49-Month Survival Following Caval Venectomy Without Nephrectomy in a Dog with a Pheochromocytoma

Introduction

Pheochromocytomas are uncommon tumors of the medullary portion of adrenal glands that tend to be locally aggressive. Macroscopic invasion of local vessels, including the caudal vena cava, is not uncommon. According to the literature 33%–82% of cases have microscopic invasion of local vessels.^1–4 Some tumor thrombi may be amenable to excision with caval venotomy, but other tumors may be too invasive and adherent to the inner wall of the caudal vena cava to be excised while leaving a patent caudal vena cava. Successful vena cava excision has been described previously with concurrent nephrectomy for locally invasive pheochromocytoma.⁵ In the case presented here, a similar procedure was successfully conducted without concurrent nephrectomy in a dog that presented with preoperative acute renal failure. The dog was followed until the time of its death, which appears to have been due to an unrelated condition.

Case Report

An 11 yr old spayed female Labrador retriever presented with a 3-mo history of vomiting, depression, and weakness. Two episodes of cyanosis and tachycardia (heart rate >200 beats/min) with intense abdominal pain had been observed. Both episodes responded in 2–4 hr following administration of a rapid IV fluid infusion by the referring veterinarian. The first episode was noted 3 wk before referral and the second episode occurred only 3 days prior to referral. Azotemia was documented during the first crisis (blood urea nitrogen [BUN] was 1 g/L; reference range, 0.2–0.5 g/L and creatinine was 101 mg/L; reference range, 6–14 mg/L). In addition, a multinodular, right adrenal mass had been diagnosed 1.5 mo prior to referral during an ultrasound exam that was performed at the referring veterinarian’s clinic for exploration of intermittent vomiting. No further information was provided by the referring veterinarian regarding either the size or invasiveness of the mass. At the time the mass was identified, no clinical signs related to the mass were evident and the mass was considered an incidental finding. Surgical removal had not been considered. The link between the adrenal mass and the episodes of collapse had not been made prior to referral.

Physical examination at the time of referral was within normal limits. Systolic blood pressure (performed by the Doppler flow ultrasonographic method) was 160 mm Hg. Serum biochemistry revealed a persistent increase in both BUN (0.7 g/L) and creatinine (21 mg/dL). In addition, elevations in alkaline phosphatase (339 U/L; reference range, 23–212 U/L), amylase (1,021 U/L; reference range, 235–870 U/L), and lipase (1,890 U/L; reference range, 60–500 U/L) were noted. Complete blood count identified a moderate neutrophilic leukocytosis (17,820 WBC/μL with 72.5% neutrophils; reference range, 6,000–13,000 WBC/μL, 60–79% neutrophils). Ultrasound of the abdomen performed by one of the authors (who is not board-certified) revealed a right, heterogeneous adrenal mass measuring 1.5 cm × 1.3 cm. Neither renal invasion nor visceral metastases were identified. The region of the vena cava was difficult to evaluate during the ultrasound examination partly due to poor patient compliance. A pheochromocytoma was suspected. The owner declined preoperative computed tomography (CT) because performing a CT would have required transferring the dog to another facility (in-house CT was not available at that time). No obvious thrombus invasion of the caudal vena cava was detected preoperatively, and local staging by ultrasound alone was considered sufficient. Thoracic radiographs (three views) revealed no pulmonary metastasis.

Laparotomy revealed neoplastic invasion of the suprarenal portion of the vena cava to the visceral border of the liver. Almost all of the tumor volume was within the lumen of the vena cava. That severity of invasion was not expected based on the ultrasound, and surgical removal of the tumor was delayed until the owners could be contacted to discuss the case. Renal biopsies were performed at that point. Histologic examination of those specimens revealed chronic membranous glomerulitis associated with moderate interstitial nephritis. Upon receipt of these results, after 8 days of fluid therapy (IV fluids at 1.5 × maintenance), the renal parameters had returned to normal (BUN was 0.4 g/L and creatinine was 14 mg/L). During hospitalization, edema of the hind limbs developed, extending from midthigh to the distal extremities. Blood pressure was repeatedly assessed in the week following the laparotomy, and no severe hypertension was documented (systolic blood pressure measurements remained between 150 mm Hg and 160 mm Hg).

