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CASE I – 314I (AFIP 2741159)
Signalment: 1.4-year-old, female mongrel hound, canine (Canis familiaris)
History: This dog was purchased for research use in a magnetic resonance imaging project for the development of magnetic resonance-guided, focused ultrasound for tissue thermal ablation.
Gross Pathology: A smooth, firm, 12-15 mm diameter, lobulated, cutaneous mass was present on the lip of the vulva.
Laboratory Results: No laboratory analyses were performed. Routine pre-issue hematology, blood chemistry, and fecal parasitology examinations were considered normal.
Contributor’s Diagnosis and Comment: Canine transmissible venereal tumor.
A large, well-circumscribed, unencapsulated, expansile, densely cellular mass is present in the dermis, submucosa, and subcutaneous connective tissue. The mass is composed of monotonous sheets of uniform round cells with lightly staining cytoplasm and large hyperchromatic nuclei. The tumor cells are situated in an arborizing fibrovascular network. Numerous mitotic figures are present (3-8 mitotic figures/hpf).
Our research group has developed the canine transmissible venereal tumor (TVT) as a large, animal-transplantable tumor model. Tumors have been experimentally transplanted in multiple dogs, with and without immunosuppression, by inoculating 0.25–0.5 ml of tumor fragments intramuscularly, subcutaneously, and submucosally.
TVT is a naturally occurring transplantable tumor that is typically propagated and maintained among the dog population by coitus and the social behavioral trait of smelling and licking of the external genitalia. Although the tumors are located most commonly on the external genitalia (prepuce, penis, vulva, and vagina), they also have been reported extragenitally in the skin, lips, buccal and nasal mucosa, and less frequently in the tonsils, liver, pancreas, spleen, lung, kidney, and inguinal and mesenteric lymph nodes. Tumors begin as nodules in the submucosa or subcutis and typically undergo spontaneous regression in 4-6 months. Tumor regression is commonly associated with infiltrating lymphocytes composed primarily of T cells.
The tumor has been reported worldwide and there are marked fluctuations in its prevalence in endemic areas every few years. TVT cells have 59 chromosomes, in comparison with normal canine cells possessing 78 chromosomes. It seems unlikely that that this tumor originated spontaneously in multiple geographic regions, but rather became widely distributed by its infectious nature. The chromosome complement of tumor cells collected from areas as widely separated as Japan and North America have been found to be closely similar, with minor variations that are considered to be within acceptable limits for stem-lines of transplantable tumors and long-term cell cultures.
AFIP Diagnosis: Mucocutaneous junction: Transmissible venereal tumor, mixed breed dog, canine.
Conference Comment: Among primary mammalian neoplasms, transmissible venereal tumor (TVT) is unique in that it represents the only naturally transplantable tumor, originally demonstrated in studies with dogs by Novinksy in 1876. The transmission of TVT represents an allogeneic cellular transplant, with tumor cells able to cross major histocompatability barriers. Tumor cells survive for a variable period of time following transplantation, until class I and class II major histocompatibility antigens are expressed and IgG antibody-mediated regression occurs. In some dogs with progressive TVT, tumor-associated antigen has been shown to block antibody development, suggesting a possible role in the tumor’s ability to evade systemic immune response and allow tumor growth. Dogs that recover from TVT after spontaneous regression acquire humoral and cellular immunity that makes them refractory to subsequent tumors.
Based on tumor histomorphology, and without the benefit of anatomic location, the differential diagnosis discussed in conference included plasmacytoma, histiocytoma, mast cell tumor, malignant lymphoma, and amelanotic melanoma. The uniform chromatin pattern, lack of nuclear atypia, and multifocal individual cell necrosis were considered compatible with TVT. Although not seen in sections viewed in conference, these tumors often have nodular lymphocytic infiltrates with scattered eosinophils, probably in association with tumor regression.
