A dog with a pulmonary papillary carcinoma and a cat with a dermal tubular adenocarcinoma had profound paraneoplastic neutrophilic leukocytosis with no clinically detectable inflammatory foci. To investigate the mechanism of the leukocytosis, oligonucleotide primers were designed from the cDNA sequences of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) of dogs. Reverse transcription polymerase chain reaction was performed on tumor tissues, and araneoplastic leukocytosis is a well-recognized syn-P drome associated with a variety of malignancies in humans andIt is characterized by a marked mature neutrophilia, with or without monocytosis, that cannot be attributed to inflammatory disease or to a primary hematopoietic neoplasm.' Paraneoplastic leukocytosis may serve as a marker of tumor response to therapy or of recurrence of the inciting neoplasm after remission! Tumors reported to be associated with paraneoplastic leukocytosis in dogs include rectal adenomatous polyps, renal tubular adenocarcinoma, and metastatic fibrosar~oma.~-~ Paraneoplastic leukocytosis has been reported in a cat with adenocarcinoma of the sweat gland. ' Tumors associated with this paraneoplastic syndrome in humans produce hematopoietic growth factors, including granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF).8,9The same mechanism has been postulated in the dog and cat of this report based on the presence of G-CSF and GM-CSF mRNA in tumor tissue detected by the polymerase chain reaction (PCR). Case ReportsCase 1A 13-year-old castrated male Domestic Short Hair cat was admitted to the Ohio State University Veterinary Teaching Hospital (OSU-VTH) for evaluation of a 15 X 15-cm cutaneous mass over the dorsal aspect of the lumbosacral spine. The mass was first observed 2 months prior to admission as a small pea-sized lesion that was drained and treated with antibiotics by the referring veterinarian. The mass continued to grow and the cat was referred for evaluation. The cat was quiet and afebrile. Other physical examination findings included moderate gingivitis and dental tartar, mildly enlarged popliteal lymph nodes, and a VVI systolic heart murmur with a point of maximal intensity at the cranial sternal border.Thoracic radiographs revealed a probable primary lung tumor of the left caudal lung lobe and a well-circumscribed soft tissue to mineral opacity mass with central lucency in the hilar region of the right cranial lung lobe. Differential diagnoses for this mass included cavitary metastasis, abscess, or granuloma. Hepatomegaly and a large subcutaneous soft tissue mass over the dorsum were detected on abdominal radiographs. Abnormalities on a CBC included marked leukocytosis (94,100 cells/pL; reference range, 4,500 to 16,500 cells/ pL), with mature nentrophilia (85,600 cells/pL; reference range, 3,000 to 13,000 cells/pL), monocytosis (4,100 cellslpL; reference range, 0 to 700 cells/pL), eosinophilia (1,900 cells/pL; referen...

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Circulating N-terminal PTH-related protein (PTHrP), N-terminal PTH, and 1,25-dihydroxyvitamin D [1,25-(OH)2D] concentrations were measured in normal dogs and dogs with cancer-associated hypercalcemia (CAH), parathyroid adenomas, and miscellaneous tumors. PTHrP was undetectable (less than 1.8 pM) in normal dogs and increased in dogs with CAH due to adenocarcinomas derived from apocrine glands of the anal sac (44.9 +/- 27 pM), lymphoma (8.3 +/- 4.4 pM), and miscellaneous carcinomas (13.3 +/- 11.4 pM). The PTHrP concentration decreased in dogs with lymphoma and anal sac adenocarcinomas after successful treatment of CAH. The PTHrP concentration had a significant linear correlation with total serum calcium in dogs with anal sac adenocarcinomas and hypercalcemia, but not in dogs with lymphoma and hypercalcemia. Serum N-terminal PTH concentrations were usually in the normal range (12-34 pg/ml) for all groups of dogs except dogs with parathyroid adenomas (83 +/- 38 pg/ml). The serum PTH concentration increased after successful treatment of CAH. Serum 1,25-(OH)2D concentrations were decreased, normal, or increased in dogs with CAH, and 1,25-(OH)2D levels decreased after treatment of CAH. In summary, circulating concentrations of PTHrP are consistently increased in dogs with CAH, and PTHrP appears to play an important role in the induction of hypercalcemia.

