The Armed Forces Institute of Pathology Department of Veterinary Pathology WEDNESDAY SLIDE CONFERENCE 2003-2004 CONFERENCE 16 25 February 2004 Conference Moderator: Dr. Laura Richman, DVM, PhD, Diplomate ACVP Pathologist/Scientist II MedImmune, Inc. Gaithersburg, MD 20878 CASE I - 991622.4 (AFIP 2739904) Signalment: Canine, Brie sheepdog, male, 14 week-old. History: This dog was presented for polyuria-polydipsia, emaciation, prostration, vomiting, and terminal seizures. Gross Pathology: Remarkable lesions were: - A diffuse thickening of the cranial bones and of the mandible (Figures 1 and 2). - An elasticity of the same bones as well as the ribs. - Both kidneys appeared retracted, deformed and fibrous (Fig. 3). - Parathyroids were enlarged (Fig. 4). Laboratory Results: Clinical investigations revealed: - BUN > 4g/l; creatinine > 200mg/l - Aregenerative anemia (Hb=7,2g/100ml, reticulocytes=0/l). Contributor’s Morphologic Diagnosis: Congenital renal dysplasia (primitive lesion) bilateral, fibrous osteodystrophy, Brie sheepdog, canine. Some mandibular sections contain a tooth with its alveolus. Contributor’s Comment: Renal lesions consist of immature (fetal-like structures) glomeruli throughout the cortex and dilatation of Bowman’s spaces. There is a separation of renal tubules by immature connective stroma minimally infiltrated by inflammatory cells (lymphocytes and plasmocytes). Many tubules are atrophic or 04WSC16 - 1 - dysplastic. Some sections reveal focal calcifications in tubules as well as some luminal granular eosinophilic casts. No cartilage nodules are noted. Bone tissue of the mandible shows osteopenia (trabecular paucity) with osteolysis and medullary fibrosis (immature connective tissue). The number of osteoclasts is greatly increased; the associated trabecular surface is particularly eroded (numerous Howship’s lacunae). In this disorganized tissue, we can observe osteoid material surrounded by some activated osteoblasts (particularly in some sections around the tooth alveolus). The diagnosis of renal dysplasia was made based on the macroscopic appearance of kidneys and histological appearance of mesenchymal tissue with primitive tubules. Although the dog is 14 weeks old, this lesion is interpreted as a primitive dysplastic lesion because immature glomeruli are not merely present in the subcapsular zone. Secondary hyperparathyroidism is confirmed by the hyperplasia of parathyroids and fibrous osteodystrophy. AFIP Diagnoses: 1. Kidney: Dysplasia with diffuse severe fibrosis, fetal glomeruli, and tubular adenomatous hyperplasia, Brie sheepdog, canine. 2. Mandible: Osteodystrophy, fibrous, diffuse, severe. Conference Comment: Renal secondary hyperparathyroidism, or renal fibrous osteodystrophy, is a complex syndrome caused by elevated parathyroid hormone levels in response to hypocalcemia. It is initiated by decreased glomerular filtration rate and the resultant inability to excrete phosphate, and inadequate production of 1,25-dihydroxycholecalciferol (calcitriol). Hyperphosphatemia, due to the mass law effect, results in concomitant hypocalcemia which stimulates the parathyroid glands to secrete parathyroid hormone (PTH). Parathyroid hormone acts principally on the bone and kidney. Parathyroid hormone stimulates bone resorption and mobilization of calcium stores, resulting in the characteristic marked softening of bones and replacement with fibrous connective tissue. The diseased kidney is unable to facilitate production of calcitriol, which normally suppresses PTH secretion, thus impairing this negative feedback system allowing the parathyroid glands to continue to produce PTH. In addition, hyperphosphatemia inhibits calcitriol production. With time, continued stimulation of PTH secretion causes parathyroid chief cell hyperplasia (renal secondary hyperparathyroidism).7-9 Contributor: Service Anatomie pathologique, Ecole Nationale Veterinaire d’Alfort 7, avenue du general de Gaulle 94704 Maisons-Alfort FRANCE 04WSC16 - 2 - References: 1. Schulze C, Meyer HP, Blok AL, Schipper K, van den Ingh TSGAM: Renal dysplasia in three young adult Dutch kooiker dogs. Vet Quart 20:146-148, 1998 2. Darrigrand-Haag RA, Center SA, Randolph JF, Lewis RM, Wood PA: Congenital Fanconi syndrome associated with renal dysplasia in 2 Border Terriers. J Vet Intern Med 10(6):412-419, 1996 3. Lobetti RG, Pearson J, and Jimenez M: Renal dysplasia in a Rhodesian ridgeback dog. J Sm Anim Pract 37:552-555, 1996 4. Autran de Morais HS, DiBartola SP, Chew DJ: Juvenile renal disease in Golden Retrievers: 12 cases (1984-1994). JAVMA 209(4):792-797, 1996 5. Kerlin RL, Van Winkle TJ: Renal Dysplasia in Golden Retrievers. Vet Pathol 32:327-329, 1995 6. Font A, Ferer L, Closa JM, Mascort J: Renal Dysplasia in a Brie sheepdog. J Sm Anim Pract 