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A 2.5-year-old, female llama with weight loss and lethargy had a packed cell volume (PCV) of 45% which increased to 57% over 3 wk. Transrectal ultrasonography revealed a mass of mixed echogenicity involving the right ovary, which was removed. A histopathological diagnosis of granulosa theca cell tumor was made. This is the first report of its kind in a llama.
Tumeur de la granulosa et de la thèque avec érythrocytose chez un lama. Un lama femelle âgé de 2,5 ans est présenté avec perte de poids et de la léthargie et une valeur d’hématocrite de 45 % qui a augmenté à 57 % après 3 semaines. Une échographie transrectale a révélé une masse d’échogénicité mixte touchant l’ovaire droit, qui a été retirée. Un diagnostic histopathologique d’une tumeur de la granulosa et de la thèque a été porté. Il s’agit du premier rapport de ce type chez un lama.
(Traduit par Isabelle Vallières)
A 2.5-year-old, 91 kg, female llama was examined because of a 6-wk history of losing weight, apparent depression, lethargy, and decreased appetite. The owner detected the clinical signs immediately after the llama was returned from a breeding farm and also noted that the llama sat in a “hunched” position. At admission, she was pregnant (5-mo gestation) and had received fenbendazole and Ivermectin 30 d and 60 d before admission, respectively.
Physical examination revealed a rectal temperature of 37.3°C, heart rate of 78 beats/min, and respiratory rate of 48 breaths/min. The llama seemed depressed, had no ruminations, and was estimated to be 5% dehydrated. Hematological analysis revealed plasma protein of 44 g/L (reference range: 56 to 72 g/L), packed cell volume (PCV) of 45% (reference range: 24% to 40%), and nucleated cell count of 12.1 × 109/L (reference range: 7.4 to 19.9 × 109/L) 75% of which was segmented neutrophils (9.1 × 109/L; reference range: 3.5 to 13.7 × 109/L), 1% immature neutrophils (0.1 × 109/L; reference range: 0 to 0.1 × 109/L), 11% lymphocytes (1.3 × 109/L; reference range: 1.3 to 5.7 × 109/L), and 5% monocytes (0.6 × 109/L; reference range: 0 to 0.8 × 109/L). Serum biochemistry analysis revealed hypocalcemia (1.8 mmol/L; reference range: 2.0 to 2.6 mmol/L), increased creatinine (300.6 μmol/L; reference range: 132.6 to 256.4 μmol/L), hypoalbuminemia (25 g/L; reference range: 30 to 49 g/L), increased creatine phospho-kinase activity (1303 U/L; reference range: 30 to 625 U/L), and hypercortisolemia (168.3 nmol/L; reference range: 27.6 to 52.4 nmol/L). The reference ranges cited are from the Clinical Pathology Laboratory, Ohio State University. The abdomen was mildly distended and the llama resented palpation of the abdomen. Abdominal ultrasonography revealed a gravid uterus, generalized abdominal effusion, and flocculent debris in the fluid.
Abdominocentesis in the right paramedian quadrant, midway between the umbilicus and the cranial brim of the pelvis at the level of the caudal angle of the last rib, yielded a bloody effusion with a specific gravity of 1.032 (normal range: 1.007 to 1.018), protein content of 53 g/L (normal range: 5.0 to 25 g/L), PCV of 49%, and white blood cell count (WBC) 8600 cells/μL (normal range: 500 to 5000 cells/μL), 92% of which (7900 cells/μL) were neutrophils (normal: up to 50%), 8% (700 cells/μL) were mononuclear cells (normal: more than 50%), and 1% (86 cells/μL) were lymphocytes. The normal ranges cited were taken from Garry (1). A clinical diagnosis of hemoperitoneum with possible peritonitis was made based on these results. An intravenous catheter was placed and 500 mL llama plasma and 1 L 0.9% saline were administered over a 2-h period. The remainder of the fluid deficit was restored using enteral polyionic electrolyte fluids. Sodium ceftiofur (Naxcel; Pfizer Animal Health, New York, New York, USA), 2 mg/kg, IV, q12h, flunixin meglumine (Banamine; Intervet Schering-Plough Animal Health, Union, New Jersey, USA), 1 mg/kg, IV, q12h, and omeprazole (Prilosec; AstraZeneca Pharmaceuticals, Wilmington, Delaware, USA), 2 mg/kg, PO, q12h, therapy was instituted.
The llama’s attitude and appetite improved markedly over the next 24 h and continued to show improvement during the following 48 h, at which time the hematological analysis was repeated. The llama’s PCV (45%) remained unchanged, but the total protein concentration increased to 62 g/L, likely due to the plasma transfusion. Serum biochemical analysis was normal at that time. Transrectal ultrasonography showed a mass of mixed echogenicity in the right caudodorsal abdominal quadrant.
Ultrasonography of the right kidney revealed a homogeneous mass immediately adjacent to it. Aspiration of the mass failed to yield a diagnostic sample, so a percutaneous tissue biopsy was performed. Histopathological analysis revealed a poorly differentiated tissue exhibiting neuroendocrine packeting. Cells included large ovoid hyperchromatic nuclei, anisokaryosis, and rare mitotic figures. The histopathologic features were consistent with a neoplasm of endocrine or ovarian tissue.
An exploratory laparotomy was done to further identify the tissue involved in the mass and determine options for treatment of the neoplasm. A right-sided laparotomy was performed and the right ovary exteriorized; it was approximately 7 cm × 5 cm and irregular, and the ovarian pedicle contained multiple irregular masses that extended dorsally to a position medial to the right kidney, but not accessible to palpation. The full extent of the lesions could not be assessed. The right ovary and several masses within the right mesovarium were removed and the specimens submitted for analysis. The histopathological appearance of the lesions was consistent with a granulosa theca cell tumor with local invasion to the mesovarium (Figure 1). Features of neoplasia extended to the margins of tissues that had been excised.
