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CASE I – 3576/99 (AFIP 2738491)
Signalment: 1-week-old, female Simmenthaler-red Holstein cross, bovine
History: Tibial fractures; abnormal x-ray of long bones.
Gross Pathology: Both tibias fractured at the proximal metaphysis with hemorrhage into the surrounding tissue; in the long bones and vertebrae, multifocal to confluent cysts and compact creamed-colored areas up to 2 x 1 x 1 cm could be found.
Laboratory Results: Virology, thymus and thyroid: Isolation of a non-cytopathogenic BVD-virus; positive BVD-virus immunoperoxidase staining.
Contributor’s Diagnosis and Comment: Bones, metaphysis: Persistent primary spongiosa with cartilage residues (osteopetrosis).
This calf lacked the domed cranium, brachygnathia and arthrogryposis described with hereditary osteopetrosis. The abrupt transition from abnormal to normal bone spicules within the metaphysis region also suggests a non-hereditary condition. As possible causes for this osteopetrosis, osteoclastic dysfunction and the production of a defective matrix resistant to osteoclastic removal is proposed.
AFIP Diagnosis: Bone, metaphysis: Osteosclerosis, multifocal, moderate, with retained cartilage cores, Simmenthaler-red Holstein cross, bovine.
Conference Comment: The term osteopetrosis implies a hereditary disease due to errors in osteoclastic function that result in decreased bone modeling and remodeling. The multifocal distribution of retained primary spongiosa in this 1-week-old calf suggests a congenital, but non-persistent, lesion. In utero infection with certain strains of bovine virus diarrhea virus (BVDV) has been shown to cause a failure of bone modeling in neonatal calves resulting in a growth retardation lattice and increased density of the metaphyseal trabeculae.
Failures of remodeling are seen with primary osteoclastic dysfunction due to a lack of hydrolytic enzymes or their secretion into the bone interface, defects in the ruffled brush border or its bony attachment, or interference with stem cell differentiation. Interference in matrix mineralization or osteoclastic binding with surface non-collagenous proteins will result in a failure of osteoclastic resorption as well. Osteoclasts lack parathormone receptors and require signals from osteoblasts or other stromal cells to initiate bone resorption. Local mediators of resorption include prostaglandins, IL-1, IL-3, IL-6, IL-11, and granulocyte-macrophage colony stimulating factor. BVDV is known to induce production of a soluble IL-1 inhibitor. Thus, defective microenvironmental signals could reduce osteoclastic differentiation, numbers or function and may explain the skeletal abnormalities seen in some calves persistently infected with BVDV.
Contributor: University of Bern, Institute of Animal Pathology, Länggass-Strasse 122, CH-3012 Bern, Switzerland
References: 1. Scruggs DW, Fleming SA, Maslin WR, Groce AW: Osteopetrosis, anemia, thrombocytopenia, and marrow necrosis in beef calves naturally infected with bovine virus diarrhea virus. J Vet Diagn Inv 7:555-559, 1995
2. Palmer N: Bones and joints. In: Pathology of Domestic Animals, ed. Jubb KVF, Kennedy PC, Palmer N, 4th ed., vol. 1, p. 41. Academic Press, San Diego, CA, 1993
CASE II – P1484/00 (AFIP 2739199)
Signalment: 13-year-old, domestic shorthair cat, feline.
History: Swollen and painful third digit of right hindleg for 6 weeks; no progression after treatment with antibiotics and painkillers; surgical removal of digit.
Gross Pathology: Ulceration of digit nailbed; approximately 2-cm diameter local swelling; not well demarcated.
Laboratory Results: None.
Contributor’s Diagnosis and Comment:
Digit: Metastasis of pulmonary adenocarcinoma.
The digit was decalcified in formic acid, stained with H&E, PAS and cytokeratin 8. In most slides, ciliated epithelial cells can be found in a few of the larger tubules. In some areas, goblet cells were found. The tumor stained positive with cytokeratin 8 and occasional cells were PAS positive.
The cat was euthanized 2 weeks after removal of the digit. The animal had multiple swollen and painful digits. Follow-up postmortem was done. Both hind legs had multiple swollen digits, some with mucinous excretion from the nailbeds. The left hindleg was edematous.
The primary tumor was present in the lungs with several large nodules (3 x 3 x1 cm) and many smaller nodules (0.5 cm diameter). Microscopically, these were epithelial tumors with tubules lined by many ciliated cells and goblets cells (adenocarcinoma). There was extensive growth of tumor cells in arteries and venules. Metastases were found in one adrenal gland, arteries of muscles of the left hindleg and multiple digits of the hindlegs.