Eight days after the first exploratory laparotomy, the decision was made to return to surgery for adrenalectomy and thrombus removal. The dog was premedicated with 0.1 mg/kg morphine^a and 0.05 mg/kg acepromazine^b intramuscularly. Anesthesia was induced with 0.25 mg/kg IV diazepam^c followed by 6 mg/kg IV propofol^d and maintained via endotracheal intubation with isoflurane^e in 100% oxygen. Anesthetic monitoring included continuous electrocardiogram, expiratory CO₂, pulse oxymetry, and noninvasive oscillometric arterial pressure (invasive blood pressure measurement by an arterial line was not part of the hospital’s anesthetic monitoring equipment). A ventral midline celiotomy was performed. Adhesions of neoplastic tissues to the right kidney were limited and were easily dissected so that the right kidney could be preserved. After further exploration, it appeared that the neoplastic tissues invaded the vena cava through a severely distended right phrenicoabdominal vein. Palpation of the vena cava revealed that its entire lumen was filled and distended with a firm tumor thrombus that extended from the visceral border of the liver to 1 cm cranial to the renal veins. The thrombus seemed to be circumferentially apposed and adherent to the caval venous wall. No residual blood flow could be seen through the vena caval wall in the area of thrombus invasion. The area of penetration of the thrombus into the vena cava through the distended phrenicoabdominal vein represented almost 40% of the vena caval circumference, and it seemed that attempting to remove the tumor thrombus by partial cavectomy and thrombectomy would lead to an unacceptable reduction in caval diameter. There was also a risk of leaving neoplastic cells in the vena cava. The longitudinal extent of the thrombus precluded transverse cavotomy and primary anastomosis, and the use of a vascular graft was not an option. In the presence of preexisting complete occlusion of caval blood flow, the decision to remove the invaded vena cava and adrenal tumor en bloc was considered less hazardous. En bloc removal had the additional benefit of reducing surgical time and limiting the risk of hypertensive episodes related to catecholamines released by the tumor.

The vena cava was circumferentially ligated with braided 3.5 metric polyester^f suture material both caudal to the liver (two circumferential ligatures) and cranial to the right renal vein (only one circumferential ligature to enable complete tumor thrombus removal without compromising the right renal vein). The neoplastic gland was then excised en bloc with the portion of the invaded caudal vena cava (Figures 1, 2). The gross appearance of the cranial extension of the thrombus was evocative of neoplastic tissue, and the caudal extension had the appearance of a blood thrombus. Caudal ligature of the vena cava had to be temporarily untied to extract a portion of the platelet thrombus that extended into the renal veins and 6 cm more caudally into the infrarenal caudal vena cava (Figure 2). No perioperative anesthetic or surgical complications occurred. Noticeably, no paroxysmal hypertension (systolic blood pressure >180 mm Hg) was noted during tumor dissection, and no severe hypotension (systolic blood pressure <80 mm Hg) occurred following tumor removal. The dog’s systolic blood pressure remained between 92 mm Hg and 173 mm Hg. Postoperative analgesia was provided by a continuous infusion of morphine^a, lidocaine^g, and ketamine^h. The hind limb edema increased in the first postoperative days. By the third day postsurgically, the dog could still use her hind limbs, but the generalized swelling had decreased the range of motion in both the hocks and stifles, and subcutaneous (SC) swelling was evident with pitting edema to the level of the hips. Hydrotherapy was maintained through the duration of hospitalization and consisted of 5 min of water jet massages q 12 hr. Heparinⁱ anticoagulation (200 IU/kg SC q 6 hr) was administered during hospitalization (for 6 days). The dog was discharged 6 days postoperatively with no apparent clinical complications. The hind limb edema had partially resolved. Carprofen^j (4 mg/kg q 24 hr) was prescribed for 7 days.

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The histologic analysis of samples removed from the tumor showed invasion of the adrenal gland by a neoplastic cell population originating from the medulla and focal capsular infiltration. Neoplastic cells were small to medium round cells with round to ovoid nuclei systematically containing a small nucleolus. Moderate to high anisocaryosis, moderate to high mitotic activity, and some images of lymphatic embolization were noted. Neoplastic cell population staining with neuron-specific enolase and chromogranin was highly positive, confirming the diagnosis of pheochromocytoma.

