January 2019

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

Aspartate beta-hydroxylase promotes cholangiocarcinoma progression by modulating RB1 phosphorylation.

Cancer Lett 2018 08 5;429:1-10. Epub 2018 May 5.

Liver Research Center and the Division of Gastroenterology, Warren Alpert Medical School of Brown University, Rhode Island Hospital, 55 Claverick St, Providence, RI, 02903, USA. Electronic address:

Cholangiocarcinoma (CCA) is a highly lethal and aggressive disease. Recently, IDH1/2 mutations have been identified in approximately 20% of CCAs which suggests an involvement of 2-oxoglutarate (2-OG) -dependent dioxygenases in oncogenesis. We investigated if the 2-OG dependent dioxygenase, aspartate beta-hydroxylase (ASPH) was important in tumor development and growth. Immunoassays were used to clarify how ASPH modulates CCA progression by promoting phosphorylation of the retinoblastoma protein (RB1). A xenograft model was employed to determine the role of ASPH on CCA growth. Knockdown of ASPH expression inhibited CCA development and growth by reducing RB1 phosphorylation. Expression of ASPH promoted direct protein interaction between RB1, cyclin-dependent kinases, and cyclins. Treatment with 2-OG-dependent dioxygenase and ASPH inhibitors suppressed the interaction between RB1 and CDK4 as well as RB1 phosphorylation. Knockdown of ASPH expression inhibited CCA progression and RB1 phosphorylation in vivo and they were found to be highly expressed in human CCAs. Knockdown of ASPH expression altered CCA development by modulating RB1 phosphorylation, as one of the major factors regulating the growth of these tumors.
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http://dx.doi.org/10.1016/j.canlet.2018.04.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985220PMC
August 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

The in vivo performance of a novel thermal accelerant agent used for augmentation of microwave energy delivery within biologic tissues during image-guided thermal ablation: a porcine study.

Int J Hyperthermia 2018 02 24;34(1):11-18. Epub 2017 Apr 24.

a Department of Diagnostic Imaging , Rhode Island Hospital , Providence , RI , USA.

Objectives: To investigate the effects of a novel caesium-based thermal accelerant (TA) agent on ablation zone volumes following in vivo microwave ablation of porcine liver and skeletal muscle, and to correlate the effects of TA with target organ perfusion.

Materials And Methods: This prospective study was performed following institutional animal care and use committee approval. Microwave ablation was performed in liver and resting skeletal muscle in eight Sus scrofa domesticus swine following administration of TA at concentrations of 0 mg/mL (control), 100 mg/mL and 250 mg/mL. Treated tissues were explanted and stained with triphenyltetrazolium chloride (TTC) for quantification of ablation zone volumes, which were compared between TA and control conditions. Hematoxylin and eosin (H&E) staining was also performed for histologic analysis. General mixed modelling with a log-normal distribution was used for all quantitative comparisons (p = 0.05).

Results: A total of 28 ablations were performed in the liver and 18 in the skeletal muscle. The use of TA significantly increased ablation zone volumes in a dose-dependent manner in both the porcine muscle and liver (p < 0.01). Both the absolute mean ablation zone volume and percentage increase in ablation zone volume were greater in the resting skeletal muscle than in the liver. In one swine, a qualitative mitigation of heat sink effects was observed by TTC and H&E staining. Non-lethal polymorphic ventricular tachycardia was identified in one swine, treated with intravenous amiodarone.

Conclusions: The use of a novel TA agent significantly increased mean ablation zone volumes following microwave ablation using a porcine model. The relationship between TA administration and ablation size was dose-dependent and inversely proportional to the degree of target organ perfusion, and a qualitative reduction in heat-sink effects was observed.
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http://dx.doi.org/10.1080/02656736.2017.1317367DOI Listing
February 2018

Human Papillomavirus Genotyping of Incidental Malignant and Premalignant Lesions on Hemorrhoidectomy Specimens.

Am J Surg Pathol 2017 Mar;41(3):382-388

Departments of *Pathology and Laboratory Medicine, Rhode Island Hospital †Pathology and Laboratory Medicine, Women and Infants Hospital of Rhode Island ‡Pathology and Laboratory Medicine §Pathology and Laboratory Medicine, The Miriam Hospital, Alpert Medical School of Brown University, Providence, RI.