This case is one of 64 cats with digital carcinomas that were examined at the Department of Veterinary Pathology of Utrecht University in the period 1993-1998. In all animals, the primary clinical sign was painful digits. Eight cats had a primary squamous cell carcinoma that involved one digit or two adjacent digits of one leg. Fifty-six cats had metastatic pulmonary carcinoma in the digits. In general, multiple digits of different legs were involved. In many of these cats, metastases also occurred to other organs, including the skin and muscles. There were no primary sweat gland carcinomas of the digits.
Cornification and the absence of PAS-positive cells or PAS-positive secretory material characterized primary squamous cell carcinoma of the digits. Immunohistochemically, these neoplasms stained negative with the monoclonal antibody CAM 5.2 directed against keratin 8.
The metastasis of pulmonary carcinoma to the digits showed one or more of the following histological features: goblet cells, ciliated epithelial cells, PAS-positive cells or lakes, and/or a PAS-positive lining of luminal membranes with no cornification. Immunohistochemically, they showed positive staining for CAM 5.2.
Thoracic radiographs from three cats with primary squamous cell carcinoma showed no abnormalities, whereas all cases available for follow-up of carcinoma metastasis to the digits showed evidence of a primary pulmonary carcinoma on radiography and/or postmortem examination (25 out of 56).
The conclusion of this study was that most carcinomas in the digits of cats were metastases of a primary pulmonary carcinoma (87.5%). Primary squamous cell carcinoma occurred infrequently. The prognosis of metastasis of a pulmonary carcinoma to the digits is poor with an average survival time of 4.9 weeks, in contrast to 29.5 weeks in cats with a squamous cell carcinoma. This data stresses the importance of taking thoracic radiographs of cats with digital tumors before surgical intervention.
AFIP Diagnosis: Haired skin and phalanx: Adenocarcinoma, with cilia and goblet cell differentiation, consistent with metastatic pulmonary adenocarcinoma, domestic shorthair cat, feline.
Conference Comment: While the periosteal new bone proliferation of the phalanx might be considered of minor significance in this case, it is interesting to note that it probably represents a reaction to altered mechanical stresses placed on the bone and digit because of pain. Neoplastic embolization into the bone might cause a similar proliferative response.
Contributor: University Utrecht, Department of Veterinary Pathology, P.O. Box 80158, 3508 TD Utrecht, The Netherlands
References: 1. van der Linde-Sipman JS, van den Ingh ThSGAM: Primary and metastatic carcinomas in the digits of cats. Vet Quart 22(3):141-145, 2000
2. Jacobs TM: The lung-digit syndrome in a cat. Fel Pract 25:31-36, 1997
3. Moore AS, Middleton DJ: Pulmonary adenocarcinoma in three cats with non-respiratory signs only. J Small Anim Pract 23:501-509, 1982
CASE III – 398/00 (AFIP 2739198)
Signalment: Juvenile, male iguanid lizard (Ctenosaura similis), reptile.
History: The iguanid lizard was one of two imported animals. The owner had noticed progressive anorexia and decline of motility for several months, despite the animal being in “good” body condition. Clinical examination revealed marked, bilaterally symmetrical swelling of the limbs and the distal thoracic vertebrae. Radiographs revealed insufficient skeletal ossification and marked increase of periosteal soft tissue. The animal was euthanized.
Gross Pathology: The lizard was in poor nutritional condition. The mandible and limbs exhibited severe, firm, elastic to hard swelling. The last 4 thoracic vertebrae were also thickened up to 1 cm in diameter. The parathyroid glands were 1.5 mm in diameter, pale, and gelatinous. The kidneys were mildly congested.
Laboratory Results: None.
Contributor’s Diagnosis and Comment: Femur: Diffuse, severe, fibrous osteodystrophy.
The bony structures, especially cortical bone, were replaced by perpendicularly arranged woven bone with chondroid metaplasia and fibrous and cartilaginous tissue. The fibrous tissue extended into the adjacent skeletal muscle. A moderate number of osteoclasts were found in the chondroid tissue. Bone trabeculae were thin or irregular and intertrabecular spaces contained various amounts of fibrous tissue.
