Extensive Venous Thrombosis and Hind-Limb Edema Associated With Adrenocortical Carcinoma in a Dog
A 10-year-old, spayed female, mixed-breed dog was referred for evaluation of bilateral hind- limb edema and weakness. Abdominal ultrasonography showed increased echogenicity of the lumen of the caudal vena cava from the level of the urinary bladder to the level of the cranial pole of the right kidney. Bilateral saphenous venograms displayed numerous filling defects in the caudal vena cava, right external iliac vein, right femoral vein, and the right common iliac vein. Extensive venous thrombosis was diagnosed, and the animal was euthanized. Necropsy confirmed the presence of venous thrombosis and revealed a right adrenocortical carcinoma that had invaded the caudal vena cava. J Am Anim Hosp Assoc 1999;35:306-10.
Michael H. Jaffe, DVM, MS Amy M. Grooters, DVM, Diplomate ACVIM
Beth P. Partington, DVM, MS, Diplomate ACVR Alvin C. Camus, DVM Giselle Hosgood, BVSc, MS, Diplomate ACVS
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From the Departments of Veterinary Clinical Sciences (Jaffe, Grooters, Partington, Hosgood) and Veterinary Pathology (Camus), School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana 70803-8410.
Address all correspondence to Dr. Jaffe.
Case Report
A 30-kg, 10-year-old, spayed female, mixed-breed dog was referred for evaluation of anorexia and hind-limb lameness of seven days duration and bilateral hind-limb weakness and edema of two days duration. Previous treatment included dexamethasone given intramuscularly one week prior to referral and furosemide given one day prior to referral. Radiographic examination of the hind limbs by the referring veterinarian had not re- vealed any abnormalities. The owners reported that the dog had demon- strated mild polyuria and polydipsia for an unknown period of time. In addition, a right femoral head ostectomy had been performed several years earlier because of degenerative joint disease of the right coxofemo- ral joint.
Physical examination at the time of referral revealed pitting edema of both hind limbs, extending from the digits to the flank area. Both hind limbs were cold to the touch, but femoral pulses were normal. Popliteal and prescapular lymph nodes were mildly enlarged. Oral mucous mem- branes were pale, and capillary refill time was slightly prolonged (three seconds). Neurological examination revealed hind-limb ataxia and paresis with normal spinal reflexes. Hyperesthesia was detected upon palpation and flexion of the hind limbs. A small amount of frank blood was evident between the digits of the right hind limb.
A complete blood count (CBC) revealed lymphopenia (lymphocyte count, 500 cells/u; reference range, 1.0 to 4.8 x103 cells/ul). Serum biochemical analysis indicated azotemia (blood urea nitrogen, 56 mg/dl; reference range, 6 to 22 mg/dl; creatinine, 1.9 mg/dl; reference range, 0.4 to 1.5 mg/dl), hypercholesterolemia (482 mg/dl; reference range, 130 to 240 mg/dl), increased creatine kinase activity (1,108 U/L; reference range, 0 to 285 U/L), and increased alkaline phosphatase activity (1,208 U/L; reference range, 0 to 135 U/L). Urinalysis indicated a urine specific gravity of 1.015 with an acellular sediment. A serum enzyme-linked immunosorbent assay (ELISA) for adult Dirofilaria antigen was negative, and a lead II electrocardiogram showed no arrhythmias.
Evaluation of the abdomen for potential causes of caudal vena caval or lymphatic obstruction was pursued because of the lack of jugular pulses, ascites, or hepatomegaly observed with more common causes (e.g., hypo-
proteinemia, vasculitis, and right-sided heart failure) of bilateral hind-limb edema. Abdominal radiographs re- vealed proliferative spondylosis of the cranial lumbar spine, severe osteoarthritis of the left coxofemoral joint, a healed right femoral head and neck ostectomy, and a distended urinary bladder. Ultrasonographicª examination of the abdomen with 5- and 7.5-MHz mechanical sector transducers showed increased echogenicity of the lumen of the caudal vena cava from the level of the urinary bladder to the level of the cranial pole of the right kid- ney. This ultrasonographic appearance was consistent with abdominal caudal vena caval thrombosis. No other abnormalities were detected during ultrasonographic ex- amination. However, the presence of gas in the stomach and duodenum (as well as the dog’s large size and deep- chested conformation) prevented adequate visualization of the area craniomedial to the right kidney.
