Ricardo V. Lloyd

University of Wisconsin–Madison, Madison, Wisconsin, United States

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Publications (412)1448.62 Total impact

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    ABSTRACT: Purpose: Notch1, a trans-membrane receptor, has been recently shown to aid in the determination of thyroid cell fate associated with tumorigenesis. The present study aimed to investigate the clinical relevance of Notch1 and its role in the regulation of differentiated thyroid cancer (DTC) behavior. Experimental design: We examined Notch1 expression level and its relationship with clinicopathologic features and outcomes of DTC. Notch1 intracellular domain (NICD) was further characterized both in vitro and in vivo by gain-of-function assays using an inducible system. Results: Notch1 expression levels were down-regulated in primary DTC tissue samples compared with contralateral non-tumor and benign thyroid tissues. Decreased Notch1 expression in DTC was associated with advanced patient age (p=0.032) and the presence of extrathyroidal invasion (p=0.005). Patients with lower Notch1 expression had a significantly higher recurrence rate (p=0.038). Restoration of NICD in a stably doxycycline-inducible metastatic DTC cell line reduced cell growth and migration profoundly. Using an orthotopic thyroid cancer model, NICD induction significantly reduced the growth of the primary thyroid tumor and inhibited the development of lung metastasis.SERPINE1 was discovered by microarray as the most significant gene down-regulated by NICD. Further validation showed that induction of NICD reduced SERPINE1 expression in a dose-dependent manner while restoration of a relative higher level of SERPINE1was observed with NICD back to minimal level. Additionally, SERPINE1 knock-down inhibited DTC cell migration. Conclusions: Notch1 regulates the aggressive phenotypes of DTC, which could be mediated by SERPINE1 inhibition. Notch1/SERPINE1 axis warrants further investigation as a novel therapeutic target for advanced DTC.
    No preview · Article · Feb 2016 · Clinical Cancer Research
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    Ranran Zhang · Heather Hardin · Jidong Chen · Zhenying Guo · Ricardo V. Lloyd
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    ABSTRACT: Non-coding (nc)RNAs are divided into small ncRNAs and long ncRNAs (lncRNAs). MicroRNAs (miRNAs) are small ncRNAS which are around 22 nucleotides in length that mediate post-transcriptional gene silencing. LncRNAs are greater than 200 bp in length. Each ncRNA can have multiple targets and can be regulated by multiple genetic factors. Because ncRNAs are not translated into proteins, they can only be detected at the nucleic acid level by in situ hybridization, by RT-PCR, or by sequencing which makes their detection more challenging in the routine pathology laboratory. A great deal of new information has accumulated about miRNAs in thyroid tissues during the past decade. Some of these studies have shown that deregulation of miRNAs may be useful in diagnostic pathology. Information about the role of lncRNA in the development of thyroid tumors is in the early stages of development, but new information is accumulating rapidly. In this review, we will discuss the recent progress in our understanding of the relationship between ncRNAs and the development of thyroid cancers and the potential uses of ncRNAs in the diagnosis and prognosis of thyroid tumors.
    Full-text · Article · Feb 2016 · Endocrine Pathology
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    ABSTRACT: Despite the established role of Ki67 labeling index in prognostic stratification of adrenocortical carcinomas and its recent integration into treatment flow charts, the reproducibility of the assessment method has not been determined. The aim of this study was to investigate interobserver variability among endocrine pathologists using a web-based virtual microscopy approach. Ki67-stained slides of 76 adrenocortical carcinomas were analyzed independently by 14 observers, each according to their method of preference including eyeballing, formal manual counting, and digital image analysis. The interobserver variation was statistically significant (P<0.001) in the absence of any correlation between the various methods. Subsequently, 61 static images were distributed among 15 observers who were instructed to follow a category-based scoring approach. Low levels of interobserver (F=6.99; Fcrit=1.70; P<0.001) as well as intraobserver concordance (n=11; Cohen κ ranging from -0.057 to 0.361) were detected. To improve harmonization of Ki67 analysis, we tested the utility of an open-source Galaxy virtual machine application, namely Automated Selection of Hotspots, in 61 virtual slides. The software-provided Ki67 values were validated by digital image analysis in identical images, displaying a strong correlation of 0.96 (P<0.0001) and dividing the cases into 3 classes (cutoffs of 0%-15%-30% and/or 0%-10%-20%) with significantly different overall survivals (P<0.05). We conclude that current practices in Ki67 scoring assessment vary greatly, and interobserver variation sets particular limitations to its clinical utility, especially around clinically relevant cutoff values. Novel digital microscopy-enabled methods could provide critical aid in reducing variation, increasing reproducibility, and improving reliability in the clinical setting.
