Publications by authors named "Murray B Resnick"

98 Publications

Human-interpretable image features derived from densely mapped cancer pathology slides predict diverse molecular phenotypes.

Nat Commun 2021 03 12;12(1):1613. Epub 2021 Mar 12.

PathAI, Inc., Boston, MA, USA.

Computational methods have made substantial progress in improving the accuracy and throughput of pathology workflows for diagnostic, prognostic, and genomic prediction. Still, lack of interpretability remains a significant barrier to clinical integration. We present an approach for predicting clinically-relevant molecular phenotypes from whole-slide histopathology images using human-interpretable image features (HIFs). Our method leverages >1.6 million annotations from board-certified pathologists across >5700 samples to train deep learning models for cell and tissue classification that can exhaustively map whole-slide images at two and four micron-resolution. Cell- and tissue-type model outputs are combined into 607 HIFs that quantify specific and biologically-relevant characteristics across five cancer types. We demonstrate that these HIFs correlate with well-known markers of the tumor microenvironment and can predict diverse molecular signatures (AUROC 0.601-0.864), including expression of four immune checkpoint proteins and homologous recombination deficiency, with performance comparable to 'black-box' methods. Our HIF-based approach provides a comprehensive, quantitative, and interpretable window into the composition and spatial architecture of the tumor microenvironment.
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http://dx.doi.org/10.1038/s41467-021-21896-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955068PMC
March 2021

Elastin in the Tumor Microenvironment.

Adv Exp Med Biol 2020 ;1272:1-16

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

Elastic fibers are found in the extracellular matrix (ECM) of tissues requiring resilience and depend on elasticity. Elastin and its degradation products have multiple roles in the oncologic process. In many malignancies, the remodeled ECM expresses high levels of the elastin protein which may have either positive or negative effects on tumor growth. Elastin cross-linking with other ECM components and the enzymes governing this process all have effects on tumorigenesis. Elastases, and specifically neutrophil elastase, are key drivers of invasion and metastasis and therefore are important targets for inhibition. Elastin degradation leads to the generation of bioactive fragments and elastin-derived peptides that further modulate tumor growth and spread. Interestingly, elastin-like peptides (ELP) and elastin-derived peptides (EDP) may also be utilized as nano-carriers to combat tumor growth. EDPs drive tumor development in a variety of ways, and specifically targeting EDPs and their binding proteins are major objectives for ongoing and future anti-cancer therapies. Research on both the direct anti-cancer activity and the drug delivery capabilities of ELPs is another area likely to result in novel therapeutic agents in the near future.
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http://dx.doi.org/10.1007/978-3-030-48457-6_1DOI Listing
October 2020

Smooth muscle tumors of the gastrointestinal tract: an analysis of prognostic features in 407 cases.

Mod Pathol 2020 07 12;33(7):1410-1419. Epub 2020 Feb 12.

University of Utah, Salt Lake City, UT, USA.

Smooth muscle tumors represent the second most common mural mesenchymal neoplasm in the gastrointestinal tract, but established criteria for prognostic assessment of these tumors are lacking. A large cohort of surgically resected intramural gastrointestinal smooth muscle tumors from 31 institutions was analyzed to identify potential prognostic features. Pathologic features were assessed by expert gastrointestinal and/or soft tissue pathologists at each center. Immunohistochemical confirmation was required. A total of 407 cases from the esophagus (n = 97, 24%), stomach (n = 180, 44%), small bowel (n = 74, 18%), and colorectum (n = 56, 14%) were identified. Patients ranged in age from 19 to 92 years (mean 55 years), with a slight female predominance (57%). Mean tumor size was 5.4 cm, with the largest tumor measuring 29 cm. Disease progression following surgery, defined as local recurrence, metastasis, or disease-related death, occurred in 56 patients (14%). Colorectal tumors were most likely to progress, followed by small bowel and gastric tumors. None of the esophageal tumors in this series progressed. Receiver operator characteristic analysis identified optimal cutoffs of 9.8 cm and 3 mitoses/5 mm for discriminating between progressive and non-progressive tumors. Histologic features strongly associated with progression by univariate analysis included moderate-to-severe atypia, high cellularity, abnormal differentiation (defined as differentiation not closely resembling that of normal smooth muscle), tumor necrosis, mucosal ulceration, lamina propria involvement, and serosal involvement (P < 0.0001 for all features). Age, sex, and margin status were not significantly associated with progression (P = 0.23, 0.82, and 0.07, respectively). A risk assessment table was created based on tumor site, size, and mitotic count, and Kaplan-Meier plots of progression-free survival for each subgroup revealed progression-based tiers. Based on our findings, it appears that nonesophageal gastrointestinal smooth muscle tumors measuring >10 cm and/or showing ≥3 mitoses/5 mm may behave aggressively, and therefore close clinical follow-up is recommended in these cases.
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http://dx.doi.org/10.1038/s41379-020-0492-5DOI Listing
July 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