Contributor: The University of Texas, MD Anderson Cancer Center, Department of Medicine & Surgery, 1515 Holcombe Boulevard, Houston, TX 77030
References: 1. Acland HM: Female reproductive system. In: Special Veterinary Pathology, ed. Thompson RG, p. 627. BC Decker, Inc., Philadelphia, PA, 1988
2. Amber EI, Isitor GN, Adeyanju JB: Viral-like particles associated with naturally occurring transmissible venereal tumor in two dogs: preliminary report. Amer J Vet Res 46(12):2613-2615, 1985
3. Gershwin LJ, Krakowka S, Olsen RG: Immunopathology. In: Immunology and Immunopathology of Domestic Animals, 2nd ed., p. 126. Mosby, St. Louis, MO, 1995
4. Hasler AH, Weber WT: Theriogenology question of the month. J Am Vet Med Assoc 216(10):1557-1559, 2000
5. Johnson D, Hagen E, Aksnes A, Fetrow N, Losco P, Harris M, Crewell C, Johnson K, Forsberg F, Merton D, Liu J, Goldberg B: Canine parenchymal transplantable tumor model (abstract). American Association of Laboratory Animal Scientists, PS41, Annual Meeting Abstracts, 1999
6. Kennedy PC, Miller RB: The female genital system. In: Pathology of Domestic Animals, ed. Jubb KVF, Kennedy PC, Palmer N, 4th ed., vol. 3, pp. 451-453. Academic Press, Inc., New York, NY, 1993
7. Mozos E, Méndez A, Gómez-Villamandos JC, Martín de les Mulas J, Pérez J: Immunohistochemical characterization of canine transmissible venereal tumor. Vet Pathol 33:257-263, 1996
8. Nielsen SW, Kennedy PC: Tumors of the genital systems. In: Tumors in Domestic Animals, ed. Moulton JE, 3rd ed., pp. 498-502. University of California Press, Berkeley, CA, 1990
9. Rogers KS, Walker MA, Dillon HB: Transmissible venereal tumor: a retrospective study of 29 cases. J Am Anim Hosp Assoc 34:463-470, 1998
10. Yang TJ, Jones JB: Canine transmissible venereal sarcoma: transplantation studies in neonatal and adult dogs. J Natl Cancer Inst 51:1915-1918, 1973
CASE II – A98-338 (AFIP 2648726)
Signalment: 210-day-old, male rhesus monkey (Macaca mulatta)
History: This animal was inoculated with SIVmac239. Seven months later, the animal was euthanized because he was in poor health.
Gross Pathology: The animal weighs 680 grams. There are numerous fibrous adhesions between the lung lobes and from the lungs to the parietal pleura. On the dorsal regions of the parietal pleura, there are red fibrous tags. The lung lobes are adhered to each other and are covered by a white fibrous membrane. Approximately 60% of the right caudal lung lobe is firm, purple, and does not collapse. There is white foam in the lumen of the trachea. Peripheral lymph nodes and thymus are small. The upper and lower incisor teeth are eroded and brown, with the upper arcade more severely affected. The mucosa at the ileocecal junction is red. The liver is diffusely tan.
Laboratory Results: By immunohistochemistry, Adenovirus–positive cells are present in the lung, duodenum, and ileum. Rare Pneumocystis carinii–positive organisms are present in the lung; no cells showed positivity for Cytomegalovirus.
Clinical Pathology: WBC=31,600/ul (H)*; segmented neutrophils=25,900/ul (H); bands=632/ul (H); eosinophils=632/ul (H)
RBC=3.61 X 106/ul (L); Hgb=8.2 g/dl (L); MCV=64 fl (L); MCHC=35.7% (H); Hct=23 % (L)
Creatinine=0.2 mg/dl (L); total protein=3.4 g/dl (L); albumin=1.6 g/dl (L); globulin=1.8 g/dl (L); calcium=6.7 mg/dl (L); alkaline phosphatase=5300 U/L (H)
*H=high, L=low
Contributor’s Diagnoses and Comment: 1. Multifocal, necrotizing and fibrinosuppurative, interstitial pneumonia, with intranuclear Cowdry type A and B viral inclusion bodies (adenovirus), lung.
2. Chronic, focally extensive to diffuse, fibrinous pleuritis, lung.
(Although the submitted slides are all from the right caudal lung lobe, the severity of the lesions varies from mild to severe.)
Since 1998, in our lab there have been seven rhesus infants, inoculated with various molecular clones of simian immunodeficiency virus (SIV), that were positive by immunohistochemistry for adenovirus. As a group, positive staining for the adenovirus hexon was found in the lung (2/7), liver (1/7), pancreas (1/7), lacrimal gland (1/7), salivary gland (1/7), stomach (1/7), duodenum (3/7), ileum (7/7), and colon (1/7). At the time of submission, virus isolation and serotyping was pending on these cases.
