Day 2 :
Keynote Forum
Reinhard Buettner
Director of Department of Pathology,University Hospital Cologne, Köln, Germany
Keynote: Experiences from the Network of Genomic Medicine (NGM)
Biography:
Dr. Reinhard Büttner is Professor and Chairman of The Institute of Pathology at University Hospital Cologne, Köln, Germany, and the Co-Founder and Chief Scientific Officer of TARGOS Molecular Diagnostics. He completed his medical degree at the University of Mainz, Mainz, Germany, in 1985, before starting a residency at Rheinisch-Westfalische Technische Hochschule RWTH Aachen, Aachen, Germany. In 1987, he began post-doctoral work at the Gene Centre Munich and MD Anderson Cancer Centre, Houston, TX, USA (1987‒1990). Returning to Germany in 1991, he took up a residency at the University of Regensburg, before becoming Professor and Chairman for Pathology at RWTH Aachen (1999‒2001). After which, he worked as a Professor and Chairman of Pathology at the University of Bonn (2001‒2011), before being appointed to his current position as Professor and Chairman of Pathology at the University of Cologne in 2011.
Abstract:
Traditionally, tumors are classified by histopathological criteria, i.e., based on their specific morphological appearances. Consequently, current therapeutic decisions in oncology are strongly influenced by histology rather than underlying molecular or genomic aberrations. The increase of information on molecular changes however, enabled by the Human Genome Project and the International Cancer Genome Consortium as well as the manifold advances in molecular biology and high-throughput sequencing techniques, inaugurated the integration of genomic information into disease classification. We have therefore introduced multiplex deep sequencing of informative gene sets into routine histopathological diagnostics and molecular pathology. This comprehensive approach integrating morphological and molecular information is currently changing cancer diagnostics in five categories: (1) Somatic genomic or epigenomic alterations acquired during cancerogenesis may be used for disease classification as we show this approach adding important information to conventional morphological classifications. (2) A significant portion of solid tumors depend on oncogenic driver lesions, which provide molecular targets for prediction of effective and selective therapies. (3) Genomic alterations in signal transduction cascades and gene expression pattern may be used as prognostic parameters predicting the need and extent of adjuvant therapy. (4) In the case of multiple syn- or metachronous tumors, genomic profiling assists allocation of metastases from tumors with unknown primary (CUP) and correct staging as multiple small primary tumors and systemic metastases are reliable being discriminated. (5) Finally, mutational profiling of tumor circulating tumor DNA may facilitate monitoring the response of tumors to therapy and development of secondary resistance.
Taken together, comprehensive molecular tumor pathology and oncology paves the way for a new rational and the basis of personalized genomic medicine. This requires state-of-the art tumor diagnostics and therapies in an interdisciplinary approach. Therefore, we will review current technology and applications of NGS for molecular and predictive cancer diagnostics.
Keynote Forum
Jim Zhai
Professor of Pathology, Mayo Clinic Jacksonville, USA
Keynote: Diagnosis of Salivary Gland Tumors: from Morphology to Molecular Markers
Biography:
Dr. Qihui Zhai is a pathologist in Jacksonville, Florida and is affiliated with Mayo Clinic. He received his medical degree from Shandong Medical University and has been in practice for more than 20 years. Dr. Zhai accepts several types of health insurance, listed below. He is one of 13 doctors at Mayo Clinic who specialize in Pathology.
Abstract:
Salivary glands tumors have numerous entities and each tumor type is of wide histologic spectrum. Clinical presentation is not particularly helpful, with the usual presentation of a bump.
The growth pattern of the tumor is a very critical histologic feature. If it is invasive and destructive, the tumor is very likely to be malignant. If it is well circumscribed/well demarcated, it is either a benign or a low grade tumor. Based on the presence of one cell type (luminal or non-luminal alone) or mixed luminal and non-luminal cell component (with an obvious extracellular matrix or not), we can classify most of the salivary gland tumors. Fine needle aspiration has been very useful in screening lesions with minimal trauma. However, previous FNA procedures can induce squamous metaplasia and tissue infarction, which sometimes misleads the pathologist. The metaplastic change also can mimic a low-grade mucoepidermoid carcinoma. On the other hand a low-grade carcinoma such as cystic mucoepidermoid carcinoma is easily misdiagnosed a benign lesion, due to unimpressive bland cytological features.