    No preview · Article · Dec 2015 · The American journal of surgical pathology
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    ABSTRACT: Introduction: INSM1 is a transcription factor associated with terminal differentiation of neuroendocrine (NE) tissue. Previous work demonstrated diagnostic and prognostic utility in evaluating expression of INSM1 in neuroendocrine neoplasms (NENs). The developmental role of Insm1 varies in different subtypes of endocrine tissue (eg, pancreatic A-cells versus B-cells). As the functional status of NENs often carries clinical and prognostic significance, we use molecular and in silico techniques to correlate INSM1 expression with hormone production in functional NENs. Methods: We used qRT-PCR to assess INSM1 mRNA expression in gastrointestinal neuroendocrine neoplasms (GI-NENs), pancreatic neuroendocrine neoplasms (PanNENs), and pituitary NENs. INSM1 transcription factor binding sites were predicted using public databases and software. 2.5 kilobases of the upstream promoter region of selected genes were downloaded from the UCSC genome browser (http://genome.ucsc.edu) and analyzed for predicted INSM1 binding sites using the JASPAR online software (http://jaspar.genereg.net/). Conservation of the binding sites was estimated using conservation tools in the UCSC genome browser. Results: In Pan-NENs, INSM1 is highly expressed in B-cell, and G-cell neoplasms, intermediate in A-cell neoplasms, and diminished in D-cell and PP secreting neoplasms. Non-functional neoplasms show a range of INSM1 expression. In pituitary neoplasms, mixed neoplasms express lower levels of INSM1, whereas neoplasms secreting a single hormone express higher levels of INSM1. GI-NENs of the foregut express dramatically higher levels of INSM1 than those of the midgut or hindgut. Those lesions with proven metastasis express INSM1 at increased levels. Expression levels do not correlate with serum chromogranin (CGA) levels. We find putative INSM1 binding sites in the promoter regions of a number of genes related to neuropeptide hormone production. Higher numbers of putative binding sites correlate with increased expression of INSM1 in neoplasms with a corresponding secretory profile. Conclusions: In hormone producing neuroendocrine neoplasms, we find that INSM1 expression level correlates with hormonal subtype, and that loss or diminished expression of INSM1 often correlates with loss or diminished production of functional hormone. Loss of hormone production by neuroendocrine neoplasms also often correlates with dedifferentiation and worsened clinical outcomes. Quantitative evaluation of INSM1 may add valuable prognostic information in the assessment of NENs.
    No preview · Poster · Nov 2015
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    ABSTRACT: Objectives: Neuroendocrine neoplasms (NENs) are heterogeneous neoplasms, which are sometimes malignant, although predicting metastasis is difficult. INSM1 is a transcription factor expressed transiently in embryonic neuroendocrine (NE) tissue, thought to coordinate termination of cell division with differentiation of NE and neuroepithelial cells. In adult tissues, INSM1 has been identified in multiple tumors of NE or neuroepithelial origin but has not been thoroughly investigated as a potential neoplastic marker. Methods: We evaluated INSM1 as a semiquantitative immunohistochemical (IHC) marker for NE and neuroepithelial neoplasms and as a quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) marker for gastrointestinal NENs (GI-NENs). Results: Using IHC, we found in normal adult tissue that INSM1 expression was highly restricted to nuclei of NE cells and tissues. INSM1 was not detected in any adult nonneoplastic, non-NE tissue. In neoplastic tissue, INSM1 was detectable by IHC in 88.3% of 129 NEN specimens. In contrast, INSM1 was detected by IHC in only one of 27 neoplasms without a neuroepithelial or NE component. Using qRT-PCR, we evaluated INSM1 gene expression in 113 GI-NEN specimens. Conclusions: INSM1 expression was significantly increased in neoplastic vs nonneoplastic tissue. Furthermore, among midgut GI-NENs, neoplasms with known metastases showed significantly higher expression than those that had not yet metastasized.