Adenoviruses are in the family Adenoviridae, which contains the genera Mastadenovirus (mammalian) and Aviadenovirus (avian). The genus Mastadenovirus includes: human adenovirus 1-49 (subgroups A-F), simian adenovirus 1-27 (including 7 in chimpanzees), bovine adenovirus 1-9, porcine adenovirus 1-4, ovine adenovirus 1-6, caprine adenovirus 1 & 2, equine adenovirus 1 & 2, infectious canine hepatitis virus (canine adenovirus 1), infectious canine tracheobronchitis (canine adenovirus 2), and murine adenovirus 1 & 2. The genus Aviadenovirus includes fowl adenoviruses 1-12, turkey adenoviruses 1-3, goose adenoviruses 1-3, pheasant adenovirus 1, and duck adenoviruses 1 & 2.
The virion of adenovirus, measuring 80-110 nm in diameter, contains linear, double-stranded DNA with a genome size of 36-38 kbp. It is a non-enveloped virus with an icosahedral capsid and surface projections (fibers) from each pentamer. Virions are assembled in the nucleus, producing intranuclear inclusions arranged in paracrystalline arrays. New virions are released via cell lysis. The many serotypes of adenovirus, determined by virus neutralization, are highly host specific.
Most infections with adenovirus are systemic, but some strains have tropism for respiratory epithelial cells, enterocytes of the alimentary tract, vascular endothelial cells, or hepatocytes. Animals infected with adenovirus typically have subclinical infections; however, upper respiratory diseases, gastroenteritis, and generalized disease processes can be seen, especially in immunocompromised individuals. Infections are associated with long periods of latency. Persistent infection of pharyngeal lymphoid tissue can serve as a source of infection to new generations of animals. Transmission of the virus is usually by aerosol or fecal-oral routes.
Cytomegalovirus (betaherpesvirus) is a major differential diagnosis for the large inclusions present in the submitted sections of lung. In nonhuman primates and man, cytomegalovirus is typically latent, but can result in disseminated disease in individuals immunocompromised with SIV or HIV. The virus is found in macrophages, and endothelial or epithelial cells. Affected tissue contains areas of necrosis with neutrophilic infiltrates. Infected cells have enlarged nuclei and increased cytoplasm, and the nucleus often contains large, eosinophilic viral inclusions.
AFIP Diagnosis: Lung: Pneumonia, bronchointerstitial, necrotizing, subacute, diffuse, severe, with type II pneumocyte hyperplasia, fibrinous pleuritis, and basophilic intranuclear inclusion bodies, rhesus macaque (Macaca mulatta), nonhuman primate.
Conference Comment: SIV infection in macaques causes an immunosuppressive disease that usually results in death as a result of profound anemia, generalized wasting, prolonged fever, lymphadenopathy, and opportunistic infections. CD4+ lymphocytes are often lost as the disease progresses, resulting in a terminal lymphopenia. Opportunistic adenoviral infections commonly are associated with fatal pneumonia or gastroenteritis in these animals.
Multinucleated cells seen within alveoli by conference participants were interpreted to be pulmonary alveolar macrophages, and not viral-induced syncytial cells.
Contributor: Harvard Medical School Research Center, Division of Comparative Pathology, One Pine Hill Drive, P.O. Box 9102, Southborough, MA 01772
References: 1. Barker IK, van Dreumel AA, Palmer N: The alimentary system. In: Pathology of Domestic Animals, ed. Jubb KVF, Kennedy PC, Palmer N, 4th ed., vol. 2, pp. 181-184. Academic Press, New York, NY, 1993
2. Dungworth DL: The respiratory system. In: Pathology of Domestic Animals, ed. Jubb KVF, Kennedy PC, Palmer N, 4th ed., vol. 2, pp. 626-628. Academic Press, New York, NY, 1993
3. Fenner FJ, Gibbs EPJ, Murphy FA, Rott R, Studdert MJ, White DO: Veterinary Virology, 2nd ed., pp. 329-336. Academic Press, Inc., San Diego, CA, 1993
4. Ochs HD, Morton WR, Tsai C-C, Thouless ME, Zhu Q, Kuller LD, Wu YP, Benveniste RE: Maternal-fetal transmission of SIV in macaques: disseminated adenovirus infection in an offspring with congenital SIV infection. J Med Primatol 20:193-200, 1991
CASE III – 99-5995 (AFIP 2741180)
Signalment: Adult, female rhesus monkey (Macaca mulatta).
