Leona A Doyle

Brigham and Women's Hospital, Boston, Massachusetts, United States

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Publications (43)164.26 Total impact

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    ABSTRACT: Epithelioid hemangioendothelioma (EHE) is a malignant endothelial neoplasm characterized by recurrent translocations involving chromosomal regions 1p36.3 and 3q25, resulting in the formation of a WWTR1-CAMTA1 fusion gene in approximately 90% of cases; a small subset (<5%) have a YAP1-TFE3 fusion gene. The WWTR1-CAMTA1 fusion gene leads to overexpression of both genes. WWTR1 protein is expressed in many different cell types, whereas CAMTA1 expression is normally limited to the brain. A prior study using a polyclonal antibody directed against regions within the C-terminus of CAMTA1 reported widespread expression in both normal tissues and diverse tumor types. In contrast, a recent study using a different polyclonal antibody directed against the C-terminus of CAMTA1 suggested that this other antibody is a potentially useful diagnostic marker for EHE. Our study aimed to validate this finding in a large series of EHE cases and to determine whether CAMTA1 is expressed in other epithelioid mesenchymal tumors that may mimic EHE. Protein expression of CAMTA1 was evaluated in whole-tissue sections of 204 tumors using a polyclonal anti-CAMTA1 antibody: 59 EHE (48 conventional, 11 "malignant"; 4 with known TFE3 gene rearrangement); 70 other epithelioid vascular tumors; and 75 nonendothelial epithelioid mesenchymal neoplasms. In total, 51/59 cases (86%) of EHE showed diffuse nuclear staining for CAMTA1, including 44/48 cases (92%) with conventional histology and 7/11 cases (64%) with "malignant" histology. Of the 8 CAMTA1-negative tumors, 6 were positive for TFE3. With the exception of 1 case previously diagnosed as epithelioid angiosarcoma on core biopsy, all other tumor types examined were negative for CAMTA1. In conclusion, in keeping with the reported frequency of WWTR1-CAMTA1 in EHE, nuclear CAMTA1 expression is identified in the majority of EHE cases, whereas other epithelioid mesenchymal neoplasms are negative for CAMTA1. These findings support the diagnostic utility of immunohistochemistry for CAMTA1 in distinguishing EHE from histologic mimics, in particular benign epithelioid vascular tumors, epithelioid angiosarcoma, and epithelioid sarcoma, an important distinction given the differences in biological potential and clinical course.
    The American journal of surgical pathology 09/2015; DOI:10.1097/PAS.0000000000000511 · 5.15 Impact Factor
  • Leona A Doyle ·
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    ABSTRACT: A variety of different non-mesenchymal neoplasms may mimic sarcoma, in particular sarcomatoid carcinoma and melanoma, but also mesothelioma and rarely some lymphomas. This article reviews the key clinical and histologic features of such neoplasms in different settings, along with the use of ancillary studies to help identify the tumor types most frequently misdiagnosed as sarcoma. Copyright © 2015 Elsevier Inc. All rights reserved.
    09/2015; 8(3):493-513. DOI:10.1016/j.path.2015.05.010
  • Leona A. Doyle · Karen J. Fritchie ·

    Surgical Pathology Clinics 09/2015; 8(3):i. DOI:10.1016/S1875-9181(15)00075-6
  • Leona A Doyle · Karen J Fritchie ·

    09/2015; 8(3):ix. DOI:10.1016/j.path.2015.07.001
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    ABSTRACT: Benign fibrous histiocytomas (FH) can be subdivided into several morphological and clinical subgroups. Recently, gene fusions involving either one of two protein kinase C genes (PRKCB and PRKCD) or the ALK gene were described in FH. We here wanted to evaluate the frequency of PRKCB and PRKCD gene fusions in FH. Using interphase fluorescence in situ hybridization on sections from formalin-fixed paraffin-embedded (FFPE) tumors, 36 cases could be analyzed. PRKCB or PRKCD rearrangements were seen in five tumors: 1/7 regular, 0/3 aneurysmal, 0/6 cellular, 2/7 epithelioid, 0/1 atypical, 2/10 deep, and 0/2 metastatic lesions. We also evaluated the status of the ALK gene in selected cases, finding rearrangements in 3/7 epithelioid and 0/1 atypical lesions. To assess the gene fusion status of FH further, deep sequencing of RNA (RNA-Seq) was performed on FFPE tissue from eight cases with unknown gene fusion status, as well as on two FH and six soft tissue sarcomas with known gene fusions; of the latter eight positive controls, the expected fusion transcript was found in all but one, while 2/8 FH with unknown genetic status showed fusion transcripts, including a novel KIRREL/PRKCA chimera. Thus, also a third member of the PRKC family is involved in FH tumorigenesis. We conclude that gene fusions involving PRKC genes occur in several morphological (regular, cellular, aneurysmal, epithelioid) and clinical (cutaneous, deep) subsets of FH, but they seem to account for only a minority of the cases. In epithelioid lesions, however, rearrangements of PRKC or ALK were seen, as mutually exclusive events, in the majority (5/7) of cases. Finally, the study also shows that RNA-Seq is a promising tool for identifying gene fusions in FFPE tissues.Laboratory Investigation advance online publication, 29 June 2015; doi:10.1038/labinvest.2015.83.