Immunohistochemistry studies are valuable when used along with histology; the main application is to demonstrate the cellular differentiation. Modern molecular tools such FISH are important in separating those tumors with overlapping morphology. Translocations are found in adenoid cystic carcinoma (49%, MYB-NFIB), low and intermediate grade mucoepidermoid carcinoma (55%, CRTC1-MAML2), low-grade hyalinizing clear cell carcinoma (>80%, EWSR1-ATF1), and secretory carcinoma (>90%, ETV6-NTRK3).
It is more stressful when we handle salivary gland tumors intra-operatively, because of the freezing artifacts and limited time, as well as the unavailability of ancillary tools. The combination of tumor demarcation, cell types, and cytological features can lead to correct diagnoses for most cases. For those rare and difficult cases, separating benign/low grade from high-grade tumors is usually sufficient to guide the immediate surgical procedure.
Keynote Forum
Jianhua Luo
Department of Pathology, University of Pittsburgh School of Medicine, USA
Keynote: Genomic Drivers of Human Cancers: Diagnostics, Prognostics and therapeutics
Biography:
Dr. Luo has been studying molecular pathology related to human malignancies in the last 24 years. Currently, he is a Professor of Pathology and Director of High Throughput Genome Center at University of Pittsburgh. In the last 16 years, Dr. Luo has been largely focusing on genetic and molecular mechanism of human prostate cancer and hepatocellular carcinomas. In this period, his group has identified and characterized several genes that are related to prostate cancer and hepatocellular carcinoma, including SAPC, myopodin, CSR1, GPx3, ITGA7, MCM7, MT1h and GPC3. He has characterized several signaling pathways that play critical role in prostate cancer development, including Myopodin-ILK-MCM7 inhibitory signaling, myopodin-zyxin motility inhibition pathway, CSR1-CPSF3, CSR1-SF3A3 and CSR1-XIAP apoptotic pathways, MT1h-EHMT1 egigenomic signaling, ITGA7-HtrA2 tumor suppression pathway, GPx3-PIG3 cell death pathway, AR-MCM7 and MCM7-SF3B3 oncogenic pathways. He proposed prostate cancer field effect in 2002. He is one of the pioneers in utilizing high throughput gene expression and genome analyses to analyze field effects in prostate cancer and liver cancer. He is also the first in using methylation array and whole genome methylation sequencing to analyze prostate cancer. Recently, Dr. Luo’s group found that patterns of copy number variants of certain specific genome loci are predictive of prostate cancer clinical outcomes, regardless tissue origin. His discovery of several novel fusion transcripts and their association with aggressive prostate cancer has brought significant new insight into the field of prostate cancer research. Overall, these findings advance our understanding on how cancer develops and behaves, and lay down the foundation for better future diagnosis and treatment of human malignancies.
Abstract:
Accurate prediction of clinical courses of human cancers remains elusive. In recent studies, we performed whole genome analysis on prostate and liver cancers. Our result showed that combination of genome copy number variance and novel fusion transcripts specific for cancer achieved high accuracy in predicting clinical outcomes of these cancers. Interestingly, some of these fusion genes are also present in a variety of human malignancies. Some of these fusion gene products trigger new pathways that are essential for carcinogenesis in multiple human cancers, and create novel functions that are not present in wild type gene counterparts. Treatment of cancers with drugs specific for fusion genes and their signaling pathways produced dramatic improvement of metastasis and survival rate of animals xenografted with cancers positive for these fusion genes. Our analyses suggest that targeting therapy for fusion genes holds promise as an effective treatment for human cancers.
Keynote Forum
Sergey V Brodsky
Professor,The Ohio State University, Columbus, OH, USA
Keynote: ARN – anticoagulant related nephropathy: lessons from patients and experimental animals
Biography:
Sergey V Brodsky has completed his MD and PhD in 1992 and 1995, perspectively from North Ossetian Medical Academy in Russia. His research interests include renal pathology, renal physiology, vascular biology and angiogenesis. After finishing a residency in anatomic pathology and a fellowship in renal pathology in 2009, he currently works as a renal pathologist at the OSU. He has published more than 95 papers in peer-reviewed journals and book chapters.