On day 5 of hospitalization, the llama’s PCV had increased to 57% and plasma protein concentration was 72 g/L, but serum biochemistry analysis remained normal. A diagnosis of erythrocytosis was made based on increased PCV in the presence of normal hydration. The cause of the erythrocytosis was presumed to be interference with blood flow to the right kidney because of compression of the renal artery by the tumor. Serum erythropoetin concentration on a sample obtained immediately before surgery was determined to further characterize the erythrocytosis and was 29.1 mIU/mL and was considered normal.
One week after surgery, chemotherapy with 5-fluorouracil, administered intraperitoneally, at a total dose of 500 mg was instituted (2). At that time, the llama weighed 86 kg, had a rectal temperature of 37.4°C, heart rate of 56 beats/min, and respiratory rate of 40 breaths/min. The llama appeared bright and alert and had improved appetite, but the PCV was 61% and plasma protein was 78 g/L. Ultrasonography confirmed that the fetus was alive and had a normal heart rate. Progesterone hormone concentration in serum was measured to assess corpus luteum activity; it was 32.1 nmol/L. The llama was discharged into the care of the owner with instructions to return in 21 d for follow-up chemotherapy. The llama died suddenly at the farm 6 d after discharge from the hospital and the owner declined postmortem examination.
This appears to be the first diagnosis of granulosa theca cell tumor of the ovary in a llama. Although ovarian neoplasms are uncommon in llamas, the most common neoplasm may be ovarian teratoma based on our clinical experiences (Anderson DE unpublished data, 2001). Granulosa theca cell tumors occasionally occur in horses and cattle, but are rarely malignant. In an abbatoir study of 1113 cows, only 3 (0.3%) cows had granulosa cell tumor of the ovary and 1 (0.1%) cow had a hemangioma of the ovary (4). Malignant granulosa cell tumors (MGCT) have been diagnosed in several cows including an 18-month-old nulligravida Holstein that had anestrus (5). The MGCT did not metastasize and unilateral ovariectomy resulted in normal ovarian cycles in the remaining ovary and a subsequent pregnancy. In women, granulosa cell tumors rarely metastasize, but have been diagnosed in pelvic, abdominal, thoracic, and spinal tissues (6,7). In the llama described herein, masses within the mesovarium were representative of local metastasis, but necropsy examination was not available to determine the presence or extent of the granulosa cecal tumor (GCT).
The llama in this report had absolute erythrocytosis associated with granulosa theca cell tumor of the ovary. Initially, we suspected that the cause of erythrocytosis was interference with renal perfusion to the right kidney. Theoretically, this may have caused excessive erythropoetin production by the right kidney because of relative hypoxia resulting in inappropriate red blood cell production (8). However, direct production of eryhthropoetin by the tumor also must be considered (9,10). Serum concentration of erythropoetin was measured in an attempt to clarify the erythrocytosis. Unfortunately, the erythropoetin assay is not validated for llamas and a reference range has not been established. The serum concentration of erythropoietin in this llama, however, was similar to that in previous case reports in which several normal, adult llamas were selected for comparison to a llama that was experiencing polycythemia (11). The authors reported absolute erythrocytosis in a llama (PCV 74%; erythropoietin, 104 mIU/mL) but the cause was undetermined. The authors measured serum erythropoetin concentration in 2 normal llamas (serum erythropoetin concentration, 39.8 and 19.6 mIU/mL). These tests argue against our hypothesis of interference with perfusion of the right kidney. In humans, increased serum erythropoietin concentration was found in 44% of patients with renal cell carcinoma but only 3% had paraneoplastic erythrocytosis (12). The authors determined that changes in structure of erythropoietin hormone had decreased the biological activity of the hormone.
Secondary erythrocytosis caused by hyperandrogenism (increased production of testosterone) has been reported in women (13). High concentrations of androgens may stimulate excessive production of erythrocytes. In cattle, GCTs have been documented to produce a variety of hormones including testosterone, estradiol, progesterone, and estrogen (5). Hyperandrogenism has been reported in an alpaca diagnosed with an ovarian interstitial-cell tumor (14). In that report, serum testosterone concentration was increased (patient testosterone, 3.4 nmol/L; reference population: 0.04 to 0.21 nmol/L). Hematological parameters were normal in that alpaca at the time of examination. The erythrocytosis in the llama reported here may have been caused by hormone secretion by the tumor. Unfortunately, limited hormone analyses were done. Progesterone concentration in serum was within reference ranges (15). Although cortisol concentration was increased at the time of admission to the hospital, this had returned to normal within 48 h (27.6 nmol/L). The theory of hyperandrogenism associated erythrocytosis can not be substantiated in this llama because the PCV continued to rise after surgical removal of the affected ovary and no postmortem examination was performed. In theory, locally invasive masses not removed at the time of surgery or metastatic lesions could have continued to stimulate inappropriate erythrocyte production, but this would be merely speculative. Other potential causes of erythrocytosis could not be investigated because the owner declined a postmortem examination or bone marrow biopsy.
In cattle, clinical signs associated with a GCT include anestrus, nymphomania, virilism, or no abnormal signs. Interestingly, this llama was able to successfully conceive and maintain a pregnancy in spite of the GCT. The llama demonstrated clinical signs of lethargy and inappetence, likely caused by the metastatic nature of the tumors and the erythrocytosis. CVJ
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