    Laboratory Investigation 06/2015; 95(9). DOI:10.1038/labinvest.2015.83 · 3.68 Impact Factor
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    ABSTRACT: Human papilloma virus (HPV) infection causes cancers and their precursors (high-grade squamous intraepithelial lesions) near cervical and anal squamocolumnar junctions. Recently described cervical squamocolumnar junction cells are putative residual embryonic cells near the cervical transformation zone. These cells appear multipotential and share an identical immunophenotype (strongly CK7-positive) with over 90% of high-grade squamous intraepithelial lesions and cervical carcinomas. However, because the number of new cervical cancers discovered yearly world wide is 17-fold that of anal cancer, we posed the hypothesis that this difference in cancer risk reflects differences in the transition zones at the two sites. The microanatomy of the normal anal transformation zone (n=37) and topography and immunophenotype of anal squamous neoplasms (n=97) were studied. A discrete anal transition zone was composed of multilayered CK7-positive/p63-negative superficial columnar cells and an uninterrupted layer of CK7-negative/p63-positive basal cells. The CK7-negative/p63-positive basal cells were continuous with-and identical in appearance to-the basal cells of the mature squamous epithelium. This was in contrast to the cervical squamocolumnar junction, which harbored a single-layered CK7-positive/p63-negative squamocolumnar junction cell population. Of the 97 anal intraepithelial neoplasia/squamous cell carcinomas evaluated, only 27% (26/97) appeared to originate near the anal transition zone and only 23% (22/97) were CK7-positive. This study thus reveals two fundamental differences between the anus and the cervix: (1) the anal transition zone does not harbor a single monolayer of residual undifferentiated embryonic cells and (2) the dominant tumor immunophenotype is in keeping with an origin in metaplastic (CK7-negative) squamous rather than squamocolumnar junction (CK7-positive) epithelium. The implication is that, at birth, the embryonic cells in the anal transition zone have already begun to differentiate, presenting a metaplasia that-similar to vaginal and vulvar epithelium-is less prone to HPV-directed carcinogenesis. This in turn underscores the link between cancer risk and a very small and discrete population of vulnerable squamocolumnar junction cells in the cervix.Modern Pathology advance online publication, 15 May 2015; doi:10.1038/modpathol.2015.54.