32(12), 640-642, 1991 7. Palmer N: Bones and joints. In: Pathology of Domestic Animals, eds. Jubb KVF, Kennedy PC, Palmer N, 4th ed., vol. 1, pp. 77-79. Academic Press, San Diego, California, 1993 8. McGavin MD, Carlton WW, Zachary JF: Thomson’s Special Veterinary Pathology, 3rd ed., pp. 238-239, 513-514. Mosby, St. Louis, Missouri, 2001 9. Jones TC, Hunt RD, King NW: Veterinary Pathology, 6th ed., pp. 919-920. Williams and Wilkins, Baltimore, Maryland, 1997 CASE II - 03-7103 (AFIP 2908326) Signalment: 17- week old, female B6.129S6-Cybbtm1Din mouse (Mus musculus). History: This mouse was from a production colony maintained in conventional housing at The Jackson Laboratory. The mouse was submitted to the diagnostic laboratory because it was found to be thin with a submandibular mass. Gross Pathology: There was a solitary, white, 1.4 x 1.0 cm, subcutaneous, multi- nodular mass containing pale yellow amorphous material. The lungs had multiple, randomly distributed, raised, white nodules of various sizes up to 2 mm in diameter. Laboratory Results: Bacterial culture positive for Staphylococcus sp. coagulase negative. Contributor’s Morphologic Diagnoses: 04WSC16 - 3 - 1. Tongue, mandible and adjacent soft tissue: Myositis, osteomyelitis and periodontitis (some sections), severe, multifocal, pyogranulomatous with intra- lesional Splendore-Hoeppli material centered on bacterial colonies. 2. Lymph node: Lymphadenitis, severe, multifocal, pyogranulomatous with intra- lesional Splendore-Hoeppli material and plasmacytosis. 3. Lung: Pneumonia, moderate, multifocal to coalescing, fibrinopurulent, pyogranulomatous with intra-lesional Splendore-Hoeppli material rarely centered on bacterial colonies. Mild, multifocal, acidophilic, macrophage pneumonia. Contributor’s Comment: The B6.129S6-Cybbtm1Din mouse was generated by the targeted disruption of the gp91phox gene1. This gene is located on the X chromosome and encodes the β subunit of the phagocyte oxidase cytochrome b 558. Oxidase cytochrome b is a membrane component of NADPH oxidase, which generates superoxide, a critical component in the process known as the respiratory burst. The absence of respiratory-burst-derived oxidants in phagocytes results in defective microbicidal activity. Neutrophils and macrophages from Cybbtm1Din hemizygous male and heterozygous females mice lack respiratory burst oxidase activity1. The lesions in the Cybbtm1Din mouse have previously been described2. The lungs of this mouse also had acidophilic macrophage pneumonia, characterized by the presence of large numbers of alveolar macrophages many containing eosinophilic, Ym1 crystals3. Acidophilic macrophage pneumonia has previously been reported in Cybbtm1Din mice and is a prominent lesion in motheaten mice (Hcph me/Hcph me)2. Hcph encodes the SHP-1 protein-tyrosine phosphatase, which is expressed primarily in hematopoietic cells. SHP-1 is a critical negative regulator in multiple signaling pathways in the hematopoietic and immune systems. Interestingly, in undifferentiated myeloid cells SHP-1 activity has been shown to decrease transcription of Cybb4. Pyogranuloma formation with intra-lesional Splendore-Hoeppli material is a background lesion found in some mice housed in our conventional facilities. While the lesion is often more extensive in immunodeficient mice such as the Cybbtm1Din mouse, it is also found in immunocompetent mice. The pathogenesis of pyogranuloma formation in these mice is unknown. However, we believe that the nidus for such lesions may be a hair foreign body secondary to grooming activity. Penetration and disruption of the oral mucosa facilitates the spread of bacteria into adjacent structures. Generally these lesions involve the cervicofacial tissues with spread to cervical lymph nodes and on occasion as this case demonstrates lymphogenous spread to the lungs. Coagulase-positive Staphylococcus aureus is the bacteria most commonly associated with botryomycosis, however in our mice coagulase-negative S. hominus and S. xylosus are most frequently recovered. 04WSC16 - 4 - AFIP Diagnoses: 1. Mandible, tongue, skeletal muscle, and tooth: Osteomyelitis, glossitis, myositis, and periodontitis, pyogranulomatous, focally extensive, severe, with Splendore- Hoeppli material, and colonies of cocci, B6.129S6-Cybbtm1Din mouse, rodent. 2. Lung: Bronchopneumonia, neutrophilic, multifocal, marked, with Splendore- Hoeppli material, and colonies of cocci. 3. Lung: Numerous intra-alveolar macrophages with eosinophilic intracellular crystals. Conference Comment: Some slides also contain lymph node with a similar pyogranulomatous inflammatory infiltrate. Botryomycosis is a term used to describe the chronic granulomatous infection caused by coagulase-positive staphylococci, most commonly Staphylococcus