Publications by authors named "Martin Hyrcza"

23 Publications

  • Page 1 of 1

Canadian Consensus for Biomarker Testing and Treatment of TRK Fusion Cancer in Adults.

Curr Oncol 2021 Jan 15;28(1):523-548. Epub 2021 Jan 15.

Department of Pathology, Laboratory Medicine Program, University Health Network, Toronto, ON M5G 2C4, Canada.

The tyrosine receptor kinase (TRK) inhibitors larotrectinib and entrectinib were recently approved in Canada for the treatment of solid tumours harbouring neurotrophic tyrosine receptor kinase ( gene fusions. These gene fusions are oncogenic drivers found in most tumour types at a low frequency (<5%), and at a higher frequency (>80%) in a small number of rare tumours (e.g., secretory carcinoma of the salivary gland and of the breast). They are generally mutually exclusive of other common oncogenic drivers. Larotrectinib and entrectinib have demonstrated impressive overall response rates and tolerability in Phase I/II trials in patients with TRK fusion cancer with no other effective treatment options. Given the low frequency of TRK fusion cancer and the heterogeneous molecular testing landscape in Canada, identifying and optimally managing such patients represents a new challenge. We provide a Canadian consensus on when and how to test for gene fusions and when to consider treatment with a TRK inhibitor. We focus on five tumour types: thyroid carcinoma, colorectal carcinoma, non-small cell lung carcinoma, soft tissue sarcoma, and salivary gland carcinoma. Based on the probability of the tumour harbouring an gene fusion, we also suggest a tumour-agnostic consensus for gene fusion testing and treatment. We recommend considering a TRK inhibitor in all patients with TRK fusion cancer with no other effective treatment options.
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http://dx.doi.org/10.3390/curroncol28010053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903287PMC
January 2021

Epidemiology of pheochromocytoma and paraganglioma: population-based cohort study.

Eur J Endocrinol 2021 Jan;184(1):19-28

Division of Endocrinology and Metabolism, Department of Medicine, University of Calgary, Calgary, Alberta, Canada.

Objective: Despite the significant morbidity and mortality associated with pheochromocytoma and paraganglioma, little is known about their epidemiology. The primary objective was to determine the incidence of pheochromocytoma and paraganglioma in an ethnically diverse population. A secondary objective was to develop and validate algorithms for case detection using laboratory and administrative data.

Design: Population-based cohort study in Alberta, Canada from 2012 to 2019.

Methods: Patients with pheochromocytoma or paraganglioma were identified using linked administrative databases and clinical records. Annual incidence rates per 100 000 people were calculated and stratified according to age and sex. Algorithms to identify pheochromocytoma and paraganglioma, based on laboratory and administrative data, were evaluated.

Results: A total of 239 patients with pheochromocytoma or paraganglioma (collectively with 251 tumors) were identified from a population of 5 196 368 people over a period of 7 years. The overall incidence of pheochromocytoma or paraganglioma was 0.66 cases per 100 000 people per year. The frequency of pheochromocytoma and paraganglioma increased with age and was highest in individuals aged 60-79 years (8.85 and 14.68 cases per 100 000 people per year for males and females, respectively). An algorithm based on laboratory data (metanephrine >two-fold or normetanephrine >three-fold higher than the upper limit of normal) closely approximated the true frequency of pheochromocytoma and paraganglioma with an estimated incidence of 0.54 cases per 100 000 people per year.

Conslusion: The incidence of pheochromocytoma and paraganglioma in an unselected population of western Canada was unexpectedly higher than rates reported from other areas of the world.
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http://dx.doi.org/10.1530/EJE-20-0628DOI Listing
January 2021

Expanding the Molecular Spectrum of Secretory Carcinoma of Salivary Glands With a Novel VIM-RET Fusion.

Am J Surg Pathol 2020 10;44(10):1295-1307

Institute of Biomedicine, Pathology, University of Turku, Turku, Finland.

Background: Secretory carcinoma (SC), originally described as mammary analogue SC, is a predominantly low-grade salivary gland neoplasm characterized by a recurrent t(12;15)(p13;q25) translocation, resulting in ETV6-NTRK3 gene fusion. Recently, alternative ETV6-RET, ETV6-MAML3, and ETV6-MET fusions have been found in a subset of SCs lacking the classic ETV6-NTRK3 fusion transcript, but still harboring ETV6 gene rearrangements.