History: The dam aborted during the 16th week of gestation. The monkey had been healthy except for two episodes of uterine bleeding, first at two weeks and again thirty-six hours prior to abortion. The fetus was viable by ultrasound within ten days of abortion. Previously, the dam delivered two healthy infants.
Gross Pathology: The fetal lungs were collapsed, mottled red/tan, and had increased firmness. The placenta was unremarkable.
Laboratory Results: Group B Streptococcus sp. was isolated from the stomach contents of the fetus; group G Streptococcus sp. was isolated from the vagina of the dam at the time of abortion.
Contributor’s Diagnoses and Comment: 1. Chorioamnionitis, acute, multifocal, moderate, placenta.
2. Pneumonia, acute, diffuse, moderate, fetal lung.
An acute inflammatory infiltrate was present in the chorionic plate of the placental disk. Prominent numbers of neutrophils, with necrosis and cellular debris, were noted in the chorion, and expanded the interface of the chorion and amnion, and the chorionic undersurface (extravillous trophoblastic layer). Bacteria also were present, usually associated with the amniotic membrane. Sections of lung contained a similar inflammatory infiltrate in small airways and alveoli mixed with lesser numbers of mononuclear cells and squames. The umbilical cord, umbilical vessels, and several branches of the umbilical blood vessels in the placental disk had similar infiltrates and/or fibrinoid change in the vessel walls. Fetal spleen and mesenteric lymph nodes had lymphoid depletion and multifocal, small aggregates of neutrophils.
In human placentas, acute chorioamnionitis (ACA) is “characterized by an acute inflammatory infiltrate in one or more of the following structures: the extraplacental membrane, chorionic plate and its undersurface, or blood vessels in the chorionic plate and umbilical cord.” Clinically, ACA may cause fever, leukocytosis, uterine tenderness and foul-smelling amniotic fluid, or no maternal signs. In the latter “silent” case, ACA is diagnosed histologically.
ACA is considered to have an infectious etiology and organisms such as streptococci, staphylococci, pseudomonas, E. coli, proteus, klebsiella, clostridia, and mycoplasma are common causes in man. The usual route of infection is ascending via the birth canal. Subsequent to infection, the fetus may develop intrauterine pneumonia, become septic, and infrequently may die. Likewise, maternal sepsis is uncommon. More frequently, acute chorioamnionitis plays an indirect role in fetal compromise or death. Specifically, ACA may initiate preterm birth, premature rupture of fetal membranes, placental abruptions, umbilical vein thrombosis, and fetal defecation with toxic consequences of meconium.
Histologically, the placenta from this rhesus monkey meets the criteria for ACA as described in humans. While the lesion was considered of bacterial origin, the placenta was not cultured. Group B streptococci were isolated from the stomach contents of the fetus, and group G streptococci were present in the vagina of the dam at the time of abortion.
The spontaneous abortion in this animal was attributed to premature labor secondary to acute chorioamnionitis and funisitis. Streptococcal organisms may have been responsible for the infection. The role of uterine bleeding in this process is of unknown significance. If bleeding were associated with an incompetent cervix, then entry of organisms would have been possible. The likelihood of survival in a 112-day-old rhesus fetus is low, considering the normal gestation period is 168 ± 7 days.
AFIP Diagnoses: 1. Chorioamnion: Chorioamnionitis, neutrophilic, acute, diffuse, moderate, with fibrinoid vasculitis, and numerous extracellular and rare phagocytosed cocci, rhesus macaque (Macaca mulatta), nonhuman primate.
2. Fetal lung: Pneumonia, acute, diffuse, moderate, rhesus macaque (Macaca mulatta), nonhuman primate.
Conference Comment: Initiation of premature labor is frequently the most critical complication of ACA. Bacterial and neutrophilic phospholipases trigger the release of prostaglandins from placental membranes, which then cause uterine contractions and cervical dilation. The release of collagenases and elastases from neutrophils produces membrane rupture and the onset of premature labor. ACA is implicated in approximately one-third of preterm deliveries in women.