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

Retrospective Analysis Confirms Tetracycline Quadruple as Best Helicobacter pylori Regimen in the USA.

Dig Dis Sci 2019 10 11;64(10):2893-2898. Epub 2019 Jun 11.

Division of Gastroenterology, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, 593 Eddy Street, Providence, RI, 02903, USA.

Background: Declining Helicobacter pylori (H. pylori) eradication rates have prompted a switch in first-line therapy from standard triple (PPI, clarithromycin, and amoxicillin) to bismuth-based quadruple therapy. A caveat of the ACG 2017 H. pylori treatment guidelines was a paucity of recent US eradication data.

Aim: To determine Rhode Island H. pylori eradication data, in the largest US study from the last two decades.

Methods: Electronic records were queried for patients with H. pylori infection diagnosed by pathology, urea breath test, or stool antigen from 2015 to 2017. Demographics, diagnostic test, treatment regimen, and test of cure were extracted. Eradication rates were calculated, and treatment regimens were compared.

Results: A total of 1710 patients were identified (64% female): 825 (46%) diagnosed by breath test, 755 (42%) by biopsy, and 191 (12%) by stool antigen. Full data were obtained on 1101 patients. Seven regimens were used: quadruple (64%), triple (25%), doxycycline quadruple (5%), and miscellaneous (6%). Quadruple was superior to triple: (85% vs. 75%, P = 0.002), quadruple 14 days versus triple 14 days (87% vs. 79%, P = 0.0052), quadruple 10 days versus triple 10 days (77% vs. 67%, P = 0.33). Increased therapy length improved eradication (quadruple 14 days  vs. 10 days, 87% vs. 77%, P = 0.002; triple 14 days  versus 10 days 79% vs. 67%, P = 0.13). Finally, substituting doxycycline for tetracycline yielded lower eradication (85% vs. 67%, P = 0.006).

Conclusion: Quadruple therapy is superior to triple therapy within the Rhode Island population. Fourteen-day therapy achieves superior eradication compared to 10-day therapy, and doxycycline is inferior to tetracycline for quadruple therapy. Our findings support adherence to ACG and international guidelines advising 14-day quadruple therapy.
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http://dx.doi.org/10.1007/s10620-019-05694-4DOI Listing
October 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

In reply to Lambein et al.: 'HER2 protein overexpression in non-amplified ductal carcinoma in situ: quality issue or transcription mechanisms gone awry?'

Histopathology 2019 03 15;74(4):666. Epub 2019 Jan 15.

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

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http://dx.doi.org/10.1111/his.13792DOI Listing
March 2019

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

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

Differentiating breast carcinoma with signet ring features from gastrointestinal signet ring carcinoma: assessment of immunohistochemical markers.

Hum Pathol 2018 07 6;77:11-19. Epub 2018 Jan 6.