Abstract:
We have recently identified a new clinical syndrome in patients receiving warfarin for anticoagulation. This syndrome has been named warfarin-related nephropathy (WRN), and patients with chronic kidney disease (CKD) appear to be particularly susceptible. WRN is defined as an acute increase in INR to greater than 3.0, followed by evidence of acute kidney injury (AKI) within a week of the INR increase, defined as a sustained increase in serum creatinine of greater than or equal to 0.3 mg/dl. The AKI cannot be explained by any other factors, and the kidney biopsy demonstrates extensive glomerular hemorrhage with tubular obstruction by red blood cells. Beyond AKI, WRN is a significant risk factor for mortality within the first two months of diagnosis and it accelerates the progression of CKD. CKD is the most important risk factor for WRN, and in CKD patients on warfarin who experience an increase in INR to > 3.0, WRN is seen in 33 – 37% of the patients
Recent evidences suggest that WRN-like syndromes are not confined to anticoagulation with warfarin, but may be seen with the newer oral anticoagulants coming into clinical use. We have thus coined the term anticoagulant-related nephropathy (ARN) to encompass the possibility that other anticoagulant drugs may put patients at risk.
We developed an animal model to study ARN. 5/6 nephrectomy rats treated with warfarin or dabigatran showed increase in serum creatinine and morphology in the kidney similar to humans.
Nephrologists and renal pathologists should be aware about this serious complication of anticoagulation therapy.
- Microbial Pathology | Breast Pathology | Dermatopathology | Veterinary pathology | Digital Pathology | | Plant pathology | Immunopathology | Histopathology | Speech & language pathology | Experimental Pathology
Session Introduction
Anita Huttner
Associate Professor of Pathology, Yale University School of Medicine, USA
Title: Recapitulating malformations of cortical development via Induced pluripotent stem cell technology
Biography:
Dr. Anita Huttner started her career as MD at the University of Erlangen-Nurnberg, Germany on 1998. she has worked as the clinical fellow at Yale Medical School - Yale-New Haven Hospital & Harvard Medical School - Brigham and Women's Hospital and Childrens' Hospital. She has completed her Pre-/Postdoctoral fellow from National Institutes of Health. Currently, she is working as the Associate Professor of Pathology, Yale University School of Medicine, USA
Abstract:
Background: Progress in our understanding of somatic cell reprogramming, particularly the isolation and characterization of human induced pluripotent stem cells (iPSCs) opened new avenues for modeling human disease. IPSCs allow the generation of large numbers of genetically modifiable cells specific to the underlying human genetic background, and form an unparalleled opportunity to gain new insight into disease pathophysiology. This will further lay the foundation for the development of patient specific pharmacological assays and/or stem cell based therapies. We focused on Walker Warburg Syndrome (WWS), a rare and severe form of lissencephaly paired with congenital muscular dystrophy. Most children die before the age of three years. Several genes have been implicated in the etiology of this syndrome, however, to this date the pathogenesis is poorly understood. In addition, none of the animal models appears to faithfully reflect the human condition. Patient derived IPSCs, however, allow the targeted differentiation of cells into tissue specific phenotypes of brain and muscle, and thus provide an assay for the recapitulation of disease specific pathophysiology.
Design: IPSC lines were derived from skin biopsy specimens of patients with WWS and normal age matched controls. The generation of iPSCs followed established protocols using nucleofection (Amaxa system) of episomal plasmids expressing OCT3/4, SHp53, SOX2, KLF4, LIN28, and MYC. The cells were grown in culture and differentiated into all lineages of the human brain. Furthermore, since one of the hallmark features of lissencephaly is altered neuronal activity, this system form a unique opportunity to monitor electrical activity of iPSC derived neurons.
Result: Directed differentiation of iPSCs into neuronal precursors was demonstrated in vitro with antibodies for CNS phenotypes, like GFAP, TUJ1, Tbr1/2. Furthermore, neuronal activity was monitored with ultrasensitive fluorescent protein calcium sensors (GCaMP6) and showed altered neuronal activity in neurons derived from patients versus normal controls.
Conclusion: This model allows the phenotypic recapitulation of complex neurogenetic traits, and provides insights into the pathophysiology of human forms of malformations of cortical development. The combination of technologies offers a unique opportunity to model human neurological disease and hold promise for the development of new treatment strategies.help this recognition.
Graciela Ghirardi
Alta Gracia, Córdoba. Argentina
Title: Atypical immature metaplasia (aim) and importance of p16 and ki67 immunohistochemical expression in a city of south america
Biography:
Graciela Ghirardi Awarded by the Council of Physicians of the Province of Córdoba. Certification for life, February 22, 2013 as “Specialist in Pathological Anatomy”. She was the Head of Pathology Anatomy at Hospital Córdoba Hospital for 13 years and she served as the President Gremial Hospital Córdoba for 3 Periods. She has Publication in book Poems "Sendas" in the year 2009.