    No preview · Article · Oct 2015 · American Journal of Clinical Pathology
  • Zhenying Guo · Ricardo V Lloyd
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    ABSTRACT: Pheochromocytomas are uncommon neuroendocrine tumors arising in the adrenal medulla, whereas paragangliomas arise from chromaffin cells in sympathetic and parasympathetic locations outside of the adrenal gland. Molecular genetic studies in the past few years have identified >10 genes involved in the pathogenesis of pheochromocytomas and paragangliomas, including RET oncogene, involved in the pathogenesis of multiple endocrine neoplasia (MEN) 2A and 2B, von Hippel-Lindau tumor-suppressor gene, neurofibromatosis type 1 gene, succinate dehydrogenase, THEM127, and several others. The presence of genetic alterations in some of these genes such as in MEN 2A and 2B can be used to diagnose these disorders clinically, and other mutations such as succinate dehydrogenase can be used in the pathologic prediction of benign and malignant pheochromocytomas and paragangliomas. Although it has been difficult to separate benign and malignant pheochromocytomas and paragangliomas, recent studies that may predict the behavior of these chromaffin-derived neoplasms have been reported. The Pheochromocytoma of the Adrenal Scale Score and the Grading system for Adrenal Pheochromocytoma and Paraganglioma scoring system are also discussed.
    No preview · Article · Sep 2015 · Advances in anatomic pathology
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    ABSTRACT: Amyloid is a characteristic histologic feature in medullary thyroid carcinomas (MTC). We utilized a novel mass spectrometry-based proteomic analysis to determine if we could identify specific proteins associated with amyloid in MTC. We studied 9 MTC (1 multiple endocrine neoplasia type 2A, 1 familial MTC, and 7 sporadic). Laser microdissection was utilized to sample the amyloid which was then trypsin digested and evaluated by liquid chromatography electrospray tandem MS (LC-MS/MS) which identified the presence of amyloidogenic proteins in all cases of MTC. High levels of calcitonin were identified in all 9 cases of MTC. Secretogranin-1 was identified in 6 of 9 MTC. Calcitonin gene-related peptide was identified in 4 of 9 cases of MTC. LC-MS/MS proteomic analysis provides a rapid, highly specific, and sensitive method for identification of the specific type of amyloid in these endocrine tumors. This approach may allow classification of different forms of endocrine amyloid present in neuroendocrine tumors.
    No preview · Article · Aug 2015 · Endocrine Pathology
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    ABSTRACT: Some thyroid nodules such as follicular adenomas (FAs), follicular variant of papillary thyroid carcinomas (FVPTCs), and follicular thyroid carcinomas (FTCs) exhibit similar clinical presentations and gross morphologic appearances. The differential diagnosis of these lesions is sometimes difficult based on morphologic, cytologic, or clinical features alone. miR-146b-5p and miR-21 deregulation has been associated with progression and metastasis of thyroid cancers. However, the utility of in situ hybridization (ISH) to determine the cellular localization, diagnostic, and prognostic significance of miR-146b-5p and miR-21 expression in thyroid tumors has not been extensively analyzed. In order to examine the expression of miR-146b-5p and miR-21 in benign and malignant thyroid tissues and to determine if these microRNAs could be assigned to distinct histomorphological types of thyroid nodules, we analyzed miR-146b-5p and miR-21 expression in thyroid nodules on tissue microarrays (TMAs) with 193 thyroid specimens by ISH. miR-146b-5p and miR-21 expression in thyroid tissues was also analyzed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). miR-146b-5p was highly expressed (89 %) in papillary thyroid carcinomas (PTCs) and 41 % of FVPTC. The expression of miR-146b-5p was not expressed in most FTCs, anaplastic thyroid carcinomas (ATCs), poorly differentiated thyroid carcinomas (PDTCs), or FAs (7, 8, 0, and 0 %, respectively). MiR-21 was overexpressed in 83 % of ATCs, 79 % of PTCs, 34 % of FVPTCs, and 19 % of PDTCs. The expression of miR-21 was not expressed in most FAs (9 %) or FTCs (4 %). Normal thyroid tissues and most benign goiters were negative for miR-146b-5p and miR-21. qRT-PCR analysis supported the ISH findings. PTC cases with positive expression of miR-146b-5p and miR-21 had significantly poorer disease-free survival rates. Immunohistochemical staining for HBME-1 showed positive staining in PTCs (100 %) and FVPTCs (92 %) with a subset of FTC (40 %) staining positive, while all FAs were negative. Since miR-146b-5p was mainly expressed in PTC including FVPTC and was not expressed in most FTC, PDTC, or ATC, it may serve as a useful diagnostic marker for PTC. ISH is a useful method to analyze microRNA expression in formalin-fixed paraffin-embedded thyroid tissues.