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

Signet ring morphology is recognized throughout the gastrointestinal tract. However, this pattern may be observed in other primary sites giving rise to diagnostic challenges in the work-up of metastases. Relatively newer immunohistochemical markers have not been evaluated in this context. We assessed expression patterns of several common immunohistochemical markers in tumors with Signet ring morphology to delineate a pragmatic approach to this differential diagnosis. Primary breast and gastrointestinal carcinomas showing Signet ring features were reviewed. Non-mammary and non-gastrointestinal tumors with this morphology were included for comparison. Estrogen receptor (ER), progesterone receptor (PR), E-cadherin, CK7, CK20, GCDFP-15, mammaglobin, CDX2, GATA-3, and HepPar-1 immunohistochemistry was performed. Expression patterns were compared between breast and gastrointestinal tumors as well as lobular breast and gastric tumors. Ninety-three cases were identified: 33 breast carcinomas including 13 lobular, 50 gastrointestinal tumors including 23 gastric, and 10 from other sites. ER (sensitivity=81.8%, specificity=100%, positive predictive value (PPV)=100%, negative predictive value (NPV)=89.3%) and GATA-3 (sensitivity=100%, specificity=98%, PPV=96.8%, NPV=100%) expression were associated with breast origin. CK20 (sensitivity=66.7%, specificity=93.3%, PPV=94.1%, NPV=63.6%) and CDX2 (sensitivity=72%, specificity=100%, PPV=100%, NPV=68.9%) demonstrated the strongest discriminatory value for gastrointestinal origin. These markers exhibited similar discriminatory characteristics when comparing lobular and gastric signet ring carcinomas. In a limited trial on metastatic breast and gastric cases, these markers successfully discriminated between breast and gastric primary sites in 15 of 16 cases. ER and GATA-3 are most supportive of mammary origin and constitute an effective panel for distinguishing primary breast from primary gastrointestinal Signet ring tumors when combined with CK20 and CDX2 immunohistochemistry.
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http://dx.doi.org/10.1016/j.humpath.2018.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6019120PMC
July 2018

Stromal Clusterin Expression Predicts Therapeutic Response to Neoadjuvant Chemotherapy in Triple Negative Breast Cancer.

Clin Breast Cancer 2018 06 19;18(3):e373-e379. Epub 2017 Aug 19.

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

Background: Expression of clusterin correlates with tumor progression and therapeutic response in several human malignancies, including breast cancer. However, its predictive value in the neoadjuvant setting in breast cancer remains unexplored. The objective of this explorative study was to determine whether clusterin expression in breast cancer correlated with clinical pathologic characteristics and whether its expression was predictive of response to neoadjuvant chemotherapy (NAC).

Materials And Methods: We determined the clusterin expression pattern in 72 triple negative breast cancers (TNBC) treated with NAC before surgery. Clusterin expression was evaluated by immunohistochemistry and was correlated with pathologic characteristics and response to NAC using residual cancer burden score.

Results: Immunohistochemistry analysis revealed a differential pattern of expression between tumor and stroma. Clusterin expression in the tumor associated stroma as opposed to expression by the neoplastic epithelium was significantly associated with neoadjuvant-treated TNBC. Low stromal clusterin, low stromal content, and high tumor-infiltrating lymphocytes were associated with a significantly greater likelihood of achieving a good pathologic response as reflected by lower residual cancer burden scores (P = .002, P = .003, and P = .001, respectively). Tumor and/or stromal clusterin expression were not associated with patient age, tumor histologic grade, stage, and lymph node status.

Conculsion: This study suggests a potential role for the assessment of stromal clusterin as a predictive biomarker for response of TNBC to neoadjuvant therapy. Further validation of this biomarker in a large study is needed.
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http://dx.doi.org/10.1016/j.clbc.2017.08.007DOI Listing
June 2018

Clinicopathologic and gene expression analysis of initial biopsies from patients with eosinophilic esophagitis refractory to therapy.

Hum Pathol 2017 10 4;68:79-86. Epub 2017 Sep 4.

Department of Pathology, Johns Hopkins University, Baltimore, MD 21231. Electronic address:

Some patients with eosinophilic esophagitis (EoE) do not respond to therapy. The clinicopathologic characteristics and gene expression profile at time of presentation could help predict response to therapy. Refractory EoE was defined as persistence of symptoms and biopsies with histologic features of EoE after 6 months of therapy with proton pump inhibitors and topical corticosteroids. Initial biopsies from refractory EoE patients (n=21), responder to therapy (n=8), patients who relapsed (n=6), and reflux controls (n=24) were studied. RNA was isolated from a subset of cases, and gene expression analysis of 285 genes involved in inflammation was performed using NanoString technology. There was no difference in the presenting symptoms among groups. The number of eosinophils/high-power field among nonresponders was higher (66±15) than responders (39±8; P<.0001) and similar to patients who relapsed (62±11). Six genes were expressed by at least 4-fold compared with reflux at a false discovery rate < 0.05, including overexpression of ALOX15, CCL26, FCER2, RTNLB, and RNASE2, and underexpression of DSG1. EoE patients refractory to therapy or who relapsed showed a trend toward higher ALOX15 expression compared with patients with good response to therapy (364.4- and 425-fold change, P=.097 and P=.07). RTNLB was significantly overexpressed in patients who were refractory to therapy versus those who responded favorably (10-fold versus 3-fold; P<.01). In conclusion, the number of eosinophils/high-power field in the initial biopsy inversely correlates with therapy response. Overexpression of RTNLB in refractory-to-therapy patients and overexpression of ALOX15 and CCL26 suggest that they are critical in the EoE pathogenesis.
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http://dx.doi.org/10.1016/j.humpath.2017.08.027DOI Listing
October 2017

Role of immune microenvironment in gastrointestinal stromal tumours.

Histopathology 2018 Feb 21;72(3):405-413. Epub 2017 Nov 21.

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

Aims: The immune microenvironment is a prognostic factor for various malignancies. The significance of key players of this immune microenvironment, including tumour-infiltrating lymphocytes (TILs) and expression of programmed death-ligand 1 (PD-L1), indoleamine 2,3-dioxygenase (IDO) and tryptophanyl-tRNA synthetase (WARS) in gastrointestinal stromal tumours (GISTs) is largely unknown.

Methods And Results: Tissue microarrays were constructed from pathology files, 1996-2016. Immunohistochemistry for PD-L1, IDO and WARS was correlated with tumour size, mitoses and outcomes. TILs expressing CD3, CD4, CD8, FoxP3 and GBP5 were counted. A total of 129 GISTs were analysed. Mean patient age was 62.5 years; 52.0% were male. Tumour location included 89 stomach (69.0%), 33 small bowel (25.6%) and seven other (5.4%). Mean tumour size was 5.6 cm; mean mitoses were 7.2 per 50 high-power field. Nineteen patients (15.0%) developed disease progression, to abdominal wall (n = 8), liver (n = 6) and elsewhere (n = 5). Median progression-free survival was 56.6 months; five patients died of disease. PD-L1 was positive in 88 of 127 tumour samples (69.0%), 114 of 127 tumours were IDO-positive (89.8%) and 60 of 127 were positive for WARS (47.2%). PD-L1 was associated with increased size (P = 0.01), necrosis (P = 0.018) and mitoses (P = 0.006). Disease progression was not associated with PD-L1 (P = 0.44), IDO (P = 0.14) or WARS (P = 0.36) expression. PD-L1-positive GISTs with CD8 or CD3 TILs were significantly smaller than tumours with CD8 or CD3 TILs.

Conclusions: PD-L1 expression was associated with increased size and mitoses. High CD8 or CD3 TIL counts were associated with decreased PD-L1/IDO GIST size. PD-L1 and IDO could be significant in GIST tumour biology, which invites consideration of immunotherapy as a potential treatment option.
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http://dx.doi.org/10.1111/his.13382DOI Listing
February 2018

ALOX15 Immunohistochemistry Aids in the Diagnosis of Eosinophilic Esophagitis on Pauci-eosinophilic Biopsies in Children.

Pediatr Dev Pathol 2017 Sep-Oct;20(5):375-380. Epub 2017 Feb 9.