    Modern Pathology 05/2015; 28(7). DOI:10.1038/modpathol.2015.54 · 6.19 Impact Factor
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    ABSTRACT: Epithelioid benign fibrous histiocytoma, also known as 'epithelioid cell histiocytoma,' has traditionally been considered a morphologic variant of cutaneous fibrous histiocytoma (dermatofibroma). In addition to its characteristic epithelioid cytomorphology, several phenotypic differences suggest that epithelioid fibrous histiocytoma may differ biologically from other variants. Recently, ALK rearrangement was described in two cases of epithelioid fibrous histiocytoma and separately in two cases reported as 'atypical' fibrous histiocytoma (with epithelioid features), with corresponding ALK expression detectable by immunohistochemistry. The goals of this study were to determine the frequency of ALK expression by immunohistochemistry in epithelioid fibrous histiocytoma, to determine its value for the diagnosis of epithelioid fibrous histiocytoma among variants and other histologic mimics, and to evaluate ALK gene rearrangement in epithelioid fibrous histiocytoma. ALK protein expression was evaluated in whole tissue sections from 33 epithelioid fibrous histiocytomas, 41 other cases of fibrous histiocytoma (11 conventional and 10 each cellular, atypical, and aneurysmal types), 10 cutaneous syncytial myoepitheliomas, and 5 atypical fibroxanthomas, using a mouse anti-ALK monoclonal antibody. Fluorescence in situ hybridization (FISH) was performed using break-apart probes. In total, 29/33 (88%) cases of epithelioid fibrous histiocytoma showed diffuse cytoplasmic ALK expression. Staining was moderate to strong in intensity in all cases except one, which showed diffuse weak expression. All other tumor types were negative for ALK expression. FISH demonstrated ALK rearrangement in all ALK-immunoreactive cases evaluated (n=13), and not in one ALK expression-negative epithelioid fibrous histiocytoma successfully examined. In conclusion, the majority of epithelioid fibrous histiocytomas demonstrate ALK expression and ALK gene rearrangement. ALK expression is not seen in other variants of fibrous histiocytoma, providing a useful diagnostic tool to distinguish epithelioid fibrous histiocytoma from most histologic mimics. The expression of ALK suggests that epithelioid fibrous histiocytoma is a biologically distinct tumor type, unrelated to conventional fibrous histiocytoma and histologic variants.Modern Pathology advance online publication, 10 April 2015; doi:10.1038/modpathol.2015.49.
    Modern Pathology 04/2015; 28(7). DOI:10.1038/modpathol.2015.49 · 6.19 Impact Factor
  • Leona A. Doyle ·
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    ABSTRACT: Significant progress has been made in the molecular characterization of soft tissue tumours arising in the gastrointestinal tract, primarily with the identification of recurrent translocations, gene amplifications and mutations in different tumour types. Translational studies have resulted in the development of many diagnostically useful immunohistochemical markers that reflect these underlying genetic changes. In addition, expression of some such markers is associated with distinctive clinical and histologic features, which may impart prognostic or predictive information, particularly for gastrointestinal stromal tumour. The advent of ‘next-generation’ immunohistochemistry has reduced the need for additional, more costly, molecular studies; however, it is important to understand the complementary role of ancillary molecular studies, which may be needed for diagnostic or therapeutic information. This review outlines the different roles of immunohistochemistry in the evaluation of select soft tissue neoplasms of the gastrointestinal tract, emphasizing their utility and limitations in clinical practice, molecular correlates, and the role of immunohistochemistry in guiding the appropriate application of ancillary molecular studies.
    Diagnostic Histopathology 04/2015; 21(3). DOI:10.1016/j.mpdhp.2015.03.001
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    ABSTRACT: Ipilimumab is a monoclonal antibody that inhibits the CTLA4 receptor on cytotoxic T lymphocytes, resulting in immune-mediated tumor cell death. Ipilimumab is most often used in the treatment of metastatic melanoma, and rarely liver toxicity necessitating cessation of treatment occurs. The aim of this study was to characterize the histologic features and clinical course of ipilimumab-associated hepatitis. Eleven patients with clinical suspicion of ipilimumab-induced hepatitis, due to the development of abnormal liver function tests (LFTs) while receiving treatment, and who underwent liver biopsy, were identified over a 6-year period. Ten patients were male and 1 female (median age 58 y), and all received 1 to 4 doses of ipilimumab. None had known preexisting liver disease. Two patients were obese, and another had a history of alcohol abuse. Viral and autoimmune serologies were negative in all patients except 1 who had a mildly elevated ANA titer. Nine biopsies showed active hepatitis with 2 distinct histologic patterns: panlobular hepatitis in 6 cases and zone 3 hepatitis in 3. The inflammatory infiltrate was similar in composition in both patterns, composed predominantly of CD8 T lymphocytes, admixed histiocytes, scattered plasma cells, and eosinophils. Prominent histiocytic sinusoidal infiltrates were present in 7 cases and frequently formed loose histiocytic aggregates. Central vein endothelialitis was present in 8 cases. Patients in this group tended to have markedly elevated ALT, AST, and total bilirubin. Two cases did not fit into the above 2 histologic groups: 1 showed portal inflammation with cholangitis, and the other showed morphologic features indistinguishable from nonalcoholic steatohepatitis. Discontinuation of ipilimumab and administration of immunosuppressives resulted in resolution or marked improvement of LFTs in all patients within 3 months of presentation. Ipilimumab may potentially unmask previously subclinical liver disease, for example, fatty liver disease, and the diagnosis of ipilimumab-induced liver injury may only be recognized with certainty after cessation of the drug leads to normalization of LFTs. Overall, ipilimumab-associated hepatitis most often presents with a panlobular active hepatitis that resembles autoimmune hepatitis. Prominent sinusoidal histiocytic infiltrates and central vein damage with endothelialitis may be helpful histologic clues to the diagnosis of ipilimumab-associated hepatitis.