Design: Forty-nine cases of SC revealing typical histomorphology and immunoprofile were analyzed by next-generation sequencing using the FusionPlex Solid Tumor kit (ArcherDX). All 49 cases of SC were also tested for ETV6, RET, and NTRK3 break by fluorescence in situ hybridization and for the common ETV6-NTRK3 fusions using reverse transcription polymerase chain reaction.

Results: Of the 49 cases studied, 37 (76%) occurred in the parotid gland, 7 (14%) in the submandibular gland, 2 (4%) in the minor salivary glands, and 1 (2%) each in the nasal mucosa, facial skin, and thyroid gland. SCs were diagnosed more frequently in males (27/49 cases; 55%). Patients' age at diagnosis varied from 15 to 80 years, with a mean age of 49.9 years. By molecular analysis, 40 cases (82%) presented the classic ETV6-NTRK3 fusion, whereas 9 cases (18%) revealed an alternate fusion. Of the 9 cases negative for the ETV6-NTRK3 fusion, 8 cases presented with ETV6-RET fusion. In the 1 remaining case in the parotid gland, next-generation sequencing analysis identified a novel VIM-RET fusion transcript. In addition, the analysis indicated that 1 recurrent high-grade case in the submandibular gland was positive for both ETV6-NTRK3 and MYB-SMR3B fusion transcripts.

Conclusions: A novel finding in our study was the discovery of a VIM-RET fusion in 1 patient with SC of the parotid gland who could possibly benefit from RET-targeted therapy. In addition, 1 recurrent high-grade case was shown to harbor 2 different fusions, namely, ETV6-NTRK3 and MYB-SMR3B. The expanded molecular spectrum provides a novel insight into SC oncogenesis and carries important implications for molecular diagnostics, as this is the first SC-associated translocation with a non-ETV6 5' fusion partner. This finding further expands the definition of SC while carrying implications for selecting the appropriate targeted therapy.
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http://dx.doi.org/10.1097/PAS.0000000000001535DOI Listing
October 2020

An Update on Endocrine Mucin-producing Sweat Gland Carcinoma: Clinicopathologic Study of 63 Cases and Comparative Analysis.

Am J Surg Pathol 2020 08;44(8):1005-1016

Departments of Ophthalmology and Visual Sciences.

Endocrine mucin-producing sweat gland carcinoma (EMPSGC) is a rare, low-grade adnexal neoplasm with predilection for the periorbital skin of older women. Histologically and immunophenotypically, EMPSGC is analogous to another neoplasm with neuroendocrine differentiation, solid papillary carcinoma of the breast. Both lesions are spatially associated with neuroendocrine mucinous adenocarcinomas of the skin and breast, respectively. EMPSGC is ostensibly a precursor of neuroendocrine-type mucinous sweat gland adenocarcinoma (MSC), a lesion of uncertain prognosis. Non-neuroendocrine MSC has been deemed locally aggressive with metastatic potential, and previous works speculated that EMPSGC-associated (neuroendocrine-type) MSC had similar recurrence and metastatic potential with implications for patient follow-up. Only 96 cases of EMPSGC have been reported (12 cases in the largest case series). Herein, we present 63 cases diagnosed as "EMPSGC" in comparison with aggregated results from known published EMPSGC cases. We aim to clarify the clinicopathologic features and prognostic significance of the neuroendocrine differentiation of EMPSGC and its associated adenocarcinoma and to determine the nosological relevance of EMPSGC association in the spectrum of MSC histopathogenesis. Results established an overall female predominance (66.7%) and average presenting age of 64 years. EMPSGC lesions were associated with adjacent MSC in 33.3% of cases. The recurrence rate for neuroendocrine-type MSC was ~21%, less than the reported 30% for non-neuroendocrine MSC. There were no cases of metastasis. EMPSGC and neuroendocrine-type MSC are distinct entities with more indolent behavior than previously reported, supporting a favorable prognosis for patients.
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http://dx.doi.org/10.1097/PAS.0000000000001462DOI Listing
August 2020

Histologic Classification and Molecular Signature of Polymorphous Adenocarcinoma (PAC) and Cribriform Adenocarcinoma of Salivary Gland (CASG): An International Interobserver Study.

Am J Surg Pathol 2020 04;44(4):545-552

Department of Pathology, Memorial Sloan-Kettering Cancer Center.