    Full-text · Article · Mar 2015 · Endocrine Pathology
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    ABSTRACT: Background: INSM1 is a transcription factor associated with terminal differentiation of neuroendocrine (NE) tissue. We previously demonstrated diagnostic and prognostic utility in evaluating expression of INSM1 in neuroendocrine neoplasms (NENs). Others have shown the role of INSM1 varies in different subtypes of endocrine tissue (e.g. pancreatic α cells versus β cells). As the functional status of NENs often carries clinical and prognostic significance, we examine the correllation between INSM1 expression and hormone production in functional NENs. Design: Immunohistochemistry (IHC) for INSM1 and pancreatic peptide hormones was performed on 21 pancreatic neuroendocrine neoplasms (Pan-NENs) from a variety of sub-types (6 non-functional, 7 β-cell, 1 α-cell, 2 G-cell, and 2 ∆-cell in pancreas). In 9 pituitary neoplasms, INSM1 IHC was correlated with IHC for prolactin (PRL), growth hormone (GH), and adrenocorticotropic hormone (ACTH). We used a tissue microarray and Vectra imaging software to semi-quantitatively assess IHC expression of INSM1 in 39 adrenal pheochromocytomas, 29 extra-adrenal pheochromocytomas (paragangliomas), and 8 normal adrenal medullas as controls. We used qRT-PCR to quantitatively assess INSM1 expression in 34 GI-NENs. We correlate our expression data with clinical features and laboratory values. Results: In Pan-NEN, INSM1 is highly expressed in β-cell, α-cell, and G-cell neoplasms, but is diminished or lost in 2/2 ∆-cell and 2/6 non-functional neoplasms. All 4 cases have proven metastases. In pituitary NEN, INSM1 is lost in 2/9 neoplasms, both of which have lost or diminished PRL staining. INSM1 is detected by IHC in 31/39 pheochromocytomas and 26/29 paragangliomas, and staining is diminished in neoplasms compared to benign adrenal medulla (p = 0.01). INSM1 expression is strongest in neoplasms that produce epinephrine, intermediate in mixed and nonfunctional neoplasms, and weakest in neoplasms that produce norepinephrine or dopamine. Diminished INSM1 expression corresponds with increased tendency for metastasis. In GI-NENs, increased expression of INSM1 mRNA corresponds with elevated serum CGA levels. Conclusions: In hormone producing neoplasms, loss or diminished expression of INSM1 often correlates with loss or diminished production of functional hormone. Loss of hormone production by neuroendocrine neoplasms also often correlates with dedifferentiation and worsened clinical outcomes. Evaluation of INSM1 may add valuable prognostic information in the assessment of NENs.
    No preview · Poster · Mar 2015
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    ABSTRACT: Background: The significance of neural differentiation in Ewing sarcoma remains uncertain. INSM1 is a transcriptional repressor implicated in terminal differentiation of neural and neuroepithelial cells, and has emerged as a novel immunohistochemical (IHC) marker for neuroepithelial and neuroendocrine tumors. Expression of INSM1 in Ewing sarcoma (EWS) has not been investigated. To better understand the possible role of neural differentiation in this tumor, we tested a panel of genetically confirmed cases of EWS, with and without microscopic evidence of neural phenotype, and other small round cell sarcomas for expression of INSM1 by IHC. Design: Cases included 23 EWS (14 bone, 9 extraskeletal), 3 desmoplastic small round cell tumors (DSRCTs), 7 alveolar rhabdomyosarcomas (ARMS), 4 embryonal rhabdomyosarcomas (ERMS), 10 poorly-differentiated synovial sarcomas (SS), 1 mesenchymal chondrosarcoma (MCS) and 11 medulloblastomas/central primitive neuroectodermal tumors (cPNETs). After confirmation of diagnosis, whole sections were analyzed for INSM1 expression by IHC. Nuclear staining was scored based on pattern as negative (<5%), focal (5-25%) or diffuse (>25%) and intensity from 1(+) to 3(+). Morphologic evidence of neural differentation such as Homer Wright rosettes was noted. Genetic, clinical and outcome data were collected. Results: All genetically confirmed Ewing sarcomas were negative for INSM1 expression, irrespective of the presence of Homer Wright rosettes (0/23). In contrast, INSM1 staining was strongly, diffusely positive in 10/11 (91%) of medulloblastomas/cPNETs. INSM1 expression was also noted in 3/7 ARMS (2 focal, 1 diffuse) and 1/3 DSRCT (focal). All other tumors including ERMS, SS, and MCS were negative for this marker. Conclusions: INSM1 is not expressed in EWS, irrespective of microscopic evidence of neural phenotype, possibly because EWS cells do not reach terminal neural differentiation regulated by INSM1. INSM1 is highly expressed in medulloblastomas/ cPNETs but its expression is rare in other translocation-associated round cell sarcomas. INSM1 expression in ARMS merits further investigation.