    The American journal of surgical pathology 04/2015; 39(8). DOI:10.1097/PAS.0000000000000453 · 5.15 Impact Factor
  • Leona A. Doyle ·
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    ABSTRACT: Recent insights into the pathogenesis of various soft tissue tumors, along with the identification of recurrent molecular alterations characteristic of specific tumor types, have resulted in the development of many diagnostically useful immunohistochemical markers. In some cases, expression of these markers is significantly associated with distinctive clinical and histologic features, which may impart prognostic or predictive information. This review outlines new diagnostic immunohistochemical markers in soft tissue tumor pathology, emphasizing their utility in clinical practice and potential pitfalls, molecular correlates and clinical associations. Copyright © 2015 Elsevier Inc. All rights reserved.
    Seminars in Diagnostic Pathology 02/2015; 32(5). DOI:10.1053/j.semdp.2015.02.012 · 2.56 Impact Factor
  • George Lin · Leona A Doyle ·
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    ABSTRACT: Context: During the last 5 to 10 years, significant progress has been made in the molecular characterization of soft tissue tumors, predominantly with the identification of recurrent translocations or amplification of certain genes in different tumor types. Alongside this, translational efforts have identified many novel and diagnostically useful immunohistochemical markers for many of these tumor types. Objective: This article reviews a select group of recently described immunohistochemical markers of particular use in the evaluation of mesenchymal neoplasms; the underlying biology of the protein product, practical utility, and limitations of each marker are discussed in detail. Data sources: Literature review, authors' research data, and personal practice experience serve as sources. Conclusions: There are many diagnostically useful immunohistochemical markers to help confirm the diagnosis of many different soft tissue tumor types, some of which have reduced the need for additional, and more costly, studies, such as fluorescence in situ hybridization. However, no one marker is 100% specific for a given tumor, and knowledge of potential pitfalls and overlap in patterns of staining among other tumor types is crucial to ensure the appropriate application of these markers in clinical practice.
    Archives of pathology & laboratory medicine 01/2015; 139(1):106-21. DOI:10.5858/arpa.2014-0488-RA · 2.84 Impact Factor
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    ABSTRACT: KRAS mutations play an important role in pancreatic cancer. GNAS mutations were discovered in intraductal papillary mucinous neoplasms (IPMN). Our aim was to identify the frequency of KRAS and GNAS mutations in pancreatic cystic neoplasms and pancreatic ductal adenocarcinoma (PDAC). Sixty-eight surgically resected formalin fixed, paraffin embedded pancreatic specimens were analyzed, including: 1) benign (20 serous cystadenoma (SCA)), 2) pre-malignant (10 mucinous cystic neoplasm (MCN), 10 branch duct intraductal papillary mucinous neoplasm (BD-IPMN), 9 main duct IPMN (MD-IPMN)), 3) malignant (19 PDAC). Total nucleic acid extraction was performed. KRAS codon 12/13 and GNAS codon 201 mutations were interrogated via targeted sequencing using the Ion Torrent's Personal Genome Machine (PGM). Mean age of 68 patients was 61.9±8.4 with 72% female. KRAS and GNAS mutations were more common in PDAC and IPMN. KRAS mutations predominated in PDAC compared to pancreatic cysts (16/19, 84% versus 10/49, 20%; P<0.001). GNAS mutations were more common in IPMN compared to non-IPMN lesions (8/19, 42% versus 2/49, 4%; P=0.0003). No GNAS mutations were detected in PDAC and MCN while 2 SCA carried GNAS mutations. Double mutations with KRAS and GNAS were only present in IPMN (5/19 versus 0/30 SCA and MCN, P=0.006). KRAS and GNAS mutations were more common in PDAC and IPMN with KRAS mutations primarily in PDAC and GNAS mutations more frequent in IPMN. No GNAS mutations occurred in MCN and double mutations were only present in IPMN.