Physical examinations performed 2 mo, 4 mo, and 18 mo postsurgically identified a healthy dog. Serum biochemistry (alkaline phosphatase, alanine aminotransferase, BUN, creatinine, total serum protein, albumin, globulins, calcium, blood glucose, cholesterol) and an abdominal ultrasound performed 18 mo postsurgically were also within normal limits. The dog died 49 mo postoperatively after a sudden onset of vomiting and diarrhea. She had not shown any precursory signs in the preceding days, and blood work performed 1 mo earlier was normal. BUN and creatinine were evaluated when the gastrointestinal discomfort began, and BUN and creatinine were mildly elevated (0.79 g/L and 24 mg/L, respectively). Fluid therapy was initiated, but the dog died a few hours later. The owner declined necropsy.

Discussion

This report describes a case of canine pheochromocytoma with a large thrombus occluding the suprarenal caudal vena cava up to the level of the visceral border of the liver. The dog was successfully treated by surgical excision of the tumor and the invaded portion of vena cava and associated thrombus. To the authors’ knowledge, this is the first report to describe an en bloc suprarenal caval venectomy without concurrent nephrectomy in a dog. A case of infrarenal caval venectomy was described for the treatment of massive thrombosis, but the dog died 2 days after surgery.⁶ Two cases of en bloc suprarenal caval venectomy with concurrent nephrectomy have been described in the dog. In the first dog, right nephrectomy was performed for renal lymphoma, and the left renal vein was anastomosed to the remaining portion of the caudal vena cava via a polytetrafluoroethylene graft.⁷ The immediate recovery was uneventful, but the dog was euthanized 2 days postoperatively after an acute episode of aspiration pneumonia, proscribing long-term evaluation of outcome. In the second case, a right pheochromocytoma was removed en bloc with the invaded right kidney and suprarenal, infrahepatic caudal vena cava.⁵ The dog recovered well and was alive without symptoms 20 mo postoperatively, but was not followed until death.

Pheochromocytoma is an uncommon tumor arising from chromaffin cells of the adrenal gland. In the case of secreting tumors (most frequent), the intermittent release of catecholamines is responsible for clinical signs such as tachycardia, hypertension, heart rhythm disturbances, pale mucous membranes, and collapse. Less specific signs (e.g., vomiting, diarrhea, weakness) can also be seen. The clinical signs may also be related to local tumor growth, with invasion or compression of the vena cava impairing venous return.^1,2 Hind limb edema observed in the case described herein was a direct consequence of caudal vena cava invasion. If the invasion extends cranially to the suprahepatic portion of the caudal vena cava, a Budd-Chiari-like syndrome can be observed, characterized by the presence of protein-rich abdominal effusion.⁸ The extent of the vena cava invasion in the current case was more limited, and no abdominal effusion was detected. The intermittent nature of clinical signs related to catecholamine release makes the clinical diagnosis very difficult because the patient may not show signs of illness when presented for examination.