Abstract:
Introduction: The term AIM was coined in 1983 to describe a squamous proliferation of the cervical transformation zone and glands associated with abnormal cytology and colposcopic findings. This condition may be a precursor of HPV integration. This subject is controversial because its biological and clinical significance are not well defined. Colposcopy suffers from the same diagnostic difficulties than Cytology and Pathology. The effect of gene inactivation in the cervical epithelium was investigated for the overexpression of p16 protein by Immunohistochemistry (IHC), which results in the loss of activation of Rb by the E7 protein of high-risk HPV.
Objective: demostration use of biological markers, such as p16 and Ki67, which can be useful when diagnosing lesions with AIM.
Material And Methods: A descriptive study of the IHC expression of p16 and Ki67 in 60 formalin-fixed paraffin-embedded cervical biopsies obtained from the private archive of a Pathology Laboratory, was conducted.
Results: Negative cases for both p16 and Ki67 represented 69% of HPV lesions without dysplasia, whereas high-grade lesions (CIN III) were 100% positive for both p16 as Ki67. CIN I lesions were positive in 64% of the cases for both markers, and the rest were negative. CIN II lesions scored higher for p16 positivity, yielding positive results in 54% of the cases and 14% for Ki67.
Conclusions: MIA is a complex entity can be associated with HSIL. The similarities between the MIA and LSIL could be considered a form of LSIL. p16 is a marker for HPV-induced dysplasia. We suggest cautious behavior, for the sake of diagnostic accuracy. Considering the increased incidence of cervical carcinoma and its relationship to HPV, we deem useful to use biological markers such as p16 and Ki67, that may allow to determine the possible progression of SIL to invasive carcinoma as more economical tool that may be more in tune with the socio-economic reality of Latin America and cost-effective, when compared to other more expensive techniques.
Paul Hartel
MD MSc, FCAP, FASCP, FFPath (RCPI) Sligo University Hospital, Sligo, Ireland
Title: Primary undifferentiated high grade sarcoma of the breast: A clinicopathologic study of 19 cases.
Biography:
Dr Hartel is Consultant Histopathologist, Sligo University Hospital, Ireland and holds faculty appointment with West Virginia University and National University of Ireland. Dr Hartel trained in pathology at West Virginia University and fellowship in pulmonary pathology at Armed Forces Institute of Pathology, Washington DC. He is active in teaching and research and has many speaker invitations nationally/internationally. He has served numerous editorial boards and law firms as expert witness. Dr Hartel is Diplomate of American Board of Pathology and Fellow, Faculty of Pathology Royal College of Physicians in Ireland, College of American Pathologists and American Society of Clinical Pathology.
Abstract:
Aims: We present 19 cases of primary undifferentiated high grade sarcoma of the breast (previously termed pleomorphic malignant fibrous histiocytoma; MFH), the largest series to date, and compare our results with those in the literature to better define MFH in this anatomic location.
Methods and Results: Twenty-seven cases (MFH, myxofibrosarcoma, or pleomorphic sarcoma NOS) were reviewed using WHO and FNCLCC criteria. Inclusion required location within breast parenchyma without extensive chest wall involvement. Morphologic features were recorded and immunohistochemistry applied. Clinical data were extracted from patients’ medical records. Clinically, there was one male patient. Five of fifteen (33% overall) patients with follow-up died of disease within an average of 7 months following diagnosis. Distant metastases and older patient age were associated with poor survival. Storiform-pleomorphic subtype was most common (10/19) with myxofibrosarcoma (6/19) and giant cell subtype (1/19) also observed. Unique lymphocyte-rich (1/19) and pleomorphic hyalinizing angiectatic tumor (PHAT)-like (1/19) morphologies are presented. Immunohistochemistry demonstrated expression of CD68 (71%), focal smooth muscle actin (36%), with rare focal ER and PR immunoreactivity. All cases were negative for CD34, S100 protein, desmin 33, and keratins, including CK7, CK20, CK5/6 and CK18.
Conclusions: MFH occurs as a primary lesion in breast parenchyma. Attention to morphologic detail and immunohistochemistry avoids misdiagnosis. Entrapped breast ductal epithelium should not be misinterpreted as the epithelial component of a biphasic tumor. A florid lymphoid response should not be confused with metaplastic carcinoma. PHAT-like features may be observed in MFH. Our study confirms the presence of MFH in breast and presents unique morphologic observations of primary breast MFH.