Two polyclonal antibodies, directed against N-terminal amino acids (1-36) or the midregion (amino acids 34-53) of parathyroid hormone-related protein (PTHrP), were used to localize PTHrP in a variety of normal and neoplastic canine tissues. Parathyroid hormone (PTH) immunoreactivity was demonstrated using anti-bovine PTH (amino acids 14-34). The following tissues (among others) stained strongly positive for PTHrP: all layers of epidermal keratinocytes, with the most intense staining of the basal layer; hair follicle keratinocytes; myoepithelial cells of dermal apocrine glands, mammary glands, and apocrine glands of the anal sac; anal sac epithelium; mammary duct epithelium; and thyroid C cells. Adenocarcinomas of the anal sac stained moderately positive (5/22 dogs), weakly positive (11/22 dogs), or did not stain (6/22 dogs). Most parathyroid gland adenomas stained moderately (2/6 dogs) or weakly positive (3/6 dogs) for PTHrP. Squamous cell carcinomas (6/6 dogs) stained strongly positive. Lymphomas stained weakly positive (2/10 dogs) or did not stain (8/10 dogs). There was no consistent relationship between the staining intensity of the tumors and serum calcium concentrations of the dogs. The anti-PTH antibodies stained only parathyroid chief cells strongly positive. Concentrations of PTHrP were measured by radioimmunoassay in protein extracts from an adenocarcinoma derived from the apocrine glands of the anal sac, pancreas, kidney, liver, heart, thyroid, adrenal, and parathyroid glands. PTHrP concentrations varied from undetectable up to 150 pg/mg in normal tissues as compared with 2,000 pg/mg in apocrine adenocarcinoma of the anal sac.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract. The presence of parathyroid hormone-related protein (PTHrP) in the apocrine adenocarcinoma tumor line (CAC-8) derived from a hypercalcemic dog was demonstrated by western and northern blot analyses. Western blots of CAC-8 tumor extracts revealed a major protein with a molecular weight of approximately 18,000 daltons that cross-reacted with antiserum to human PTHrP. Northern blots demonstrated multiplesized messenger RNA transcripts in CAC-8 that hybridized to a full-length cDNA probe to human PTHrP. Adenocarcinomas derived from apocrine glands of the anal sac also were stained immunohistochemically for antigens that cross-react with antiserum to human PTHrP. The tumor line (CAC-8) maintained in nude mice stained positively for PTHrP in 13 of 24 tumors. Three of ten apocrine adenocarcinomas from dogs with hypercalcemia stained for PTHrP, whereas zero of ten tumors were positive from normocalcemic dogs. Normal canine epidermal keratinocytes and areas of squamous metaplasia in a perianal gland carcinoma also were positive for PTHrP. These data demonstrated that canine tissues contained a homologue to human PTHrP that likely is important in the pathogenesis of humoral hypercalcemia of malignancy.Key words: Anal sac; apocrine adenocarcinoma; dog; humoral hypercalcemia of malignancy; hypercalcemia; parathyroid hormone-related protein.The adenocarcinoma derived from apocrine glands of the anal sac commonly induces the syndrome of humoral hypercalcemia of malignancy (HHM) in dogs.15 An animal model of HHM has been developed in nude mice using a serially transplantable canine apocrine adenocarcinoma (CAC-8) derived from a hypercalcemic dog.26 Dogs and nude mice with the apocrine adenocarcinoma develop a syndrome of HHM that closely parallels the condition in human beings.16,26 Nude mice with transplanted CAC-8 develop the following: severe hypercalcemia and hypophosphatemia, increased serum 1,25-dihydroxycholecalciferol concentrations, decreased serum immunoreactive parathyroid hormone (PTH), hypercalciuria, increased urinary excretion of CAMP and hydroxyproline, and increased osteoclastic bone resorption and bone formation.22.26 Serum calcium concentration returns to the normal range within 2 days of surgical removal of the tumor.22The clinical disturbances of HHM are due to the release of humoral factors from neoplasms that have effects in tissues distant from the tumor, e.g., bone, kidney, and intestine.22 The factors most likely involved in the pathogenesis of HHM include PTH-like factors (proteins that bind to PTH receptors but do not cross-react immunologically with PTH), transforming growth factors a and /3, colony stimulating factors, and interleukin-1 .22 Many of the functional disturbances of HHM mimic the effects of excess PTH and result from a PTH-like protein(s) that binds to and stimulates PTH receptors in bone and kidney.18 Extracts of CAC-8 contain parathyroid hormone-like activity that will induce bone resorption and stimulate adenylate cyclase in vitro by binding to the PTH receptors of bone a...