Polymorphous adenocarcinoma (PAC) shows histologic diversity with streaming and targetoid features whereas cribriform adenocarcinoma of salivary gland (CASG) demonstrates predominantly cribriform and solid patterns with glomeruloid structures and optically clear nuclei. Opinions diverge on whether CASG represents a separate entity or a variant of PAC. We aimed to assess the level of agreement among 25 expert Head and Neck pathologists in classifying these tumors. Digital slides of 48 cases were reviewed and classified as: PAC, CASG, tumors with ≥50% of papillary architecture (PAP), and tumors with indeterminate features (IND). The consensus diagnoses were correlated with a previously reported molecular alteration. The consensus diagnoses were PAC in 18/48, CASG in16/48, PAP in 3/48, and IND in 11/48. There was a fair interobserver agreement in classifying the tumors (κ=0.370). The full consensus was achieved in 3 (6%) cases, all of which were classified as PAC. A moderate agreement was reached for PAC (κ=0.504) and PAP (κ=0.561), and a fair agreement was reached for CASG (κ=0.390). IND had only slight diagnostic concordance (κ=0.091). PAC predominantly harbored PRKD1 hotspot mutation, whereas CASG was associated with fusion involving PRKD1, PRKD2, or PRKD3. However, such molecular events were not exclusive as 7% of PAC had fusion and 13% of CASG had mutation. In conclusion, a fair to moderate interobserver agreement can be achieved in classifying PAC and CASG. However, a subset (23%) showed indeterminate features and was difficult to place along the morphologic spectrum of PAC/CASG among expert pathologists. This may explain the controversy in classifying these tumors.
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http://dx.doi.org/10.1097/PAS.0000000000001431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437128PMC
April 2020

Computer-assisted image analysis of the tumor microenvironment on an oral tongue squamous cell carcinoma tissue microarray.

Clin Transl Radiat Oncol 2019 Jul 18;17:32-39. Epub 2019 May 18.

Department of Radiation Oncology, University of Toronto, Canada.

Oral tongue squamous cell carcinoma (OTSCC) displays variable levels of immune cells within the tumor microenvironment. The quantity and localization of tumor infiltrating lymphocytes (TILs), specific functional TIL subsets (e.g., CD8+), and biomarker-expressing cells (e.g., PD-L1+) may have prognostic and predictive value. The purpose of this study was to evaluate the robustness and utility of computer-assisted image analysis tools to quantify and localize immunohistochemistry-based biomarkers within the tumor microenvironment on a tissue microarray (TMA). We stained a 91-patient OTSCC TMA with antibodies targeting CD3, CD4, CD8, FOXP3, IDO, and PD-L1. Cell populations were segmented into epithelial (tumor) or stromal compartments according to a mask derived from a pan-cytokeratin stain. Definiens Tissue Studio was used to enumerate marker-positive cells or to quantify the staining intensity. Automated methods were validated against manual tissue segmentation, cell count, and stain intensity quantification. Univariate associations of cell count and stain intensity with smoking status, stage, overall survival (OS), and disease-free survival (DFS) were determined. Our results revealed that the accuracy of automated tissue segmentation was dependent on the distance of the tissue section from the cytokeratin mask and the proportion of the tissue containing tumor vs. stroma. Automated and manual cell counts and stain intensities were highly correlated (Pearson coefficient range: 0.46-0.90; p < 0.001). Within this OTSCC cohort, smokers had significantly stronger PD-L1 stain intensity and higher numbers of CD3+, CD4+ and FOXP3+ TILs. In the subset of patients who had received adjuvant radiotherapy, a higher number of CD8+ TILs was associated with inferior OS and DFS. Taken together, this proof-of-principle study demonstrates the robustness and utility of computer-assisted image analysis for high-throughput assessment of multiple IHC markers on TMAs, with potential implications for studies on prognostic and predictive biomarkers.
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http://dx.doi.org/10.1016/j.ctro.2019.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536490PMC
July 2019

Secretory carcinoma of the major salivary gland: Provincial population-based analysis of clinical behavior and outcomes.

Head Neck 2019 05 28;41(5):1227-1236. Epub 2018 Dec 28.

Department of Pathology, BC Cancer Agency - Vancouver Centre, Vancouver, Canada.

Background: Our aim was to identify the number of cases of secretory carcinoma (SC) of the major salivary gland in a population-based cohort and review its clinical behavior with long-term follow-up.

Methods: All malignant salivary gland tumors (MSGTs) diagnosed between 1980 and 2014 were assessed for histological features compatible with SC and 140 were selected for further analysis.

Results: Twenty two new cases of SC were identified, 19 of which were originally classified as acinic cell carcinoma, and 3 as adenocarcinoma, not otherwise specified (NOS). Lymph node involvement was less common in SC tumors (5%) than in the control group (11%). Disease recurrence was seen less frequently in SC (9%) than the control group (20%). Mean disease-free survival was 192 months for SC compared with 162 months for controls (P = 0.15).