The delivery of preterm infants is further complicated in cases in which intrauterine fetal pneumonia develops. Occasionally, extension of ACA infection into the amnion occurs, with development of fetal septicemia secondary to pulmonary aspiration of infected amniotic fluid and resultant fetal pneumonia.
Aspiration of infected amniotic fluid is likely in this case, since there is little inflammatory response in fetal vessels. Intrauterine death or neonatal morbidity and mortality are possibilities with this infrequent complication. Infected amniotic fluid also can be aspirated into the middle ears or swallowed into the gastrointestinal tract.
Contributor: The University of Texas, MD Anderson Cancer Center, Department of Medicine & Surgery, 1515 Holcombe Boulevard, Houston, TX 77030
References: 1. Crum CP: The female genital tract. In: Robbins Pathologic Basis of Disease, ed. Cotran RS, Kumar V, Robbins S, 6th ed., pp. 1079-1091. WB Saunders, Philadelphia, PA, 1999
2. Doyle L, Young CL, Jang SS, Hillier SL: Normal vaginal aerobic and anaerobic bacterial flora of the rhesus macaque (Macaca mulatta). J Med Primatol 20:409-413, 1991
3. Joshi VV: Lesions of the membranes. In: Handbook of Placental Pathology, pp. 75-80. Igaku-Shoin, New York, NY, 1994
4. Kaplan C, Lowell DM, Salafia C: College of American Pathologists Conference XIX on the examination of the placenta: report of the working group on the definition of structural changes associated with abnormal function in the maternal/fetal/placental unit in the second and third trimesters. Arch Pathol Lab Med 115:709-716, 1991
5. Lewis SL, Benirschke K: Overview of placental pathology. In: Pathology of the Placenta, ed. Lewis SH, Perrin E, 2nd ed., pp. 10-11. Churchill Livingstone, Philadelphia, PA, 1999
6. Hyde, SR, Altshuler, G: Infectious disorders of the placenta. In: Pathology of the Placenta, ed. Lewis SH, Perrin E, 2nd ed., pp. 317-325. Churchill Livingstone, Philadelphia, PA, 1999
7. Naeye RL: The placenta: medicolegal considerations. In: Pathology of the Placenta, ed. Lewis SH, Perrin E, 2nd ed., pp. 387-391. Churchill Livingstone, Philadelphia, PA, 1999
CASE IV – 37447/616 (AFIP 2749923)
Signalment: 1.7-year-old, male Fischer 344 rat
History: The rat was in a 2-year toxicity/carcinogenicity study. The animal was found dead after inhalation exposure to a nasal carcinogen 6 hours per day, 5 days per week for 1.5 years.
Gross Pathology: There was a nasal mass that completely obliterated nasal tissues in one side of the nasal cavity, with focal invasion through the cribriform plate and into the brain.
Laboratory Results: Not applicable.
Contributor’s Diagnosis and Comment: Nasal cavity, olfactory epithelium: Neuroblastoma.
One half of the nasal cavity contains a highly invasive neoplasm that has completely obliterated nasal bone, turbinates, and nerves. Component neoplastic cells are moderately anaplastic and arranged as variably sized lobules, islands, nests, cords and occasional pseudorosettes separated by scant to moderate amounts of fibrovascular stroma. Cells are small to medium-sized, round to oval to polygonal, with scant, eosinophilic cytoplasm and pleomorphic hyperchromatic nuclei. Mitotic figures are 8-12 per high magnification field. In some sections, there are focal areas of squamous epithelial differentiation. Focal areas of hemorrhagic necrosis are present in the center of some islands and nests of neoplastic cells. In some sections, small nests of neoplastic cells are present in the submucosa of the nasal septum, and neoplastic cells have obliterated segments of the respiratory epithelium lining the nasal septum.
Olfactory neuroblastomas are rare spontaneous neoplasms in rats. However, they have been induced by exposure to potent nasal carcinogens. Synonyms for olfactory neuroblastomas include esthesioneuroblastoma, olfactory neuroepithelioma, and olfactory neuroepithelial carcinoma. It has been suggested that these neoplasms be classified under the general term ‘olfactory neuroepithelial carcinoma’ since this term allows for possible histogenesis from any one of the cell types in the olfactory region. Olfactory neuroblastomas are aggressive neoplasms that frequently invade the cribriform plate and extend into the brain. They are often accompanied by an increased incidence of focal olfactory epithelial hyperplasia.