    No preview · Conference Paper · Feb 2015
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    ABSTRACT: Background: Merkel cell carcinoma (MCC) is a rare, clinically aggressive, cutaneous neuroendocrine (NE) neoplasm. As a tumor with small, round, blue cells, the differential diagnosis for MCC can include melanoma, metastatic small cell carcinoma, nodular hematopoietic tumors, basal cell carcinoma and atypical variants of squamous cell carcinoma. Immunohistochemistry is essential to the definitive diagnosis of MCC, and in difficult cases the diagnosis may hinge entirely on the immunoprofile of the tumor cells. INSM1 is a transcription factor expressed in tissues undergoing terminal NE differentiation. As a nuclear protein tied both to differentiation and the cell-cycle, INSM1 may offer utility over traditional, cytoplasmic markers of NE differentiation. Design: 15 cases of MCC and 17 non-MCC specimens (including melanoma, basal cell carcinoma, squamous carcinoma, metastatic small cell NE carcinoma, and hematopoietic malignancy) were selected from tissue archives (2007 – 2014). Non-MCC specimens were selected for their potential diagnostic confusion with MCC. Cases were confirmed by H&E and were evaluated for INSM1 expression using an established protocol. INSM1 expression was evaluated for both intensity (0 – 3+) and pattern (focal, patchy, diffuse). Results: Patients had a mean age at diagnosis of 73 (range: 61 - 89), and a male predilection of 5.5 to 1. INSM1 was detected in 14/15 MCC specimens (93%), demonstrating diffuse 2/3+ nuclear positivity. The single specimen that was negative for INSM1 was also negative for CK20, chromogranin A (CGA) and synaptophysin. Normal tissue was consistently negative for INSM1 expression, including squamous epithelium, melanocytes, adnexae, and lymphoid tissue. Among non-MCC neoplasms, only other NE neoplasms (e.g. small cell NE carcinoma) expressed INSM1. We compared INSM1 to other markers of NE differentiation, including CGA and synaptophysin. Conclusions: INSM1 is a sensitive marker of MCC, with strong nuclear expression. The nuclear expression pattern makes INSM1 staining easier to interpret and distinguish from background or artifactual staining. INSM1 functions in both the cell-cycle and differentiation, which may help elucidate the mechanism of disease and the associated Merkel cell polyoma virus. IHC for INSM1 is an attractive new tool in the diagnosis of MCC.
    No preview · Poster · Feb 2015
  • Jason Nathaniel Rosenbaum · Ricardo V. Lloyd
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    ABSTRACT: Pancreatic neuroendocrine neoplasms (Pan-NENs) are rare but clinically important lesions. Pan-NENs are known for and often categorized by their capacity to produce clinical syndromes mediated by the production of hormones. Despite sometimes presenting dramatically from excessive hormone production, not all Pan-NENs produce functional hormone, and they can pose diagnostic challenges to practicing pathologists. Distinguishing Pan-NENs from mimics can be crucial, because Pan-NENs carry different prognoses and have unique treatments available due to their specific biological properties. This article reviews the current categorization and features of Pan-NENs.