Clinical history most often raises the hypothesis of pheochromocytoma, as in the case presented here, and diagnostic imaging can further increase suspicion if an adrenal mass is demonstrated. Ultrasound is the imaging exam of choice for the identification of an adrenal mass.^9,10 Local and regional staging can also be performed during the abdominal ultrasound. Pheochromocytomas are more likely than other adrenal tumors to invade the vena cava and have adhesions to the kidneys and other surrounding tissues. Therefore, particular attention should be paid to these areas during the ultrasound evaluation.^4,11 Conditions of the exam can sometimes hinder proper visualization of the area. The probe may have to be applied with significant pressure to the abdominal wall to improve the deeper image, which can prove uncomfortable to the conscious patient, eliciting movements that interfere with evaluation. This occurred in our patient. Another factor that may have hindered the ultrasonographic evaluation of vena cava in the current case was the continuity between the neoplastic tissues and the inner wall of vena cava, which led to the absence of an echogenic interface. Use of color Doppler imaging could have helped to visualize vena caval blood flow obstruction, but this technique was not performed due to the patient’s lack of cooperation. Although useful in assessment, ultrasound can fail in detecting vascular invasion by adrenal masses. The reported sensitivity and specificity to that regard are 80% and 90%, respectively.⁴ Ultrasound is an operator-dependant technique and if a board-certified specialist had performed the exam, the caval invasion may not have been missed in this case. Retrospectively, the lack of adequate visualization of the caudal vena cava in the initial regional staging of the tumor should have warranted further investigation. Contrast-enhanced CT would have been appropriate as it has been shown to provide better sensitivity and specificity in detecting vascular invasion by adrenal masses (92% and 100%, respectively).¹² Injectable contrast medium can delineate the contour of an intraluminal tumor thrombus, thus helping in its identification and qualification. Disadvantages of using CT include the cost, the necessity of anesthesia, and the risk of inducing tumor release of catecholamines after contrast medium injection, which is associated with episodes of potentially severe hypertension. This complication has been observed in humans, and it is now recommended to pretreat human patients with phenoxybenzamine before contrast-CT in cases of suspected pheochromocytoma.¹⁰ The staging of the tumor should also include thoracic radiographs to assess the lungs for metastases. If CT is performed, thoracic evaluation may be performed with CT instead.

The treatment of pheochromocytomas is surgical and involves the excision of the neoplastic adrenal gland. Anesthetic management must take into consideration the risk of hypertensive episodes and cardiac arrhythmias associated with episodic catecholamine release by the tumor during surgery (the risk is increased during tumor manipulation). Premedication with α-adrenergic antagonist is indicated in the hours before surgery. In the report described herein, acepromazine was administered. In the days preceding surgery, phenoxybenzamine (a long-lasting, noncompetitive α-adrenergic antagonist) is widely prescribed in human patients before adrenalectomy for pheochromocytoma, and is advised as a pretreatment for dogs before pheochromocytoma excision as well.¹³ In the current case, pretreatment with phenoxybenzamine was not possible as it is not available to veterinarians in France. However, prazosin (a competitive selective α₁-antagonist) could have been used and has also been recommended as a pretreatment for pheochromocytomas.¹⁴ The authors chose to not pretreat the patient with prazosin because she was not severely hypertensive (systolic blood pressure did not exceed 180 mm Hg), and the authors were aware of controversies over the necessity of treating normotensive human patients preoperatively.¹⁵ In a recent study, a decrease in mortality rate after adrenalectomy was documented in dogs suffering from pheochromocytomas that were treated with phenoxybenzamine in the preoperative period compared to dogs that were not pretreated (13% versus 48% mortality).³ This recent evidence and expert recommendations support the systematic use of preoperative α-blockade even in apparently normotensive patients who may still have decreased circulatory volume and intermittent hypertension as a result of circulatory catecholamine secreted by the tumor and who may benefit from either phenoxybenzamine or prazosin pretreatment. Nonetheless, no anesthetic complications occurred in this case such as arrhythmias and perioperative changes in arterial blood pressure. Monitoring the patient with an arterial catheter connected to a pressure transducer for immediate assessment of blood pressure during anesthesia would have been more appropriate than the noninvasive oscillometric pressure monitor that was used. Direct monitoring is more reliable and might have identified more transient peaks in arterial pressure that might have remained unnoticed between intermittent oscillometric measurements.

Surgical resection of a pheochromocytoma may be complicated by the presence of a tumor thrombus in the vena cava, requiring a venotomy for removal of the thrombus.^4,11,16 In human patients, the removal of very large neoplastic inferior vena caval (IVC) thrombi extending up to the right atrium is described. Cardiopulmonary bypass and deep hypothermic circulatory arrest can be a useful adjunct with very large thrombi (i.e., those extending above the liver), but are costly procedures that are associated with their own morbidity. Various authors also report the successful removal of large thrombi by venovenous bypass and even without any extracorporeal circulation.^17–22 Circulatory bypass equipment is rarely available for veterinary patients, and most cavotomies are performed with temporary occlusion of vena caval blood flow. In recent reports, the procedure of adrenal tumor thrombus removal with caval venotomy in dogs has not been associated with a decreased long-term prognosis.^3,4,11,16 In cases of adhesion of the thrombus and/or tumor to the caudal vena cava, the removal of the thrombus by venotomy may prove impossible, as described herein. The only solution was en bloc surgical removal of the concerned portion of the vena cava. Only one canine case of successful en bloc resection of the caudal vena cava has been described, but that dog had concurrent ipsilateral nephrectomy.⁵ It seemed important in the current case to preserve both kidneys due to the preoperative renal insufficiency. To reinforce this consideration, preoperative renal failure and concurrent nephrectomy have both been identified as risk factors associated with shorter survival after adrenalectomy.^3,11,16