Bilateral saphenous venograms were obtained in or- der to confirm the vena caval thrombosis and to further assess its extent. The dog was anesthetized (premedica- tion, 7.5 mg butorphanol and 5 mg diazepam intrave- nously [IV]; induction, 75 mg propofol given to effect IV; maintenance, isoflurane in oxygen), and an 18-gauge through-the-needle catheterb was placed in each lateral saphenous vein. Fluoroscopy was performed, and radio- graphs of the hind limbs were obtained following rapid hand injection of iodinated contrast medium.º Multiple radiolucent filling defects were observed within the lu- men of the left lateral saphenous and distal femoral
veins. In addition, there was a large filling defect at the junction of the left external iliac vein with the caudal vena cava [Figure 1]. The mid and proximal portions of the left femoral, left external iliac, and left common iliac veins appeared to be patent [Figure 2]. Numerous filling defects were observed within the lumen of the right lateral saphenous and right femoral veins, with almost complete obstruction of the right external iliac and right common iliac veins [Figure 3]. Multiple collateral ves- sels extending from the right external iliac vein were filled with contrast medium. Following completion of the lateral saphenous venogram, a 6-French vascular sheathd was placed in the right jugular vein and was used to introduce a 5-French NIH cathetere into the caudal vena cava to a point just caudal to the diaphragm. Hand injection of iodinated contrast medium” into the caudal vena cava demonstrated an intraluminal mass that com- pletely filled the abdominal vena cava from a point just
caudal to the diaphragm to the bifurcation of the com- mon iliac veins.
Due to the poor prognosis associated with extensive venous thrombosis and the expense of thrombolytic agents, therapy was not attempted, and the dog was euthanized. Necropsy revealed a 4 by 3 by 1-cm sublumbar mass located near the cranial pole of the right kidney in the region of the right adrenal gland. The multilobular mass was hemorrhagic, friable, and con- tained multiple, pale-tan foci suggestive of necrosis. The invasive neoplasm had traversed the wall of the caudal vena cava and extended 4 cm cranially, partially occlud- ing its lumen. Caudal to the mass, a large, dull, red-to- gray, well-organized thrombus was adhered to the wall of the abdominal cava and extended into the lumens of the right renal, external iliac, and femoral veins. The right adrenal gland could not be identified; the left adre- nal gland was grossly normal. The liver contained mul- tiple, well-demarcated, 1- to 2-cm, friable, pale-tan
nodules located within the parenchyma and extending slightly above the capsular surface. Histological exami- nation indicated right adrenocortical carcinoma with mul- tiple hepatic metastases.
Discussion
Thrombosis (i.e., the intravascular deposition of a fibrin- platelet mass) develops in response to alterations in the anticoagulant mechanisms of the normal hemostatic sys- tem.1 Factors that interact to produce thrombosis include endothelial damage, vascular stasis, and hypercoagula- bility.1,2 In small animals, the most common causes of thrombosis include: vascular endothelial injury associ- ated with infections (e.g., dirofilariasis, sepsis, bacterial endocarditis) or vascular immune complex deposition; endocardial damage and stasis resulting from cardiac disease (e.g., feline hypertrophic cardiomyopathy); thrombocytopathies (e.g., myeloproliferative disorders, diabetes mellitus); and disorders associated with hyper- coagulability, hypofibrinolysis (e.g., hyperadreno- corticism, disseminated intravascular coagulation, neoplasia, and antithrombin-III deficiency secondary to protein-losing nephropathy or enteropathy), or both.1-7
In the dog of this report, thrombosis likely resulted from endothelial injury and venous stasis associated with neoplastic vascular invasion. In addition, hyperadre- nocorticism may have contributed to thrombus forma- tion through its tendency to cause a hypercoagulable state.4 This possibility is supported by previous findings that endothelial damage and stasis without hypercoagu- lability may be inadequate to cause thrombosis.8 Hyper- coagulability in dogs with hyperadrenocorticism may result from increased hepatic synthesis of vitamin K- dependent coagulation factors II, VII, IX, and X, or increased synthesis or release of factor V and von Willebrand factor-related antigen (vWF:Ag).9 Unfortu- nately, it is not clear whether or not the adrenocortical carcinoma in the dog described here was functional. The dog had exhibited polyuria and polydipsia prior to pre- sentation, but there was no evidence of hyperadre- nocorticism on physical examination. The increased alkaline phosphatase activity and hypercholesterolemia may have been associated with hyperadrenocorticism, but they also may have resulted from corticosteroid therapy administered prior to referral. Adrenal function testing was not performed because of the owners’ deci- sion not to pursue therapy. Unilateral functional adreno- cortical neoplasia may result in gross or microscopic cortical atrophy of the contralateral adrenal gland.10 In the dog of this report, the contralateral adrenal gland was grossly normal at necropsy; however, histopathology was not performed.