Conclusion: The clinical course of SC is typically indolent with a low risk of relapse not significantly different from other low-grade MSGT.
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http://dx.doi.org/10.1002/hed.25536DOI Listing
May 2019

Primary Secretory Carcinoma of the Lacrimal Gland: Report of a New Entity.

Am J Ophthalmol 2018 09 28;193:178-183. Epub 2018 Jun 28.

Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, British Columbia, Canada.

Purpose: Secretory carcinoma has been described in the breast, salivary glands, skin, and other organs, but has not been reported in the lacrimal gland to date. Since lacrimal and salivary glands show similar tumors, we hypothesized that lacrimal secretory carcinoma may exist but has been misclassified in the past.

Design: We undertook a retrospective review of all lacrimal gland tumors at 2 tertiary institutions with centralized ocular pathology practices.

Methods: A total of 350 lacrimal tumors were reviewed by the authors. Candidate tumors were tested for ETV-NTRK rearrangement by fluorescence in situ hybridization and the presence of the translocation was confirmed by next-generation sequencing.

Results: We identified a single case of secretory carcinoma. The diagnosis was confirmed by demonstrating specific immunohistochemical profile and the presence of ETV6-NTRK3 gene fusion, which is characteristic of secretory carcinoma of other sites. The tumor occurred in a young man who was treated with surgery alone with no recurrence during 12 years of follow-up.

Conclusion: Secretory carcinoma is a new lacrimal gland carcinoma type that should be added to the spectrum of low-grade lacrimal gland tumors.
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http://dx.doi.org/10.1016/j.ajo.2018.06.019DOI Listing
September 2018

Adenocarcinoma Arising from a Gastric Duplication Cyst.

ACG Case Rep J 2018 6;5:e42. Epub 2018 Jun 6.

Division of Gastroenterology, McMaster University, Hamilton, Ontario, Canada.

Gastric duplication cysts are rare congenital anomalies, and malignant transformation has only been reported in 11 cases. A healthy 57-year-old woman presented with abdominal discomfort, and computed tomography revealed a 5.8 × 6.6 × 8.2 cm mass at the gastric fundus. On endoscopic ultrasound, the mass was mostly hypoechoic with anechoic cystic cavities arising from the submucosal layer. Fine-needle aspiration was suspicious for adenocarcinoma. Surgical pathology confirmed high-grade adenocarcinoma, clear cell cytology arising from a foregut duplication cyst. Endoscopic ultrasound is underutilized in the evaluation duplication cysts and should be considered in routine workup.
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http://dx.doi.org/10.14309/crj.2018.42DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992336PMC
June 2018

Molecular Profiling of Mammary Analog Secretory Carcinoma Revealed a Subset of Tumors Harboring a Novel ETV6-RET Translocation: Report of 10 Cases.

Am J Surg Pathol 2018 02;42(2):234-246

Departments of Pathology.

ETV6 gene abnormalities are well described in tumor pathology. Many fusion partners of ETV6 have been reported in a variety of epithelial, mesenchymal, and hematological malignancies. In salivary gland tumor pathology, however, the ETV6-NTRK3 translocation is specific for (mammary analog) secretory carcinoma, and has not been documented in any other salivary tumor type. The present study comprised a clinical, histologic, and molecular analysis of 10 cases of secretory carcinoma, with typical morphology and immunoprofile harboring a novel ETV6-RET translocation.
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http://dx.doi.org/10.1097/PAS.0000000000000972DOI Listing
February 2018

Pituitary Adenomas Presenting as Sinonasal or Nasopharyngeal Masses: A Case Series Illustrating Potential Diagnostic Pitfalls.

Am J Surg Pathol 2017 Apr;41(4):525-534

Departments of *Laboratory Medicine and Pathobiology †Pathology ‡Medicine, University Health Network, University of Toronto, Toronto, ON, Canada.

