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Why do you need expert histopathology? | Services | Benefits | Submission Process | Downloadable Brochure
The Comparative Pathology Laboratory at The University of Georgia is dedicated to providing expert diagnostic and research pathology services to investigators using laboratory animals in their research projects.
« Why do you need expert histopathology?
Abstract
Genetically engineered mice (GEM) are a staple of modern biomedical research. While genetic engineering technology has become more and more sophisticated, proper pathological analysis of these animals is often lacking. Proper pathological analysis is often replaced by Do-it-Yourself (DIY) pathology, which often resulted in surprising "scientific discoveries".
Do-it- Yourself (DIY) Pathology
Conflict between pathology and genetic manipulation in the mouse
- Molecular biology is the driving force behind genetic manipulation in the mouse
- Scientists who create GEM often do not have training or knowledge on normative biology and disease processes within the context of a whole organism
- Adequate pathologic analysis is usually not performed
- One can publish a phenotypic analysis in a leading biomedical journal without input from a pathologist
The rise of Do-it-Yourself pathology
- Pathologists with rodent pathology training are few
- Pathological analysis is done by not adequately trained basic scientists
Consequences
- Adequate pathologic analysis is usually not performed
- The percentage of scientific reports on phenotypic analysis without input from a pathologists is actually decreasing (Figure 1.)
Modified from Cardiff et al. Lab Invest 88:18-26, 2008
Figure 1. The decrease of the percentage of scientific reports on phenotypic analysis without proper pathological analysis
Scientific Consequences of DIY Pathology
Histopathological interpretation by "wallpaper matching"
- GEM lesions are often unique
- Lesion interpretation in GEM should be done by an experienced comparative pathologist
- Histopathology knowledge cannot be acquired without the proper background in medicine and participation in a rigorous post-graduate training program
Normal organs identified as lesions>
- GEM lesions are often unique
Image from Fu L et al., Cell 111:51-50, 2002
Figure 2. The image above taken from a publication in Cell where the authors identified the bilaterally symmetrical preputial glands (white arrows) as "Mature cystic teratoma of hyperkeratotic skin with sebaceous glands".
Misinterpretation of inflammatory lesions as neoplastic processes
- Inflammatory lesions are sometimes misinterpreted as lymphoma
Image from Belpoggi et al. Eur J Oncol 4:563–572, 1999
Figure 3. The image above taken from a publication where this Mycoplasma-induced mixed inflammatory infiltrate around a bronchiole in rats treated with methyl-tertiary-butyl-ether was interpreted as lymphoma
Misinterpretation of proliferative lesions as neoplastic processes
- Inflammatory lesions are sometimes misinterpreted as lymphoma
Image from Berg et al., J Clin Invest. 98:1010-1020, 1996
Figure 4. The image above taken from a publication where crypt herniation (white arrows) through the muscularis mucosae was interpreted as an example of adenocarcinoma. Despite their appearance, these lesions will disappear with antibiotic treatment.
Solutions to DIY Pathology
The immediate future – large scale mouse mutagenesis programs that will require adequate pathology analysis
- Knock Out Mouse Project (KOMP) – NIH>
- North American Conditional Mouse Mutagenesis Program (NorCOMM) – Canada
- European Conditional Mouse Mutagenesis Program (EUCOMM) – Europe
- International Mouse Knockout Consortium
- "Complex Traits" Consortium
Responsibilities of scientific journals
- Editors should recruit comparative pathologists to review manuscripts on GEM
- Editors should require expert pathology interpretation in each GEM manuscript>
- Journals should use appropriately-sized histologic images in publications (i.e., much larger than a postage stamp)>
Responsibilities of biomedical investigators – follow published reports (see examples in References section)
- Mouse models of intestinal cancer
- Prostate pathology of GEM
- Proliferative pulmonary lesions
- Classification of non-lymphoid hematopoietic neoplasms
Responsibilities of training institutions
- Current veterinary and human pathology training programs should focus on comparative pathology as well>
- Training programs should expose their trainees to pathology of genetically engineered mice
- Encourage their interested trainees to attend appropriate workshops on mouse pathology>
References
- Cardiff et al. "One medicine – one pathology": are veterinary and human pathology prepared? Lab Invest 88:18-26, 2008
- Fu et al. The circadian gene Period2 plays an important role in tumor suppression and DNA damage response in vivo. Cell 111, 41-50, 2002
- Belpoggi et al. Immunoblastic lymphomas in Sprague-Dawley rats following exposure to the gasoline oxygenated additives methyl-tertiary-butyl-ether (MTBE) and ethyl-tertiary-butyl-ether (ETBE): Early observations on their natural history. Eur J Oncol 4: 563–572, 1999
- Berg et al., Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4(+) TH1-like responses. J Clin Invest. 98:1010-1020, 1996
- Boivin et al. Pathology of mouse models of intestinal cancer: consensus report and recommendations. Gastroenterology 124:762–777, 2003
- Nikitin et al. Classification of proliferative pulmonary lesions of the mouse: recommendations of the mouse models of human cancers consortium. Cancer Res 64:2307–2316, 2004
- Kogan et al. Bethesda proposals for classification of nonlymphoid hematopoietic neoplasms in mice. Blood 100:238–245; 2002
Acknowledgments
The author wishes to express his gratitude to the following individuals who were instrumental in shaping his career: Peter Aronson, MD (Yale University), Sean McDonough, DVM, PhD (Cornell University), Brain Summers, BVSc, PhD (Royal Veterinary College), Donald Schlafer, DVM, PhD (Cornell University), and Jun-Lin Guan, PhD (University of Michigan).
Comparative Pathology Laboratory
Department of Pathology
501 DW Brooks Drive
Athens, GA 30602-7388
Contact Information
Tamas Nagy, DVM, PhD, Diplomate, American College of Veterinary Pathologists
Director, Comparative Pathology Laboratory
Department of Pathology
College of Veterinary Medicine
University of Georgia
Athens, GA 30602-7388
Phone: 706.202.8608
FAX: 706.542.5828
Email: tnagy@uga.edu
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Laboratory Staff
Tamas Nagy, DVM, PhD, Diplomate, American College of Veterinary Pathologists
Director
tnagy@uga.edu
Rhonda Wheeler
Research Technician III
rwheeler@uga.edu