    No preview · Article · Dec 2014 · Surgical Pathology Clinics
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    ABSTRACT: The diagnosis of malignant thyroid tumors in some cytologic and histologic specimens remains challenging. High-mobility group A2 (HMGA2) expression and insulin-like growth factor II mRNA-binding protein-3 (IMP3) expression were evaluated by relative quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The aim of this study was to evaluate whether the combination of HMGA2 and IMP3 qRT-PCR was diagnostically useful in differentiating benign from malignant thyroid neoplasms. Fine-needle aspiration (FNA) specimens from 120 patients including 56 benign lesions and 64 carcinomas were used. The available 80 corresponding formalin-fixed paraffin-embedded (FFPE) thyroid tissues from 66 patients were also included in this study. HMGA2 and IMP3 expression levels were detected by qRT-PCR and reported as relative fold change after normalizing with a calibrator. The diagnostic utilities of HMGA2 and IMP3 qRT-PCR tests were evaluated individually and in combination. In FNA specimens, HMGA2 and IMP3 expression was consistently higher in thyroid malignancies compared with benign lesions in all subgroups except in Hürthle cell tumors. After exclusion of Hürthle cell tumors, the sensitivity was 90.2% for HMGA2, 88.2% for IMP3, and 98% for HMGA2+IMP3; the specificity was 97.1% for HMGA2, 79.4% for IMP3, and 79.4% for HMGA+IMP3. qRT-PCR data showed similar results in FFPE tissues: the sensitivity was 84.2% for HMGA2, 85.7% for IMP3, and 94.7% for HMGA2+IMP3; the specificity was 96.9% for HMGA2, 91.2% for IMP3, and 90.6% for HMGA2+IMP3. qRT-PCR data were concordant between FNA and FFPE samples for HMGA2 (97.4%) and IMP3 (96.9%). The results indicate that HMGA2 qRT-PCR with high specificity may be a useful ancillary technique to assist in the classification of difficult thyroid specimens, excluding Hürthle cell tumors. The HMGA2 and IMP3 qRT-PCR combination model with increased sensitivity and negative predictive value (96.4%) may be useful in screening thyroid cytology specimens.
    No preview · Article · Oct 2014 · Applied immunohistochemistry & molecular morphology: AIMM / official publication of the Society for Applied Immunohistochemistry
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    ABSTRACT: Anaplastic thyroid cancer (ATC), accounting for less than 2% of all thyroid cancer, is responsible for the majority of death from all thyroid malignancies and has a median survival of 6 months. The resistance of ATC to conventional thyroid cancer therapies, including radioiodine and thyroid-stimulating hormone suppression, contributes to the very poor prognosis of this malignancy. This review will cover several cellular signaling pathways and mechanisms, including RET/PTC, RAS, BRAF, Notch, p53, and histone deacetylase, which are identified to play roles in the transformation and dedifferentiation process, and therapies that target these pathways. Lastly, novel approaches and agents involving the Notch1 pathway, nuclear factor κB, Trk-fused gene, cancer stem-like cells, mitochondrial mutation, and tumor immune microenvironment are discussed. With a better understanding of the biological process and treatment modality, the hope is to improve ATC outcome in the future.
    Preview · Article · Sep 2014 · The Oncologist
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    ABSTRACT: Introduction Follicular variant of papillary thyroid cancer (FVPTC) is the most common and fastest growing subtype of papillary thyroid cancer (PTC) with features of both PTC and follicular thyroid cancer (FTC). The purpose of this study was to determine the patient and tumor features associated with lymph node metastases (LNM) in FVPTC. Methods This was a retrospective review of adult (≥18) patients with histologically confirmed diagnoses of FVPTC within the SEER database between 1988 and 2009. LNM were defined by at least two lymph nodes with metastatic disease. To determine factors associated with LNM, we constructed a multivariate logistic regression model from significant variables (p
    No preview · Article · Aug 2014 · Annals of Surgical Oncology
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    ABSTRACT: Histological and cytological criteria in predicting clinical outcomes in patients with oncocytic poorly differentiated carcinoma (PDC) of the thyroid were investigated. In a set of 102 PDC patients, we performed a computer-assisted evaluation of cell size based on two different methods. Univariate analysis showed that cell size was a discriminant prognostic parameter in oncocytic PDC (30 cases) but not in the non-oncocytic carcinomas cases (72 cases). Patients with oncocytic PDC with small medium cell size had a significantly increased risk of death (p=0.029) and a decrease of disease-free survival (p=0.014). This correlation was absented in cases of non-oncocytic PTC, where age and extensive vascular invasion were significant indicators of progression. The proposed morphological signature shows a robust discriminatory ability when tested on the oncocytic PDC group and cell size assessment could thus be proposed as an inexpensive and readily evaluable parameter for predicting prognosis and planning therapy in this tumor type.