Routine histopathologic examination of hemorrhoidectomy specimens is controversial having been described as not useful and expensive with few of these common cases demonstrating incidental lesions. However, unexpected premalignant and malignant lesions have been detected on excised hemorrhoids. The high-risk human papillomavirus (HR-HPV) types associated with these incidentally identified high-grade lesions are presently unknown. We aimed to identify cases of incidental high-grade anal intraepithelial neoplasia (HG-AIN) and anal squamous cell carcinoma incidentally discovered on hemorrhoidectomy specimens, genotype HR-HPVs from these lesions, and assess p53 and p16 expression by immunohistochemistry to identify risk factors for their development. With institutional approval, cases with associated demographics from 1995 to 2015 were reviewed to identify and confirm incidental HG-AIN or squamous cell carcinoma in hemorrhoidectomy specimens. Genotyping for HR-HPV types and immunohistochemical staining for p53 and p16 was performed. Statistical analysis comparing HPV genotypes, p53 and p16 staining, and potential risk factors by the Fisher exact test was performed. In the largest series of incidental high-grade lesions on hemorrhoidectomy, HPV 16 was the most common HR-HPV detected though multiple-type infections were common including some HPV 16/18-negative cases. By genotyping, HPV 39 was significantly associated with IV-drug abuse history (P=0.0015) and HIV-positive status (P=0.037), whereas HPV 58 detection correlated with chemotherapy-induced immunosuppression (P=0.029). There was frequent overlap between p53 staining and HPV positivity, particularly when HPV 31 was detected. We also identified several mimickers of HG-AIN that may present diagnostic challenges in these specimens. Our data support continued routine examination of hemorrhoidectomy specimens and suggest that adjunctive studies such as immunohistochemistry for challenging cases may be useful.
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http://dx.doi.org/10.1097/PAS.0000000000000809DOI Listing
March 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

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

Fatty acid-binding protein 1 is preferentially lost in microsatellite instable colorectal carcinomas and is immune modulated via the interferon γ pathway.

Mod Pathol 2017 01 30;30(1):123-133. Epub 2016 Sep 30.

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

Fatty acid-binding protein 1 (FABP1) is an intracellular protein responsible for the transportation of long chain fatty acids. Aside from its functions in lipid metabolism and cellular differentiation, FABP1 also plays a role in inflammation through its interaction with peroxisome proliferator-activated receptors (PPARs). Previously, we compared expression of colonic epithelium genes in a subset of microsatellite instable (MSI) colorectal carcinomas (medullary carcinomas) to normal colonic mucosa and found that FABP1 expression was markedly decreased in the tumors. Further analysis of RNA expression in the colorectal subtypes and The Cancer Genome Atlas data set found that FABP1 expression is decreased in the CMS1 subset of colorectal carcinomas, which is characterized by microsatellite instability. As MSI colorectal carcinomas are known for their robust immune response, we then aimed to link FABP1 to the immune microenvironment of MSI carcinomas. To confirm the gene expression results, we performed immunohistochemical analysis of a cohort of colorectal carcinomas. FABP1 was preferentially lost in MSI carcinomas (123/133, 93%) compared with microsatellite stable carcinomas (240/562, 43%, P<0.0001). In addition, higher numbers of tumor-infiltrating lymphocytes were present in tumors with loss of FABP1 (P<0.0001). Decreased expression of the fatty acid storage and glucose regulator, PPARγ, was associated with the loss of FABP1 (P<0.0001). Colorectal cancer cell lines treated with interferon γ exhibited decreased expression of FABP1. FABP1 expression was partially recovered with the treatment of the cell lines with rosiglitazone, a PPARγ agonist. This study demonstrated that the loss of FABP1 expression is associated with MSI carcinomas and that interferon γ stimulation plays a role in this process via its interaction with PPARγ.
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http://dx.doi.org/10.1038/modpathol.2016.170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5218856PMC
January 2017

ARID1A alteration in aggressive urothelial carcinoma and variants of urothelial carcinoma.

Hum Pathol 2016 09 30;55:17-23. Epub 2016 Apr 30.