We present a series of nonectopic pituitary adenomas presenting as polypoid sinonasal or nasopharyngeal masses. Thirteen cases diagnosed by biopsies from the nasal cavity, sinuses, or nasopharynx were identified from a series of 1288 surgical pituitary specimens. The patients included 5 men and 8 women ranging from 29 to 69 years of age. The presentations included nasal obstruction (4 cases), headaches (3), visual defects (2), recurrent nose bleeds (1), rhinorrhea (1), sepsis (1), fatigue (1), and hyperthyroidism (1). All patients had large tumors involving the sella and extending inferiorly to involve the sphenoid sinus in 10 cases, ethmoid in 8, nasopharynx in 3, nasal cavity in 6, maxillary and frontal sinuses in 1 case each. In 3 patients, the biopsy was from the nasopharynx, in 4 from the nasal cavity, in 4 from the sphenoid sinus, and in 2 from the ethmoid sinus. The correct diagnosis of pituitary adenoma was initially made in 10 cases. In 3 cases the initial diagnosis was incorrect; 2 tumors were classified as olfactory neuroblastoma, one of those was reclassified as neuroendocrine carcinoma, and 1 case was initially diagnosed as neuroendocrine carcinoma with aberrant adrenocorticotrophic hormone expression. Clinical follow-up (2 to 25 y) and treatment information was available in 10 cases. All 10 patients were alive, either free of disease (4 cases) or with disease (6 cases). In 2 cases, the wrong diagnoses led to incorrect treatment with significant morbidity. These cases illustrate that pituitary adenomas can invade nasopharynx and sinonasal cavities and when they do, they present a possible diagnostic pitfall with potentially serious consequences. We demonstrate the need to always consider this entity when encountering a nasopharyngeal or sinonasal tumor with neuroendocrine features.
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http://dx.doi.org/10.1097/PAS.0000000000000784DOI Listing
April 2017

Gene of the month: BAP1.

J Clin Pathol 2016 Sep 27;69(9):750-3. Epub 2016 May 27.

Department of Laboratory Medicine and Pathobiology, University Health Network, University of Toronto, Toronto, Ontario, Canada.

The BAP1 gene (BRCA1-associated protein 1) is a tumour suppressor gene that encodes a deubiquitinating enzyme (DUB), regulating key cellular pathways, including cell cycle, cellular differentiation, transcription and DNA damage response. Germline BAP1 mutations cause a novel cancer syndrome characterised by early onset of multiple atypical Spitz tumours and increased risk of uveal and cutaneous melanoma, mesothelioma, renal cell carcinoma and various other malignancies. Recognising the clinicopathological features of specific BAP1-deficient tumours is crucial for early screening/tumour detection, with significant impact on patient outcome.
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http://dx.doi.org/10.1136/jclinpath-2016-203866DOI Listing
September 2016

TFE3-Expressing Perivascular Epithelioid Cell Neoplasm (PEComa) of the Sella Turcica.

Endocr Pathol 2017 Mar;28(1):22-26

Department of Pathology, University Health Network, Toronto, ON, Canada.

We report a primary central nervous system (CNS) perivascular epithelioid cell tumor (PEComa) in a middle-aged female patient. The tumor occurred in suprasellar location with secondary extension into the sella turcica. The patient presented with intracranial hemorrhage and an altered level of consciousness. The tumor had morphologic features matching those of other previously described TFE3-translocated PEComas, including epithelioid morphology, diffuse and strong nuclear immunoreactivity for TFE3, and minimal staining with myoid markers. The TFE3 break-apart FISH testing showed a slight splitting of one of the TFE3 signals in 49.5 % of nuclei. This case illustrates that PEComas should be added to the growing list of mesenchymal tumors that can be encountered in the CNS and specifically in the vicinity of the pituitary gland. The recognition of this entity is of significance given their underlying pathogenesis and possible management implications.
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http://dx.doi.org/10.1007/s12022-016-9434-7DOI Listing
March 2017

Parathyroid Lipoadenoma: a Clinicopathological Diagnosis and Possible Trap for the Unaware Pathologist.

Endocr Pathol 2016 Mar;27(1):34-41

Department of Pathology, University Health Network, M5G 2C4, Toronto, ON, Canada.

The authors present clinicopathological features of parathyroid lipoadenoma in a 48-year-old woman who presented with symptomatic primary hyperparathyroidism manifesting with pathological fractures and osteoporosis. Preoperative sestamibi scan failed to localize the source of her disease. Exploratory surgery identified an enlarged parathyroid gland with abundant fat tissue. The significant drop of intraoperative serum parathyroid hormone after the removal of this gland and postoperative biochemical cure justified the presence of a single gland disease presenting as parathyroid lipoadenoma. From an educational perspective, the presented case emphasizes why the historical approach to parathyroid proliferations by assessing alone the ratio of parenchymal cells to adipocytes is not a reliable method in the diagnostic evaluation of parathyroid disease. While the accurate size and weight of a parathyroid gland are defining parameters of an abnormal gland, intraoperative and postoperative biochemical workup distinguishes uniglandular disease (adenoma) from multiglandular disease (hyperplasia). The authors also provide a brief review of the previously published cases of parathyroid lipoadenomas to highlight their clinicopathological characteristics of relevance to surgical pathologists.
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http://dx.doi.org/10.1007/s12022-015-9404-5DOI Listing
March 2016

Clear cell myoepithelial carcinoma of salivary glands showing EWSR1 rearrangement: molecular analysis of 94 salivary gland carcinomas with prominent clear cell component.