Peter E.Stoemmer
Anja Meyer and Thomas Pusl Pathologie Augsburg Hermanstrasse 1 and Intensive care unit, ZK Augsburg, Germany
Title: An unusual case of Gynecomastia and Urothelial Bladder Cancer
Biography:
Peter Stoemmer has studied medicin at the university of Erlangen-Nuremberg, Germany and completed his MD, PhD and specialisation as general pathologist (including cytopathology and molecular pathology) at the age of 36 years) from Friedrich Alexander University Erlangen; after postdoctoral studies from Yale University School of Medicine in the laboratory of Juan Rosai and the supervision of A.B.
He is the director and partner of Pathologie Augsburg, an independent Laboratory for surgical Pathology. He is senior lecturer and professor at the institute of pathology at the Friedrich Alexander university and published more than 125 papers in journals
Abstract:
A 29-year old patient was referred to the medical clinics of ZK Augsburg; he complained of bilateral rather indolent asymmetric enlargement of his breasts: the left mamma being larger. Few small nodal consistences in the left breast was palpated; no nipple discharges were found. Ultrasonics and mammography showed a gynecomastia without features of a malignant tumor.
Anamnestically, the patient practiced bodybuilding (and denied the use of androgenic steroidal anabolics); erectile functions were normal; undescended testes were corrected by surgery in childhood., the left testis was atrophic.
Hormonal studies showed testosteron in the high-normal range and his estradiol and HCG were elevated, while the gonadotropins were suppressed; normal fetoprotein.
Cranial MRI and Chest-CT-Scan were normal; the bladderwall in abdominal CT thickened.
Cystoscopy, performed due to painless macrohematuria showed a small unifocal papillary tumor in the bladderwall followed by transurethral resection.
Histology: Multiple particles of a soft, grey focal hemorrhagic tissue together 0.5g with up to 10 layers of atypical urothelia; some preserved umbrella cells.No invasion into the muscularis. IHC: ectopic expression of HCG.
Diagnosis: Papillary urothelial carcinoma of the bladder with no invasion into the lamina propria (pTa G1 cN0 cM0)
In the following weeks, HCG was no longer detectable, his sex hormones returned to normal, and gynecomastia completely regressed.
HCG-producing tumors of the bladder are known since 1904 (1), but these were ectopic choriocarcinomas. In our case, the tumorcells are typical urothelia with ectopic HCG-production; we assume that this is the cause of estrogen- induced proliferation of male mammary glands.
Rana Ezzeddini
Department of Clinical biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
Title: High Expression of HIF1α is a predictor in patients with gastric adenocarcinoma
Biography:
Rana Ezzeddini is a PhD student in Clinical Biochemistry at Tarbiat Modares University. She received her master degree in Clinical Biochemistry, as well. Her main research interest is clinical laboratory trials, with a focus on addressing biochemical questions for cancer and genetic deficienses.
Abstract:
Background: Gastric adenocarcinoma has been known as one of the virulent diseases with weak prognosis. New findings of gastric cancers according to histologic features and molecular phenotypes improve early diagnosis, prevention and treatment. Hypoxia inducible factor 1α (HIF1α) are expressed in some human cancers and were previously suspected of promoting tumor growing and poor patient outcome. The objective of this study is to investigate the expression of HIF1α protein in adenocarcinoma tissues.
Materials & Methods: We selected 105 gastric cancer patients and 130 healthy control with the age range of 30-80 in order to carry out this study. The ethical committee of Tarbiat Modares University (Tehran, Iran) authorized this study. The study was explained to the participants and Informed consent was obtained from all individuals. Formalin-fixed, paraffin wax-embedded sections were cut at approximately 5 μm. Immunohistochemical staining for HIF1α were performed in all samples. Image J software was used for microscopic investigation and comparing the outcomes. We used t test for data analysis. P values less than 0.05 was considered as statistically significant difference in all cases.
Results: Our findings indicated significant upregulation of HIF1α expression in gastric adenocarcinoma tissues (0.25±0.07) compare to control group (0.18±0.04) ( P = 0.0001).
Conclusion: As a result, the present study suggested that increased HIF1α were involved in progression of gastric adenocarcinoma cells that can be used for distinguished classification.
Keywords: Gastric adenocarcinoma, Immunohistochemistry, HIF1α