    JOP: Journal of the pancreas 12/2014; 15(6):581-6.
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    ABSTRACT: Increasingly, tumors are being analyzed for a variety of mutations and other genomic changes, with the goal of guiding personalized therapy and directing patients to appropriate clinical trials based on genotype, as well as identifying previously unknown genomic changes in different tumor types and thereby providing new insights into the pathogenesis of human cancers. Next-generation sequencing (NGS) is a powerful research tool now gaining traction in the clinic. In this report, we demonstrate the utility of NGS assays in providing diagnostic information when evaluating tumor specimens. This is illustrated by a case previously thought to represent an atypical carcinoid tumor, in which an EWSR1-ERG translocation was detected during next generation sequencing using a hybrid capture approach, leading to a revised diagnosis of Ewing sarcoma. The role of translocation detection in these assays is also discussed.
    Cancer Genetics 08/2014; 207(7). DOI:10.1016/j.cancergen.2014.08.004 · 2.98 Impact Factor
  • Leona A. Doyle ·
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    ABSTRACT: The 2013 World Health Organization Classification of Tumors of Soft Tissue and Bone incorporates changes in tumor classification, as well as new genetic insights into the pathogenesis of many different tumor types that have emerged over the 11 years since the publication of the prior volume. This article reviews changes in the classification of soft tissue and bone sarcomas as well as tumors of intermediate biologic potential in the 2013 World Health Organization volume, new molecular insights into these tumors, and associated surgical and clinical implications. Cancer 2014. © 2014 American Cancer Society.
    Cancer 06/2014; 120(12). DOI:10.1002/cncr.28657 · 4.89 Impact Factor
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    Clinical Cancer Research 05/2014; 19(19_Supplement):A11-A11. DOI:10.1158/1078-0432.OVCA13-A11 · 8.72 Impact Factor
  • Leona A Doyle · Jason L Hornick ·
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    ABSTRACT: Mastocytosis encompasses a group of clinically and pathologically heterogeneous disorders most commonly involving the skin, which typically takes the form of urticaria pigmentosa. Mastocytosis may also involve other organs, most often bone marrow, followed by gastrointestinal tract, liver, spleen, and lymph nodes. The presence of extracutaneous involvement by mastocytosis is a major diagnostic criterion for systemic disease. However, mast cell infiltrates are often subtle in skin and extracutaneous organs, and the histologic features of mastocytosis at different anatomic sites may be variable. This article reviews the pathologic features and clinical correlates of mastocytosis involving skin and other extramedullary sites.
    Immunology and allergy clinics of North America 05/2014; 34(2):323-339. DOI:10.1016/j.iac.2014.01.010 · 1.82 Impact Factor
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    ABSTRACT: Cutaneous fibrous histiocytoma (FH) is a common mesenchymal neoplasm. Metastasis is rare, disproportionately occurring among the aneurysmal, cellular, atypical, and deep variants. We determined whether DNA copy number changes occurred in atypical FH (AFH), and whether they were similar to those in metastasizing FH (MetFH) and benign cellular FH (CFH). Five primary tumors of MetFH were evaluated by array-based comparative genomic hybridization analysis, with tissue from local recurrences and lung metastases in 2 and 2 patients, respectively. Seven indolent AFH and 5 CFH were identified for comparison. Substantial differences between the groups were found both in the frequency of chromosomal aberrations (higher among MetFH and absent or solitary in CFH) and array-based comparative genomic hybridization profiles (frequent gains of 7 and 8q and losses of Xq in MetFH; recurrent losses of chromosomes 9 and 22 in AFH; isolated loss of 5q and gain in chromosome 20 in 2 CFH). Fatal MetFH cases (2 of 5 cases) exhibited the highest rate of chromosomal aberrations. This study included a small sample size with a short-term follow-up. Benign CFH, indolent AFH, and MetFH represent distinct biological entities within the spectrum of FH; array-based comparative genomic hybridization may be a tool in recognizing FH cases with metastatic potential and increasingly aggressive behavior.