Olfactory neuroblastomas are often highly anaplastic, poorly differentiated neoplasms, and are difficult to distinguish from poorly differentiated adenocarcinomas that may arise from the Bowman’s glands. Immunohistochemical staining and/or electron microscopic evaluation for neuronal features may be necessary to definitively identify these neoplasms. Component neoplastic cells form lobules, solid sheets, nests, ribbons, or narrow cords that are often separated by scant fibrovascular stroma. Cells may be pleomorphic with scant eosinophilic cytoplasm and round to oval, basal hyperchromatic nuclei. True (Flexner-Wintersteiner) and/or pseudo- (Homer-Wright) rosettes often are prominent features of the neoplasms. Electron microscopy is useful to identify neurogenic features, including electron-dense neurosecretory granules and neurofilaments.
AFIP Diagnosis: Nasal cavity: Neuroblastoma, olfactory, Fischer 344 rat, rodent.
Conference Comment: The contributor has provided a good summary of the histopathological features of neuroblastoma.
Laboratory rats make an ideal model for use in inhalation carcinogenicity studies because their long nasal passages trap and absorb inhaled hazardous materials that would easily travel into the lower respiratory tract of man. Because of differences in distribution of histological cell types in the nasal cavities and respiratory organs between man and rodents, some agents capable of causing lung cancer in man may cause nasal cavity tumors in rats. The variation in anatomical features within the nasal passages make it important that special attention be given to fixation and histological sectioning in order to obtain uniform and standard sections, and to make accurate histopathological diagnoses. Typically, 3 or 4 levels of the nasal passages are examined in the laboratory rat to adequately sample: squamous epithelium (nares, vestibule, anterior ventral meatus, and incisive duct); poorly ciliated transitional epithelium (anterior lateral wall and anterolateral surfaces of maxillary and nasal turbinates); pseudostratified ciliated respiratory epithelium (nasal septum and area between transitional and olfactory epithelium); and olfactory epithelium (mid dorsal meatus and ethmoid turbinates).
(Invitation: Those with additional interest in the features of the rodent respiratory tract as it relates to comparative inhalation studies, or in any other pursuit of toxicological pathology, are invited to contact us (frostd@afip.osd.mil) and request a guest pass to the Registry of Toxicologic Pathology for Animals’ online web conference.)
Contributor: National Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, NC 27709
References: 1. Brown HR, Monticello TM, Maronpot RR, Randall HW, Hotchkiss JR and Morgan KT: Proliferative and neoplastic lesions of the rodent nasal cavity. Toxicol Pathol 19(4):358-372, 1991
2. Brown HR: Neoplastic and potentially preneoplastic lesions in the upper respiratory tract of rats and mice. Environ Health Perspect 85:291-304, 1990
3. Herbert RA, Leininger JR: Nose, larynx, and trachea. In: Pathology of the Mouse, ed. Maronpot RR, Boorman GA, Gaul BW, pp. 286-292. Cache River Press, 1999
4. Mohr U, Capen CC, Dungworth DL, Greeisemer RA, Ito , Turusov VS: Respiratory system. In: International Classification of Rodent Tumors, Part II: The Mouse, no. 22, pp. 1-57. IARC Scientific Publications, Lyon, France, 1998
5. Mohr U: Respiratory system and mesothelium. In: International Classification of Rodent Tumors, Part I: The Rat, no. 1, pp. 1-44. IARC Scientific Publications, Lyon, France, 1992
6. Schuller HM, Gregg M, Reznik GK: Tumours of the nasal cavity. In: Pathology of Tumours in Laboratory Animals: Tumours of the Rat, ed. Turusov V, Mohr U, 2nd ed., vol. 1, no. 99, pp. 259-266. IARC Scientific Publications, Lyon, France, 1990
7. Schwartz LW, Hahn FF, Keenan KP, Keenan CM, Brown HR, Mann
PC: Proliferative lesions of the rat respiratory tract, R-1. In:
Guides for Toxicologic Pathology, pp. 1-24. STP/ARP/AFIP, Washington,
DC, 1994
*Sponsored by the American Veterinary Medical Association, the American College of Veterinary Pathologists and the C. L. Davis Foundation.
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