    Full-text · Article · Jul 2014 · Human pathology
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    ABSTRACT: Thyroid carcinoma is the most common endocrine malignancy, and papillary thyroid carcinoma represents the most common thyroid cancer. Papillary thyroid carcinomas that invade locally or metastasize are associated with a poor prognosis. We found that, during epithelial-mesenchymal transition (EMT) induced by transforming growth factor-β1 (TGF-β1), papillary thyroid carcinoma cells acquired increased cancer stem cell-like features and the transcription factor paired-related homeobox protein 1 (PRX-1; alias PRRX1), a newly identified EMT inducer, was markedly up-regulated. miR-146b-5p was also transiently up-regulated during EMT, and in siRNA experiments miR-146b-5p had an inhibitory role on cell proliferation and invasion during TGF-β1-induced EMT. We conclude that papillary thyroid carcinoma tumor cells exhibit increased cancer stem cell-like features during TGF-β1-induced EMT, that miR-146b-5p has a role in cell proliferation and invasion, and that PRRX1 plays an important role in papillary thyroid carcinoma EMT and disease progression.
    Full-text · Article · Jun 2014 · American Journal Of Pathology
  • Ricardo V. Lloyd · Long Jin · Darya Buehler · Heather Hardin · Weihua Shan
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    ABSTRACT: Many recent advances have been made in elucidating the molecular pathology of endocrine tumors. Multiple approaches such as fluorescence in situ hybridization, polymerase chain reaction, comparative genomic hybridization, and loss of heterozygosity analyses have led to many new discoveries and allowed correlation of traditional morphological and immunohistochemical findings with new molecular discoveries. New findings have included BRAF mutations and their prognostic significance in thyroid cancers, multiple mutations including MEN2A and MEN2B in medullary thyroid carcinomas and pheochromocytomas and succinic dehydrogenase mutations in pheochromocytomas and paragangliomas. Gene expression profiling and genomic analyses have provided a great deal of new information that is currently being analyzed to determine their significance in personalized medicine © Springer Science+Business Media New York 2013. All rights are reserved.
    No preview · Chapter · May 2014
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    Ricardo V. Lloyd · Zhenying Guo · Heather Hardin
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    ABSTRACT: Thyroid cancer is one of the most rapidly increasing malignancies. The reasons for this increase is not completely known, but increases in the diagnosis of papillary thyroid microcarcinomas and follicular variant of papillary thyroid carcinomas along with the enhanced detection of well differentiated thyroid carcinomas are probably all contributing factors. Although most cases of well differentiated thyroid carcinomas are associated with an excellent prognosis, a small percentage of patients with well differentiated thyroid carcinomas as well as most patients with poorly differentiated and anaplastic thyroid carcinomas have recurrent and/or metastatic disease that is often fatal. The cancer stem cell model suggests that a small number of cells within a cancer, known as cancer stem-like cells, are responsible for resistance to chemotherapy and radiation therapy, as well as for recurrent and metastatic disease.. In this review we will focus on current studies about thyroid cancer stem-like cells, the processes of epithelial to mesenchymal transition, and mesenchymal to epithelial transition that provide plasticity to cancer stem-like cell growth in addition to the role of microRNAs in cancer stem cell development and regulation. Understanding the biology of cancer stem cells, epithelial to mesenchymal transition and the metastatic cascade should lead to the design of more rational targeted therapies for highly aggressive and fatal thyroid cancers.