Peripheral edema is defined as an abnormal increase in the volume of fluid within a defined tissue space.11 There are several mechanisms by which this may de- velop. Increased capillary hydrostatic pressure, decreased
capillary oncotic pressure, increased interstitial oncotic pressure, decreased lymphatic drainage, and increased interstitial gel matrix can individually or in combination result in the formation of peripheral edema.11 In the dog described here, the peripheral edema formed as a result of increased capillary hydrostatic pressure in the hind limbs, which occurred secondary to postcapillary (vena cava, external iliac vein, common iliac vein) obstruction owing to thrombus formation.11 Other causes of hind- limb edema in small animals include right heart failure, hypoproteinemia, vasculopathy, lymphatic obstruction, primary lymphedema, and extraluminal compression of the caudal vena cava. 12
Tumors of the adrenal gland may invade local tissues such as the vena cava, renal vein, kidney, liver, aorta, and retroperitoneum.10 In one retrospective study of adrenocortical tumors, three of 14 dogs with adrenocor- tical carcinomas had neoplastic invasion of the caudal vena cava, and one had invasion of the adjacent renal vein.13 In the same study, none of 11 adrenocortical adenomas invaded local tissues.13 In a second retrospec- tive study, four of six dogs with adrenocortical carcino- mas had evidence of venous invasion at surgery or necropsy.14 Pheochromocytomas also are likely to ex- tend into local tissue.15,16 Previous reports have identi- fied neoplastic invasion of the caudal vena cava in 15% to 38% of dogs with pheochromocytomas.15,17 Clinical signs in affected animals have included ascites, hind- limb edema, and distention of the caudal epigastric veins. 15,16
Although ultrasonographic examination failed to iden- tify the right adrenal gland mass in the dog of this report, ultrasonography is often a useful tool for the evaluation of small animal patients with suspected adrenal neopla- sia. Ultrasonographic findings associated with adrenal neoplasia include adrenomegaly that is typically asym- metrical and sometimes severe; variable and often heter- ogenous echogenicity; and distortion of the normal adrenal shape and contour.14,18,19 Other findings that are less consistently present include adrenal mineralization, renal displacement, compression or invasion of the cau- dal vena cava, and decreased thickness of the contralat- eral adrenal gland.20,21 Adrenocortical adenomas often appear as hyperechoic nodules that may cause only mini- mal distortion of the normal adrenal contour. Although adrenal mineralization often is identified during ultraso- nographical examination of adrenal tumors, it also has been identified in dogs with adrenocortical hyperplasia secondary to pituitary-dependent hyperadrenocor- ticism.22 Advantages of ultrasonography in the evalua- tion of adrenal neoplasia include determination of the affected side and identification of vascular invasion or metastasis. Ultrasonographic visualization of focal he- patic lesions or regional lymphadenopathy in an animal with an adrenal mass is suggestive of metastasis; how- ever, the absence of ultrasonographic lesions does not
rule out the presence of metastatic disease, as demon- strated in the dog described here. The major disadvantages of ultrasonography are the experience and equipment needed to allow complete evaluation of both adrenal glands.
Therapy for venous thrombosis consists of limiting thrombogenesis and enhancing thrombolysis. Although percutaneous thrombectomy is often utilized in the man- agement of venous thrombosis in human patients,23 little data is available regarding its use in small animal pa- tients. Anticoagulants such as heparin (short term) and coumadins (long term) and antiplatelet drugs such as aspirin will depress thrombogenesis.24 Thrombolytic agents such as streptokinase, urokinase, and tissue plas- minogen-activator have been used in human and small animal patients to lyse existing thrombi.6,24 Although thrombolytic agents have the potential to cause severe hemorrhage, this appears to occur infrequently in human and canine patients.6,24 Minor adverse reactions associ- ated with streptokinase infusion in dogs have included epistaxis and petechial and ecchymotic hemorrhage.6 Thrombolytic therapy was not attempted in the dog de- scribed here because of the severe extent of venous thrombosis.
Hind-limb edema is a common manifestation of cau- dal vena caval thrombosis, but this is an unusual present- ing sign in a dog with adrenocortical neoplasia. Although neoplastic invasion of the caudal vena cava is not an uncommon finding in dogs with adrenal neoplasia, the extent of venous thrombosis and associated edema present in the dog described here is unusual.
a Ultramark 8; Advanced Technologies Laboratories, Inc., Bothel, WA
b I-Cath; CharterMed, Inc., Lakewood, NJ
c Iohexol 240; Winthrop Laboratories, New York, NY
d Catheter Sheath Introducer System; Cordis Corp., Miami, FL
e NIH Cardiovascular Catheter; C.R. Bard, Inc., Billerica, MA
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