    Journal of the American Academy of Dermatology 04/2014; 71(2). DOI:10.1016/j.jaad.2014.03.015 · 4.45 Impact Factor
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    ABSTRACT: Counting mast cells in gastrointestinal (GI) mucosal biopsies is becoming an increasingly common practice. The primary reason for this exercise is to evaluate for possible involvement by systemic mastocytosis (SM). However, the features of mastocytosis in GI biopsies are not well described. In addition, recent studies have suggested that increased mast cells may be involved in the pathogenesis of some cases of diarrhea-predominant irritable bowel syndrome (IBS); the term "mastocytic enterocolitis" has been proposed for such cases. As the baseline mast cell density in colonic biopsies from normal patients has not been established in large cohorts, there is no widely accepted threshold for what constitutes increased mucosal mast cells. The aims of this study were (1) to determine the utility of GI biopsies for the diagnosis of SM, (2) to characterize the clinical, histologic, and immunohistochemical features of mastocytosis in the GI tract, (3) to determine mast cell density in normal colonic mucosa from a large cohort of asymptomatic patients, and (4) to compare these findings with those from patients with diarrhea-predominant IBS. Twenty-four patients with SM involving the GI tract, 100 asymptomatic patients, and 100 patients with IBS (the latter 2 groups with histologically normal colonic biopsies) were included. For the mastocytosis group, 107 biopsies (70 involved by mastocytosis; 67 mucosal, 3 liver) from 20 women and 4 men were evaluated (median age 59 y). The most commonly involved site was the colon (19 patients, 95%), followed by ileum (86%), duodenum (80%), and stomach (54%). In 16 cases (67%), the first diagnosis of SM was made on the basis of GI biopsies. Seventeen patients had documented cutaneous mastocytosis. Fifteen of 17 patients who underwent bone marrow biopsy had marrow involvement by SM. Eighteen patients had indolent disease, and 6 had aggressive disease (including all 3 with liver involvement). The most common GI symptom was diarrhea, followed by abdominal pain, nausea, weight loss, bloating, vomiting, or reflux. Liver disease presented with hepatomegaly and ascites. Endoscopic abnormalities (observed in 62%) included erythema, granularity, and nodules. Histologically, involved biopsies were characterized by infiltrates of ovoid to spindle-shaped mast cells in aggregates or sheets in the lamina propria, sometimes forming a confluent band underneath the surface epithelium; 25% of biopsies had only focal involvement (single aggregate). Prominent eosinophils were seen in 44% of involved colonic/ileal biopsies and 16% of duodenal biopsies. Mast cells were highlighted by diffuse membranous staining for KIT and CD25. In the nonmastocytosis groups, all biopsies contained singly dispersed mast cells with no aggregates. The mean highest mast cell counts (in a single high-power field) for asymptomatic patients and IBS patients were 26 (range, 11 to 55) and 30 (range, 13 to 59), respectively. In summary, GI (especially colonic) biopsies can establish a diagnosis of SM in patients with GI symptoms. GI involvement is usually subtle and is often associated with prominent eosinophils, which may obscure the mast cell infiltrate. KIT and CD25 are invaluable markers for the diagnosis. Mast cell density in colonic mucosa from asymptomatic patients is highly variable. Although patients with diarrhea-predominant IBS on average have mildly increased mast cells, the overlap in range with that of control patients is too great for this difference to be clinically useful. These findings argue against the utility of counting GI mucosal mast cell in patients with chronic diarrhea.