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

Histologically, esophageal biopsies should have ≥15 intraepithelial eosinophils (IEEs) per high power field (HPF) to support a clinicopathologic diagnosis of eosinophilic esophagitis (EoE). Children with clinically apparent EoE may show pauci-eosinophilic biopsies due to patchy involvement. Immunostaining (Immunohistochemistry) for arachidonate-15 lipooxygenase (ALOX15) has been demonstrated to be a sensitive marker for EoE. We retrospectively assessed the expression of ALOX15 in 48 biopsies from 21 patients with established diagnosis of EoE and with tissue fragments below the threshold of 15 IEEs/HPF. Fragments were classified into pauci-eosinophilic and non-pauci-eosinophilic groups using cutoffs of 10 and 15 IEEs/HPF. Controls included patients with reflux and normal biopsies. Sixty-five (43.9%) fragments showed <10 IEEs/HPF and 83 (56.1%) showed ≥10 IEEs/HPF. Using a cutoff of 15 IEEs/HPF, 87 (58.7%) fragments showed <15 IEEs/HPF while 61 fragments (41.2%) had ≥15 IEEs/HPF. ALOX15 was positive in 53/65 (81.5%) of fragments with <10 IEEs/HPF versus 82/83 (98.8%) of fragments with ≥10 IEEs/HPF ( P < .001). For a cutoff of 15 IEEs/HPF, 75/87 (86.2%) of pauci-eosinophilic fragments were ALOX15-positive, while 60/61(98.4%) of biopsies meeting the threshold were positive ( P < .001). In 3/21 (14.3%) patients with EoE, all of the fragments (n = 7) were pauci-eosinophilic and all of them were positive for ALOX15. Two of 24 patients with reflux (one with 9 and one with 14 IEEs/HPF) were also positive. Fragments from normal controls (0 IEEs/HPF) were negative. Our results support the utility of ALOX15 immunohistochemistry in supporting the diagnosis of EoE in rare situations with strong clinical suspicion where no fragments reach 15 IEEs/HPF.
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http://dx.doi.org/10.1177/1093526617693106DOI Listing
May 2019

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

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

The Inflammatory Milieu of Eosinophilic Esophagitis: A Contemporary Review With Emphasis in Putative Immunohistochemistry and Serologic Markers.

Appl Immunohistochem Mol Morphol 2018 08;26(7):435-444

Departments of Pathology and Laboratory Medicine.

Eosinophilic esophagitis is a chronic disease characterized by esophageal dysfunction, frequent clinical history of atopy, and eosinophilic inflammation of the esophagus. Within the esophageal mucosa, there is a wide variety of immune mediators, chemotactic factors, mediators of transcription, and markers of epithelial differentiation and integrity that are overexpressed or underexpressed in eosinophilic esophagitis, offering many candidates for biomarkers with diagnostic or prognostic potential. In this review, we summarize the results from studies performed so far to evaluate the detection of these markers by immunohistochemistry on esophageal biopsies. In addition, we briefly describe some attempts to identify markers that could be detected in serum to be used to diagnose or monitor the disease without the need of a biopsy.
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http://dx.doi.org/10.1097/PAI.0000000000000450DOI Listing
August 2018

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

Identification of stromal ColXα1 and tumor-infiltrating lymphocytes as putative predictive markers of neoadjuvant therapy in estrogen receptor-positive/HER2-positive breast cancer.

BMC Cancer 2016 Apr 18;16:274. Epub 2016 Apr 18.

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

Background: The influence of the tumor microenvironment and tumor-stromal interactions on the heterogeneity of response within breast cancer subtypes have just begun to be explored. This study focuses on patients with estrogen receptor-positive/human epidermal growth factor receptor 2-positive (ER+/HER2+) breast cancer receiving neoadjuvant chemotherapy and HER2-targeted therapy (NAC+H), and was designed to identify novel predictive biomarkers by combining gene expression analysis and immunohistochemistry with pathologic response.

Methods: We performed gene expression profiling on pre-NAC+H tumor samples from responding (no or minimal residual disease at surgery) and non-responding patients. Gene set enrichment analysis identified potentially relevant pathways, and immunohistochemical staining of pre-treatment biopsies was used to measure protein levels of those pathways, which were correlated with pathologic response in both univariate and multivariate analysis.

Results: Increased expression of genes encoding for stromal collagens, including Col10A1, and reduced expression of immune-associated genes, reflecting lower levels of total tumor-infiltrating lymphocytes (TILs), were strongly associated with poor pathologic response. Lower TILs in tumor biopsies correlated with reduced likelihood of achieving an optimal pathologic response, but increased expression of the Col10A1 gene product, colXα1, had greater predictive value than stromal abundance for poor response (OR = 18.9, p = 0.003), and the combination of increased colXα1 expression and low TILs was significantly associated with poor response in multivariate analysis. ROC analysis suggests strong specificity and sensitivity for this combination in predicting treatment response.