Am J Surg Pathol 2015 Mar;39(3):338-48

*Department of Pathology, Faculty of Medicine in Plzen, Charles University ††Bioptic Laboratory Ltd, Molecular Pathology Laboratory, Plzen ∥The Fingerland Department of Pathology, Faculty of Medicine and University Hospital, Charles University in Prague, Hradec Kralove, Czech Republic †Department of Pathology, University Health Network, Toronto, ON ‡Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC §Department of Anatomical Pathology, University of Calgary, Foothills Medical Centre, Calgary, AB, Canada ¶Institute of Pathology, University Hospital, Erlangen, Germany #Department of Pathology, N.N. Alexandrov's Research Center of Oncology and Medical Radiology, Minsk, Republic of Belarus **Department of Pathology, Medical University of Gdansk, Poland ‡‡Department of Pathology, Cytopathos, Slovakia §§Department of Pathology, University of Zagreb, Croatia ∥∥Department of Pathology, National Cancer Institute, Fondazione "G.Pascale", Naples, Italy.

This study examines the presence of the EWSR1 rearrangement in a variety of clear cell salivary gland carcinomas with myoepithelial differentiation. A total of 94 salivary gland carcinomas with a prominent clear cell component included 51 cases of clear cell myoepithelial carcinomas de novo (CCMC), 21 cases of CCMCs ex pleomorphic adenoma (CCMCexPA), 11 cases of epithelial-myoepithelial carcinoma (EMC), 6 cases of EMC with solid clear cell overgrowth, and 5 cases of hyalinizing clear cell carcinoma of minor salivary glands. In addition, 10 cases of myoepithelial carcinomas devoid of clear cell change and 12 cases of benign myoepithelioma were included as well. All the tumors in this spectrum were reviewed, reclassified, and tested by fluorescence in situ hybridization (FISH) for the EWSR1 rearrangement using the Probe Vysis EWSR1 Break Apart FISH Probe Kit. The EWSR1 rearrangement was detected in 20 of 51 (39%) cases of CCMC, in 5 of 21 (24%) cases of CCMCexPA, in 1 of 11 (9%) cases of EMC, and in 4 of 5 (80%) cases of hyalinizing clear cell carcinoma. The 25 EWSR1-rearranged CCMCs and CCMCexPAs shared similar histomorphology. They were arranged in nodules composed of compact nests of large polyhedral cells with abundant clear cytoplasm. Necrosis, areas of squamous metaplasia, and hyalinization were frequent features. Immunohistochemically, the tumors expressed p63 (96%), cytokeratin CK14 (96%), and S100 protein (88%). MIB1 index varied from 10% to 100%, with most cases in the 20% to 40% range. Clinical follow-up information was available in 21 cases (84%) and ranged from 3 months to 15 years (mean 5.2 y); 4 patients were lost to follow-up. Ten patients are alive with no evidence of recurrent or metastatic disease in the follow-up period from 3 months to 15 years (mean 5 y), 3 patients are alive with recurrent and metastatic disease, and 8 died of disseminated cancer 9 months to 16 years after diagnosis (mean 6 y). Lymph node metastasis appeared in 5 patients within 5 months to 4 years after diagnosis (mean 22 mo), distant metastases were noted in 7 patients with invasion of orbit (2 cases), and in 1 case each metastasis to the neck soft tissues, liver, lungs, mediastinum, and thoracic vertebra was noted. We describe for the first time EWSR1 gene rearrangement in a subset of myoepithelial carcinomas arising in minor and major salivary glands. The EWSR1-rearranged CCMC represents a distinctive aggressive variant composed predominantly of clear cells with frequent necrosis. Most EWSR1-rearranged CCMCs of salivary glands are characterized by poor clinical outcomes.
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http://dx.doi.org/10.1097/PAS.0000000000000364DOI Listing
March 2015

Images in endocrine pathology: papillary variant of medullary thyroid carcinoma with cystic change.

Endocr Pathol 2015 Mar;26(1):87-9

Department of Pathology, University Health Network, 200 Elizabeth Street, 11th floor, Toronto, ON, M5G2C4, Canada.