    The American journal of surgical pathology 03/2014; 38(6). DOI:10.1097/PAS.0000000000000190 · 5.15 Impact Factor
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    ABSTRACT: Current diagnostic tools for pancreatic cysts fail to reliably differentiate mucinous from nonmucinous cysts. Reliable biomarkers are needed. MicroRNAs (miRNA) may offer insights into pancreatic cysts. Our aims were to (1) identify miRNAs that distinguish benign from both premalignant cysts and malignant pancreatic lesions using formalin-fixed, paraffin-embedded (FFPE) pathology specimens; (2) identify miRNAs that distinguish mucinous cystic neoplasm (MCN) from branch duct-intraductal papillary mucinous neoplasm (BD-IPMN). A total of 69 FFPE pancreatic specimens were identified: (1) benign (20 serous cystadenoma (SCA)), (2) premalignant (10 MCN, 10 BD-IPMN, 10 main duct IPMN (MD-IPMN)), and (3) malignant (19 pancreatic ductal adenocarcinoma (PDAC)). Total nucleic acid extraction was performed followed by miRNA expression profiling of 378 miRNAs interrogated using TaqMan MicroRNA Arrays Pool A and verification of candidate miRNAs. Bioinformatics was used to generate classifiers. MiRNA profiling of 69 FFPE specimens yielded 35 differentially expressed miRNA candidates. Four different 4-miRNA panels differentiated among the lesions: one panel separated SCA from MCN, BD-IPMN, MD-IPMN, and PDAC with sensitivity 85% (62, 97), specificity 100% (93, 100), a second panel distinguished MCN from SCA, BD-IPMN, MD-IPMN, and PDAC with sensitivity and specificity 100% (100, 100), a third panel differentiated PDAC from IPMN with sensitivity 95% (76, 100) and specificity 85% (72, 96), and the final panel diagnosed MCN from BD-IPMN with sensitivity and specificity approaching 100%. MiRNA profiling of surgical pathology specimens differentiates serous cystadenoma from both premalignant pancreatic cystic neoplasms and PDAC and MCN from BD-IPMN.
    Clinical and Translational Gastroenterology 01/2014; 5(1):e47. DOI:10.1038/ctg.2013.18
  • Leona A Doyle · Derrick Tao · Adrián Mariño-Enríquez ·
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    ABSTRACT: A recurrent intrachromosomal rearrangement on chromosome 12q in solitary fibrous tumor leads to the formation of a NAB2-STAT6 fusion oncogene. As a result, nuclear expression of the cytoplasmic transcription factor STAT6 is found in solitary fibrous tumor and serves as a useful diagnostic marker. STAT6 is located in 12q13, a region containing well-characterized oncogenes that are commonly amplified in dedifferentiated liposarcoma; we have previously reported that STAT6 is expressed in a subset of dedifferentiated liposarcoma. The aim of this study was to determine the frequency of STAT6 expression in dedifferentiated liposarcoma and the underlying genetic mechanism. STAT6 protein expression was analyzed by immunohistochemistry in a well-characterized series of 35 previously unpublished cases of dedifferentiated liposarcoma, all with nuclear MDM2 and/or CDK4 expression by immunohistochemistry and/or cytogenetic features of dedifferentiated liposarcoma. FISH for STAT6 was performed in all cases with STAT6 expression, and a subset of control cases without STAT6 expression. In total 4/35 cases (11%) showed STAT6 expression (three with multifocal staining of moderate to strong intensity and one with weak focal staining). FISH demonstrated amplification of STAT6 in all cases positive for STAT6 by immunohistochemistry; in contrast, FISH performed on four STAT6-negative dedifferentiated liposarcomas demonstrated no STAT6 amplification (P=0.0286). Of the four STAT6 amplified cases, three patients were male and one was female, ranging in age from 51 to 76 years. Tumors were located in the mediastinum (n=2), paratesticular soft tissue (n=1), and perirenal soft tissue (n=1). Three patients received pre-operative chemotherapy +/- radiation therapy. In conclusion, STAT6 is amplified in a subset of dedifferentiated liposarcoma, resulting in STAT6 protein expression that can be detected by immunohistochemistry and may be a potential pitfall in the differential diagnosis of dedifferentiated liposarcoma and solitary fibrous tumor. These findings suggest a role for STAT6-mediated transcriptional activity in some cases of dedifferentiated liposarcoma and highlight the genomic complexity and heterogeneity of dedifferentiated liposarcoma.Modern Pathology advance online publication, 24 January 2014; doi:10.1038/modpathol.2013.247.
    Modern Pathology 01/2014; 27(9). DOI:10.1038/modpathol.2013.247 · 6.19 Impact Factor

Publication Stats

408 Citations
164.26 Total Impact Points


  • 2013-2015
    • Brigham and Women's Hospital
      • • Department of Pathology
      • • Department of Medicine
      Boston, Massachusetts, United States
  • 2012-2015
    • Harvard Medical School
      • Department of Pathology
      Boston, Massachusetts, United States
  • 2011-2014
    • Harvard University
      Cambridge, Massachusetts, United States