Fibrous osteodystrophy belongs to the group of metabolic bone diseases. It is characterized by extensive osteoclastic resorption of bone and formation of fibrocollagenous tissue. Osteoclastic activity is enhanced by prolonged and excessive secretion of parathyroid hormone. In the endosteum, the resorbed bone is replaced initially by highly cellular connective tissue. In later stages, the connective tissue is more fibrous and less cellular. The bone cavity is replaced by fibrocellular tissue that contains irregular bone trabeculae. The original compact bone is reduced in thickness and can be completely replaced by soft tissue. The intense osteoclastic activity in the epiphysis results in destruction of not only the epiphyseal trabeculae, but also of the calcified zone of the articular cartilages. The lack of support for the articular cartilage results in collapse into the epiphysis.
Pathological findings due to hyperparathyroidism can be caused by three main mechanisms: primary hyperparathyroidism, renal disease, and nutritional derangements. In reptiles, hyperparathyroidism is mostly due to an imbalanced feeding regime. The nutritional imbalance leading to the development of fibrous osteodystrophy is a deficiency of calcium, vitamin D, or an excess of phosphorus that causes increased secretion of parathyroid hormone. Parathyroid hormone is a potent systemic stimulator of osteoclastic bone resorption. Osteoclasts, however, lack receptors for parathyroid hormone. Osteoblasts express receptors for parathyroid hormone and control the initiation of bone resorption. In response to parathyroid hormone, osteoblasts contract and leave exposed bone surfaces on which the osteoclasts can attach. The activated osteoblasts secrete or activate collagenases that remove a thin layer of normal, unmineralized fibers from the bone spicules so that the osteoclast can attach to a fully mineralized surface. Osteoclasts are unable to resorb unmineralized matrix. In addition, osteoblasts release cytokines that attract and stimulate inactive osteoclasts within the local environment. Calcitonin is a systemic inhibitor of osteoclasts. Osteoclasts have receptors for calcitonin and respond by involution of their brush border and detaching from the bone surface. The role of phosphorous is not fully understood. High plasma phosphate depresses ionized calcium and thereby stimulates the release of parathyroid hormone. Plasma inorganic phosphate concentration does not directly influence parathyroid activity, but at high concentrations depresses the 1-a -hydroxylation of 25-hydroxycholecalciferol and stimulates the 24-hydroxylation. Parathyroid hormone stimulates the 1-a -hydroxylation. Thus, high plasma phosphate appears to stimulate the release of hormone while blocking some of its effects.
The absolute or relative deficiency of vitamin D3, the main cause of osteodystrophy in reptiles, results in reduced calcium absorption from intestinal contents. With decreased plasma calcium levels, mineralized bone matrix formation is retarded, or arrested entirely, and release of parathyroid hormone is stimulated.
AFIP Diagnosis: Bone: Osteopenia of compact bone, diffuse, moderate, with endosteal and periosteal myxoid fibrosis, and marked reactive periosteal osteocartilaginous proliferation, consistent with fibrous osteodystrophy, iguanid lizard (Ctenosaura similis), reptile.
Conference Comment: The effect of vitamin D metabolism in the pathogenesis of metabolic bone disease of iguanids is not completely understood. Vitamin D is required for intestinal absorption of calcium and the regulation of calcium and phosphorous balance. Basking in the sun is important to many lizard species both for thermoregulation and stimulation of cutaneous synthesis of vitamin D. Some species of lizards require ultraviolet light B (UVB) from 290 to 315 nm wavelength to maintain adequate circulating levels of vitamin D. Dietary supplementation of vitamin D, without access to UVB light, is inadequate to prevent metabolic bone disease in these lizards.
The cutaneous conversion of the vitamin D precursor, 7-dehydrocholesterol, to pre-vitamin D (pre-D3) occurs during exposure to UVB. Skin temperature is important in the subsequent conversion of pre-D3 to vitamin D. Thus, not only is UVB exposure critical to the synthesis of vitamin D, but these lizards must be sufficiently warm to allow thermal isomerization to occur.
Contributor: Institut für Veterinaer-Pathologie, Frankfurter Strasse 96, 35390 Giessen, Germany
References: 1. Allen ME, Bush M, Oftedal OT, Rosscoe R, Walsh T, Holick MF: Update on vitamin D and ultraviolet light in basking lizards. Proc Am Assoc Zoo Vet 1:314-316, 1994
2. Carlton WW, McGavin MD: Diseases of the bone and joints. In: Thomson’s Special Veterinary Pathology, 2nd ed., pp. 437-440. Mosby-Year Book, Inc., St. Louis, MO, 1995
3. Frye FL: Pathological conditions of the skeletal system. In: Reptile Care: An Atlas of Diseases and Treatments, vol. 2, pp. 536-537. TFH Publications, Inc., Neptune City, NJ, 1991
4. Palmer N: Bones and joints. In: Pathology of Domestic Animals, ed. Jubb KVF, Kennedy PC, Palmer N, 4th ed., vol. 1, pp. 72-79. Academic Press, San Diego, CA, 1993
CASE IV – 00-2008 (AFIP 2741049)
Signalment: Two-year-old, male St. Bernard, canine
History: 3-month lameness of left front leg. Painful to palpation of left shoulder.