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http://dx.doi.org/10.1007/s12022-014-9332-9DOI Listing
March 2015

Low-grade intraductal carcinoma of the lacrimal gland.

Orbit 2014 Apr 6;33(2):135-8. Epub 2013 Nov 6.

Department of Ophthalmology, Western University , London, Ontario , Canada .

Intraductal carcinoma has been described in the salivary glands as a relatively benign tumour with low-grade histopathologic features. To our knowledge, this tumour has not previously been reported in the lacrimal gland. We report the first case of low-grade intraductal carcinoma occurring in the lacrimal gland. This tumour was discovered incidentally on neuro-imaging in an asymptomatic 65-year-old patient. Incisional biopsy revealed uniform, polygonal cells with eosinophilic cytoplasm and minimal nuclear atypia, arranged in solid, cribiform and micropapillary nests. The patient underwent complete surgical excision with no evidence of recurrence at 8 months of follow-up.
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http://dx.doi.org/10.3109/01676830.2013.851257DOI Listing
April 2014

HIV delays IFN-α production from human plasmacytoid dendritic cells and is associated with SYK phosphorylation.

PLoS One 2012 31;7(5):e37052. Epub 2012 May 31.

Department of Immunology, University of Toronto, Toronto, Ontario, Canada.

Plasmacytoid dendritic cells (pDC) are the major producers of type I interferons (IFNs) in humans and rapidly produce IFN-α in response to virus exposure. Although HIV infection is associated with pDC activation, it is unclear why the innate immune response is unable to effectively control viral replication. We systematically compared the effect of HIV, Influenza, Sendai, and HSV-2 at similar target cell multiplicity of infection (M.O.I.) on human pDC function. We found that Influenza, Sendai, HSV-2 and imiquimod are able to rapidly induce IFN-α production within 4 hours to maximal levels, whereas HIV had a delayed induction that was maximal only after 24 hours. In addition, maximal IFN-α induction by HIV was at least 10 fold less than that of the other viruses in the panel. HIV also induced less TNF-α and MIP-1β but similar levels of IP-10 compared to other viruses, which was also mirrored by delayed upregulation of pDC activation markers CD83 and CD86. BDCA-2 has been identified as an inhibitory receptor on pDC, signaling through a pathway that involves SYK phosphorylation. We find that compared to Influenza, HIV induces the activation of the SYK pathway. Thus, HIV delays pDC IFN-α production and pDC activation via SYK phosphorylation, allowing establishment of viral populations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0037052PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3365039PMC
October 2012

Immune activation and neuropsychiatric symptoms in HIV infection.

J Neuropsychiatry Clin Neurosci 2010 ;22(3):321-8

St. Michael's Hospital, Neurobehavioural Research Unit in HIV/AIDS, 30 Bond Street, Shuter Wing, Rm. 2-044, Toronto, ON, M5B 1W8.

This study examined the role of biological processes in the development of specific neuropsychiatric complications in HAART-naive adults with HIV/AIDS. Depressive symptoms were modestly associated with elevated IL-6 mRNA expression (r(s)=0.40, p<0.05) even after removing the influences of other subjective complaints (pr=0.39, p<0.05). Elevated serum neopterin was strongly associated with depressive symptoms in individuals taking antidepressants (r(s)=0.83, p<0.001), though the association was nullified in those not on antidepressants (r(s)=-0.25, p>0.05). Mean neopterin levels were higher in the depressed as compared with nondepressed group but only for those taking antidepressants (F=45.66, df=1, 11, p<0.001). Neuropsychological impairment was not associated with the biological markers. These findings suggest that systemic immune markers (like neopterin) may be useful in differentiating treatment-resistant individuals at greater risk of developing chronic depression.
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http://dx.doi.org/10.1176/jnp.2010.22.3.321DOI Listing
November 2010

The impact of CCL3L1 copy number in an HIV-1-infected white population.

AIDS 2010 Jun;24(10):1589-91

Department of Immunology, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.

We examined the effect of CCL3L1 gene copy number on disease progression in a North American white cohort of HIV-1-infected individuals. Although CCL3L1 copy number is enriched in uninfected Caucasians, in HIV-1-infected individuals CCL3L1 copy number did not correlate either with long-term nonprogression or with CD4 cell count or viral load in chronic progressors. These findings underscore the heterogeneity of factors involved with long-term nonprogression when comparing cohorts of varying ethnic backgrounds.
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http://dx.doi.org/10.1097/QAD.0b013e3283398294DOI Listing
June 2010

Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection.