Gradual experimental occlusion of the suprarenal vena cava has been performed in dogs. Good tolerance and only a transient decrease in renal function occurred.²³ The restoration of a functional venous return could be explained by collateral neovascularization development simultaneous to the development of tumor thrombus, joining the renal capsule and vena cava upstream of the occlusion to preexisting tracks (i.e., vertebral venous sinuses, azygos vein) in which blood flow is consequently increased. In the current case, the long-standing presence and gradual growth of the caval thrombus before surgery most probably induced the same mechanism as observed with the experimental gradual occlusion of the caudal vena cava.

In human patients, surgical interruption of the inferior vena cava is not an uncommon procedure. Emergency ligation of the IVC is an accepted practice in trauma surgery to limit further hemorrhage when the injured portion of IVC cannot be reconstructed, but is associated with a high mortality rate.²⁴ Ligation above the renal veins has an even higher mortality rate, and survival is rare.²⁴ Ligation of the IVC was used as a means of preventing pulmonary embolization in cases of deep vein thrombosis in patients for whom anticoagulation therapy was not advisable.²⁵ In those cases, IVC ligation was performed on the infrarenal portion, but due to the acute character of the interruption in venous return, the procedure was still followed by significant morbidity and mortality (up to 14% operative mortality and 33% postoperative venous stasis). IVC filters are now used instead of IVC ligation with lower morbidity.²⁵ Planned ligation/excision of a portion of the IVC may also have to be performed in cases of either locally invasive neoplasms or neoplasms presenting with massive vena caval thrombi when removal of the thrombus via a cavotomy is not an option.^26–29 Many surgeons elect to replace the excised IVC with a synthetic vascular graft, especially in cases where collateral circulation may not have been established, when vena caval neoplastic occlusion is only partial, or when oliguria or circulatory compromise was recognized during surgery.^27–29 Excision without replacement can be followed with an acceptable outcome when complete occlusion of the vena cava was sufficiently long that collateral circulation had time to develop.^26–29 Excision without replacement may be preferable to avoid the risk of thrombosis and sepsis associated with synthetic grafts.^26,28 Preoperative cavography can assess the development of such a collateral circulation.²⁸ As the initial plan was to remove the thrombus via cavotomy, a contrast study was not performed preoperatively in the canine patient described in this report. When cavectomy was considered, the authors had to assume that the collaterals had developed sufficiently. Human patients undergoing excision of the IVC without replacement in adequately selected situations usually tolerate the procedure well. The most common postoperative complications is transient renal insufficiency and/or transient edema of the lower extremities.^26,28,29

Tumor and thrombus removal, decreased venous blood flow distal to the ligated vena cava, and age of the patient were considered cumulative risk factors for the occurrence of postoperative thrombosis, which prompted the authors to choose a rather aggressive heparinization protocol. Unfractionated heparin pharmacokinetics and its biologic activity are variable. Ideally, the heparin is titrated to effect and the activated partial thromboplastin time is monitored, which was not done in this case. Evidence is sparse for the definition of an appropriate dosage of heparin for thromboprophylaxis in dogs, but current recommendations suggest lower doses than used in the current case (35 U/kg q 8 hr SC tapered to 10 U/kg SC over 4 days then discontinuing).³⁰

Conclusion

This report shows that ligature-excision of the infrahepatic and suprarenal part of the vena cava can be successfully carried out in some dogs with locally invasive tumors. The exceptionally long survival of our patient suggests that the long-term prognosis can be good.