Conclusions: Increased expression of stromal colXα1 and low TILs correlate with poor pathologic response in ER+/HER2+ breast tumors. Further studies are needed to confirm their predictive value and impact on long-term outcomes, and to determine whether this collagen exerts a protective effect on the cancer cells or simply reflects other factors within the tumor microenvironment.
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http://dx.doi.org/10.1186/s12885-016-2302-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4835834PMC
April 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

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

Mutation Profiling of Clinically Advanced Cancers Using Next-Generation Sequencing for Targeted Therapy: A Lifespan Experience.

R I Med J (2013) 2015 Oct 1;98(10):16-20. Epub 2015 Oct 1.

Director of the Brown University Oncology Group and Professor of Medicine at the Alpert Medical School of Brown University.

The application of modern molecular tests such as next-generation sequencing (NGS) to human malignancies has led to better understanding of tumor biology and the design of targeted molecular therapies. In the research setting, important genomic alterations in tumors have been discovered with potential therapeutic implications but data regarding the impact of this technology in a real world oncology practice is limited. As a result, we decided to review the results of NGS in 144 advanced-stage cancer patients referred to the oncology practices of Lifespan-affiliated centers in Rhode Island. Most cancers revealed genomic alterations in genes commonly mutated in cancer. However, several unexpected genomic alterations were discovered in certain cancers with potential therapeutic intervention. Most cancers contained "actionable" genomic alterations despite being of advanced stage. Our experience demonstrates that application of NGS in the clinical setting contributes both to increasing the therapeutic armamentarium as well as our understanding of tumor biology.
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October 2015

Advances in the Molecular Profiling of Tumor Tissue.

R I Med J (2013) 2015 Oct 1;98(10):15. Epub 2015 Oct 1.

Assistant Professor of Medicine, Division of Hematology/ Oncology, at The Warren Alpert Medical School of Brown University.

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October 2015

Mucinous cystic neoplasm of the pancreas with increased IgG4+ plasma cells and histopathologic features of autoimmune pancreatitis/IgG4-related disease.

Pancreas 2015 May;44(4):674-6

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

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http://dx.doi.org/10.1097/MPA.0000000000000296DOI Listing
May 2015

Cadherin 17 is a sensitive and specific marker for metanephric adenoma.

Am J Surg Pathol 2015 Apr;39(4):479-86

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

Metanephric adenoma (MA) is a rare benign renal neoplasm that shares morphologic and immunophenotypic overlap with epithelial-predominant Wilms tumor (e-WT) and with the solid variant of papillary renal cell carcinoma (s-PRCC). Cadherin 17 (CDH17) is expressed primarily in the normal intestine and digestive tract tumors and has not been detected in tumors from other sites including the kidney. We investigated the diagnostic utility of CDH17 in differentiating between MA, e-WT, and s-PRCC. Immunohistochemical analysis for CDH17, CD57, AMACR, WT-1, and CDX2 was performed on 17 e-WTs, 15 s-PRCCs, and 21 MAs and assessed on the basis of a combined score of extent and intensity. Normal adult kidney parenchyma was negative for CDH17 staining. CDH17 was expressed in the late stages of fetal kidney development at the junction of the glomerular space and proximal nephron. The majority of MAs (81%) demonstrated membranous CDH17 immunoreactivity in all components (acinar, tubular, and papillary), whereas all cases of e-WTs and s-PRCCs were negative (P<0.0001). WT-1 was negative in s-PRCC and was positive in all cases of e-WT and MA. All MAs were strongly positive for CD57; however, this marker was also moderate to strongly positive in 6 (35%) e-WTs and 2 (13%) s-PRCCs. AMACR was strongly positive in all s-PRCCs, but moderate reactivity was seen in 3 (17%) e-WTs and 2 MAs (10%). CDH17 is a sensitive (81%) and highly specific (100%) marker for MA and should be considered in the immunohistochemistry panel for distinguishing MA from its mimics.
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http://dx.doi.org/10.1097/PAS.0000000000000401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4360917PMC
April 2015