    Full-text · Article · Apr 2014 · Endocrine Related Cancer
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    ABSTRACT: Background: INSM1 is a transcription factor expressed during the normal development of neuroendocrine tissues and neuroepithelia. Molecular detection of INSM1 has been demonstrated throughout neural and neuroendocrine tissue in developing embryos. In adults, INSM1 has only been detected in neoplasms. The spatio-temporal restriction of INSM1 expression makes it an attractive candidate as a tumor marker, and confers advantages over traditional neuroendocrine markers. Design: INSM1 is detected by immunohistochemistry (IHC) using a commercial antibody and established protocol. The antibody is validated on fetal autopsy tissue. Selecting specimens from the University of Wisconsin Department surgical pathology archives, we assay a spectrum of neuroendocrine and non-neuroendocrine neoplasms (Table 1). We grade the degree of staining from 0 - 3. Quantitative expression of INSM1 for a subset of samples is evaluated using qRT-PCR, and correlated IHC. INSM1 is directly compared against traditional neuroendocrine markers chromogranin and synaptophysin. Results: Nuclear expression of INSM1 is detected in fetal neuroendocrine tissue. Among the adult tissues tested, INSM1 is detected in most neural and neuroendocrine neoplasms, and is not detected in non-neuroendocrine tumors or most healthy tissues (Table 1). INSM1 is detected, though, in non-neoplastic pancreatic islets and Kulchitsky cells. Qualitiative analysis of IHC correlates closely with quantitative detection of INSM1 expression levels by qRT-PCR. Table 1. Neoplasms Staining with INSM1 Tumor Type Specimens Staining Positively / Total Specimens Carcinoid (Lung) 6 / 6 Esthesioneuroblastoma 1 / 1 GI-NEN (GI carcinoid) 11 / 16 Hypothalamic Hamartoma 0 / 1 Large Cell NE Carcinoma 2 / 2 Medullary Thyroid Carcinoma 2 / 3 Medulloblastoma 2 / 2 Merkel Cell Carcinoma 6 / 6 Neuroendocrine Carcinoma of the Breast 1 / 1 Pan-NEN 7 / 8 Paraganglioma 9 / 9 Parathyroid Adenoma 0 / 4 Parathyroid Carcinoma 0 / 2 Pheochromocytoma 6 / 7 Pituitary Adenoma 4 / 6 Pituitary Carcinoma 3 / 3 Small Cell Carcinoma (Lung) 3 / 3 Adenocarcinoma 0 / 3 Anaplastic Thyroid Carcinoma 0 / 1 Follicular Thyroid Carcinoma 0 / 1 Melanoma 0 / 4 Total 89 Conclusions: As a nuclear protein, INSM1 staining is easier to interpret than cytoplasmic markers, and is independent of the number of cytoplasmic granules. Staining is both specifi c (100%) and sensitive (79%) to neural and neuroendocrine tumors, (though sensitivity does vary with tumor type - Table 1). INSM1 is a valuable tool in diagnosing neuroendocrine and neuroepithelial neoplasms.
    No preview · Conference Paper · Feb 2014

Publication Stats

13k Citations
1,448.62 Total Impact Points


  • 2010-2015
    • University of Wisconsin–Madison
      • Department of Pathology and Laboratory Medicine
      Madison, Wisconsin, United States
  • 1993-2015
    • Mayo Clinic - Rochester
      • Department of Laboratory Medicine & Pathology
      Рочестер, Minnesota, United States
  • 1989-2013
    • St. Michael's Hospital
      • Department of Surgery
      Toronto, Ontario, Canada
  • 2003-2008
    • Uppsala University Hospital
      Uppsala, Uppsala, Sweden
    • Università degli Studi di Torino
      Torino, Piedmont, Italy
  • 1992-2007
    • University of Toronto
      • • Department of Laboratory Medicine and Pathobiology
      • • Laboratory Medicine Program
      Toronto, Ontario, Canada
    • Stanford University
      • Department of Surgery
      Palo Alto, California, United States
  • 2003-2005
    • Wayne State University
      Detroit, Michigan, United States
  • 2002
    • Wakayama Medical University
      Wakayama, Wakayama, Japan
  • 2001
    • University of Cincinnati
      • Department of Pathology and Laboratory Medicine
      Cincinnati, OH, United States
  • 2000-2001
    • University of Santiago de Compostela
      • Department of Anatomy and Animal Production
      Santiago, Galicia, Spain
    • Kitasato University
      Edo, Tōkyō, Japan
    • Harvard Medical School
      • Department of Pathology
      Boston, Massachusetts, United States
  • 1983-1994
    • University of Michigan
      • • Department of Pathology
      • • Department of Internal Medicine
      Ann Arbor, Michigan, United States
    • Memorial Sloan-Kettering Cancer Center
      New York City, New York, United States
  • 1983-1993
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
  • 1986
    • Vanderbilt University
      Nashville, Michigan, United States
    • University of Michigan-Dearborn
      • Department of Natural Sciences
      Dearborn, Michigan, United States