J Exp Med 2008 Nov 10;205(12):2763-79. Epub 2008 Nov 10.

Department of Immunology, University of Toronto, Toronto, ON, Canada.

Progressive loss of T cell functionality is a hallmark of chronic infection with human immunodeficiency virus 1 (HIV-1). We have identified a novel population of dysfunctional T cells marked by surface expression of the glycoprotein Tim-3. The frequency of this population was increased in HIV-1-infected individuals to a mean of 49.4 +/- SD 12.9% of CD8(+) T cells expressing Tim-3 in HIV-1-infected chronic progressors versus 28.5 +/- 6.8% in HIV-1-uninfected individuals. Levels of Tim-3 expression on T cells from HIV-1-infected inviduals correlated positively with HIV-1 viral load and CD38 expression and inversely with CD4(+) T cell count. In progressive HIV-1 infection, Tim-3 expression was up-regulated on HIV-1-specific CD8(+) T cells. Tim-3-expressing T cells failed to produce cytokine or proliferate in response to antigen and exhibited impaired Stat5, Erk1/2, and p38 signaling. Blocking the Tim-3 signaling pathway restored proliferation and enhanced cytokine production in HIV-1-specific T cells. Thus, Tim-3 represents a novel target for the therapeutic reversal of HIV-1-associated T cell dysfunction.
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http://dx.doi.org/10.1084/jem.20081398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2585847PMC
November 2008

Distinct transcriptional profiles in ex vivo CD4+ and CD8+ T cells are established early in human immunodeficiency virus type 1 infection and are characterized by a chronic interferon response as well as extensive transcriptional changes in CD8+ T cells.

J Virol 2007 Apr 24;81(7):3477-86. Epub 2007 Jan 24.

Clinical Sciences Division, University of Toronto, Medical Sciences Building, Rm. 6271, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.

Changes in T-cell function are a hallmark of human immunodeficiency virus type 1 (HIV-1) infection, but the pathogenic mechanisms leading to these changes are unclear. We examined the gene expression profiles in ex vivo human CD4+ and CD8+ T cells from untreated HIV-1-infected individuals at different clinical stages and rates of disease progression. Profiles of pure CD4+ and CD8+ T-cell subsets from HIV-1-infected nonprogressors with controlled viremia were indistinguishable from those of individuals not infected with HIV-1. Similarly, no gene clusters could distinguish T cells from individuals with early infection from those seen in chronic progressive HIV-1 infection, whereas differences were observed between uninfected individuals or nonprogressors versus early or chronic progressors. In early and chronic HIV-1 infection, three characteristic gene expression signatures were observed. (i) CD4+ and CD8+ T cells showed increased expression of interferon-stimulated genes (ISGs). However, some ISGs, including CXCL9, CXCL10, and CXCL11, and the interleukin-15 alpha receptor were not upregulated. (ii) CD4+ and CD8+ T cells showed a cluster similar to that observed in thymocytes. (iii) More genes were differentially regulated in CD8+ T cells than in CD4+ T cells, including a cluster of genes downregulated exclusively in CD8+ T cells. In conclusion, HIV-1 infection induces a persistent T-cell transcriptional profile, early in infection, characterized by a dramatic but potentially aberrant interferon response and a profile suggesting an active thymic output. These findings highlight the complexity of the host-virus relationship in HIV-1 infection.
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http://dx.doi.org/10.1128/JVI.01552-06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1866039PMC
April 2007

Genomic DNA functions as a universal external standard in quantitative real-time PCR.

Nucleic Acids Res 2006 Jul 13;34(12):e85. Epub 2006 Jul 13.

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8.

Real-time quantitative PCR (qPCR) is a powerful tool for quantifying specific DNA target sequences. Although determination of relative quantity is widely accepted as a reliable means of measuring differences between samples, there are advantages to being able to determine the absolute copy numbers of a given target. One approach to absolute quantification relies on construction of an accurate standard curve using appropriate external standards of known concentration. We have validated the use of tissue genomic DNA as a universal external standard to facilitate quantification of any target sequence contained in the genome of a given species, addressing several key technical issues regarding its use. This approach was applied to validate mRNA expression of gene candidates identified from microarray data and to determine gene copies in transgenic mice. A simple method that can assist achieving absolute quantification of gene expression would broadly enhance the uses of real-time qPCR and in particular, augment the evaluation of global gene expression studies.
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http://dx.doi.org/10.1093/nar/gkl400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1524913PMC
July 2006