Department of Pathology and Laboratory Medicine, Warren Alpert Medical School of Brown University, Rhode Island Hospital, 593 Eddy St, Providence, RI 02903. Electronic address:

ARID1A mutation leads to loss of the products of this tumor-suppressor gene. Studies demonstrated ARID1A mutation in 20% of stage IV urothelial carcinomas (UCs) with worse prognosis. The expression of ARID1A in aggressive variants of UC is not studied properly. From 2000 to 2015, 81 variants of UC (29 micropapillary, 33 sarcomatoid, 31 small cell, 2 nested, and 3 plasmacytoid variants) were identified in the archives of Rhode Island Hospital. Immunohistochemistry for anti-ARID1A antibody (Sigma-Aldrich, St Louis, MO) was performed. The staining pattern was semiquantitatively scored, and results were analyzed by Fisher exact test (2 tailed) on contingency tables, survival curve, and log-rank test. Patients were predominantly male (78%) with mean age of 67.9 years. The plasmacytoid variant group occurred in younger ages (mean: 54 years). Half of the specimens contained concurrent conventional UCs. Normal urothelium invariably exhibited strong ARID1A nuclear staining. There was no difference in expression between upper and lower tracts. ARID1A expression was lower in the variants compared with conventional UCs (P<.0001). In micropapillary UCs, an inverse correlation between stage and ARID1A expression was noted, with significant correlation between ARID1A expression and overall survival (P=.0221). Sarcomatoid UCs and small cell CCs showed lower ARID1A expression compared with UCs that was not statistically significant, and neither showed any significant correlation with stage or overall survival. ARID1A expression is significantly decreased in higher stages of UC and its aggressive variants; therefore, ARID1A mutation appears to play an important role in the prognosis of UC and its aggressive variants. This finding may have therapeutic implications.
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http://dx.doi.org/10.1016/j.humpath.2016.04.006DOI Listing
September 2016

Medullary carcinoma of the colon: a distinct morphology reveals a distinctive immunoregulatory microenvironment.

Mod Pathol 2016 05 11;29(5):528-41. Epub 2016 Mar 11.

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

Medullary carcinoma of the colon is a unique histologic subtype of microsatellite unstable colorectal carcinoma but little is known regarding its tumor-immunoregulatory microenvironment. The aims of this study were to characterize the immune environment of medullary carcinoma and compare it with other microsatellite unstable and microsatellite stable colorectal carcinomas. An initial gene expression microarray analysis of six cases of medullary carcinoma was used to detect potentially differentially expressed genes. We extended this analysis utilizing genomic data from the Cancer Genome Atlas to compare eight cases of medullary carcinoma with other microsatellite unstable and stable carcinomas. Finally, we evaluated expression of key immune pathway proteins and lymphocyte subsets via immunohistochemistry of a large group of medullary carcinomas (n=105) and compared these findings with three other groups: poorly differentiated, microsatellite unstable well-differentiated and microsatellite stable well-differentiated carcinomas. Microarray and the Cancer Genome Atlas data analysis identified significant upregulation of several immunoregulatory genes induced by IFNγ including IDO-1, WARS (tRNA(trp)), GBP1, GBP4, GBP5, PDCD1 (PD-1), and CD274 (PD-L1) in medullary carcinoma compared with other microsatellite unstable and microsatellite stable tumors. By immunohistochemistry, IDO-1 was expressed in 64% of medullary carcinomas compared with 19% (9/47) of poorly differentiated carcinomas, 14% (3/22) of microsatellite unstable, and 7% (2/30) of the microsatellite stable well-differentiated carcinomas (P<0.0001). tRNA(trp) was overexpressed in 81% (84/104) of medullary carcinomas, 19% (9/47) of poorly differentiated, 32% (7/22) of microsatellite unstable, and 3% (1/30) of microsatellite stable well-differentiated carcinomas (P<0.0001). Medullary carcinoma had higher mean CD8+ and PD-L1+ tumor-infiltrating lymphocytes compared with all other groups (P<0.0001). This study demonstrates overexpression of several immunoregulatory genes in microsatellite unstable colorectal carcinomas and that expression of these genes and proteins is more prevalent in the medullary carcinoma subtype, which may be of use both diagnostically and therapeutically.
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http://dx.doi.org/10.1038/modpathol.2016.54DOI Listing
May 2016