Gross Pathology: Firm, nodular, thickened pieces of synovium were received in formalin. The surgeon described these nodules as cartilaginous, arising in a thickened synovium. The lesion involved the entire shoulder joint and the bicipital bursa.
Laboratory Results: None.
Contributor’s Diagnosis and Comment: Synovium: Synovial chondroid metaplasia.
Disease: Synovial chrondromatosis
Primary synovial chondromatosis (PSC) is a condition of multifocal cartilage metaplasia within the synovial membrane of a joint, bursa or tendon sheath with no evidence of significant underlying disease. In man, the condition is usually monoarticular and consists of fibrocartilage or hyaline cartilage with secondary endochondral ossification possible (osteochondromatosis). Secondary synovial chondromatosis (SSC) is similar in appearance but is usually a sequela to degenerative joint disease. Due to secondary changes in the joint that can occur with PSC, it might not always be possible to make a definitive diagnosis of PSC. The condition has been reported in dogs and horses. In dogs, it is usually monoarticular, with a predilection for the shoulder. In horses, cases have been reported to be bilateral and symmetrical in joints of the rear limbs. In man, recurrence after synovectomy occurs but is uncommon. Malignant transformation is reported in humans but is rare. The cause of the condition in both humans and domestic animals is not known. In humans, some cases have been reported to have clonal structural abnormalities and re-arrangements of chromosome 6, suggesting PSC is neoplastic. Interestingly, similar chromosomal abnormalities were found in a synovial chondroma but are not found in classic chondrosarcomas.
AFIP Diagnosis: Synovium: Hyperplasia, diffuse, moderate, with multifocal nodular cartilaginous metaplasia, St. Bernard, canine.
Conference Comment: Synovial chondroid metaplasia or synovial chondromatosis is characterized by chondral or osteochondral nodule formation in synovial tissue sometimes attached by pedunculated stalks. The nodules may detach from the synovium, forming loose “joint mice” that continue to grow with nourishment provided by synovial fluid. Their appearance in PSC is usually in absence of any etiologic agent, synovial cell hyperplasia, or other evidence of joint capsule inflammation. The presence of these nodules may contribute to progressive, radiographically detectable, degenerative joint disease. Often, surgical removal of the nodules and area debridement results in pain relief and abatement of clinical lameness.
The distinction between primary and secondary synovial chondroid metaplasia is often difficult to make, but the secondary form is considered more common. SSC occurs following traumatic, degenerative, or inflammatory joint diseases. Detached cartilage or subchondral bone fragments that become embedded in the synovium serve to incite chondroid metaplasia. Again, the disease responds favorably to surgical removal of the fragments.
Often, the distinction between chondroid metaplasia, idiopathic hyperplasia, and benign neoplasia cannot be easily made grossly. Careful histologic evaluation is required to confirm the diagnosis.
Contributor: The Ohio State University, Department of Veterinary Biosciences, 1925 Coffey Road, Columbus, OH 43210
References: 1. Davis M, Hamilton A, Biggart JD: Primary synovial chondromatosis: a clinicopathologic review and assessment of malignant potential. Human Pathol 29(7):683-688, 1998
2. Flo GL, Stickle RL, Dunstan RW: Synovial chondrometaplasia in five dogs. J Am Vet Med Assoc 191(11):1417-1422, 1987
3. Pool RR: Joints and adjacent soft tissues. In: Tumors in Domestic Animals, ed. Moulton JE, 3rd ed., pp. 121-123. University of California Press, Berkeley, CA, 1990
4. Sciot R, Dal Cin P, Bellemans J, Samson I, Van den Berghe H, Van Damme B: Synovial chondromatosis: clonal chromosome changes provide further evidence for a neoplastic disorder. Virchows Arch 433:189-191, 1998
5. Smith RKW, Coumbe A, Schramme MC: Bilateral synovial chondromatosis
of the metatarsophalangeal joints in a pony. Eq Vet J 27(3):234-238,
1995
*Sponsored by the American Veterinary Medical Association, the American College of Veterinary Pathologists and the C. L. Davis Foundation.
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