JAVMA
AVMA®
Adrenal tumors treated by adrenalectomy following spontaneous rupture carry an overall favorable prognosis: retrospective evaluation of outcomes in 59 dogs and 3 cats (2000-2021)
Marine Traverson, DVM, MS, DACVS1 *; Junxian Zheng, DVM1,2; Giovanni Tremolada, DVM, PhD, DACVS3; Carolyn L. Chen, DVM4; Megan Cray, VMD, DACVS5; William T. N. Culp, VMD, DACVS6; Erin A. Gibson, DVM, DACVS6; Michelle L. Oblak, DVM, DVSc, DACVS7; Vanna M. Dickerson, DVM, MS, DACVS8; Daniel J. Lopez, DVM, DACVS2; Elizabeth A. Maxwell, DVM, MS, DACVS9; Pierre Ansellem, DVM, MS, DACVS, DECVS10; Owen T. Skinner, BVSc, DECVS, DACVS11; Laura E. Selmic, BVetMed, MPH, DACVS, DECVS, MRCVS4
1Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC
2Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY
3Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO
4Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 5Angell Animal Medical Center, Boston, MA
6Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California-Davis, Davis, CA 7Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada
8Department of Small Animal Clinical Sciences, School of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX
9Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 10Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN
11Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri, Columbia, MO
*Corresponding author: Dr. Traverson (matraver@ncsu.edu)
Received June 14, 2023 Accepted August 23, 2023
doi.org/10.2460/javma.23.06.0324
@AVMA
OBJECTIVE
To conduct a retrospective multi-institutional study reporting short- and long-term outcomes of adrenalectomy in patients presenting with acute hemorrhage secondary to spontaneous adrenal rupture.
ANIMALS
59 dogs and 3 cats.
METHODS
Medical records of dogs and cats undergoing adrenalectomy between 2000 and 2021 for ruptured adrenal masses were reviewed. Data collected included clinical presentation, preoperative diagnostics, surgical report, anesthesia and hospi- talization findings, histopathology, adjuvant treatments, and long-term outcome (recurrence, metastasis, and survival).
RESULTS
Median time from hospital admission to surgery was 3 days, with 34% of surgeries being performed emergently (within 1 day of presentation). Need for intraoperative blood transfusion was significantly associated with emergent surgery and presence of active intraoperative hemorrhage. The short-term (≤ 14 days) complication and mortality rates were 42% and 21%, respectively. Negative prognostic factors for short-term survival included emergent surgery, intraoperative hypo- tension, and performing additional surgical procedures. Diagnoses included adrenocortical neoplasia (malignant [41%], benign [12%], and undetermined [5%]), pheochromocytoma (38%), a single case of adrenal fibrosis and hemorrhage (2%), and a single case of hemangiosarcoma (2%). Local recurrence and metastasis of adrenocortical carcinoma were con- firmed in 1 and 3 cases, respectively. Overall median survival time was 574 days and 900 days when short-term mortality was censored. No significant relationship was found between histopathological diagnosis and survival.
CLINICAL RELEVANCE
Adrenalectomy for ruptured adrenal gland masses was associated with similar short- and long-term outcomes as compared with previously reported nonruptured cases. If hemodynamic stability can be achieved, delaying surgery and limiting additional procedures appear indicated to optimize short-term survival.
Keywords: adrenalectomy, hemorrhage, survival, rupture, adrenal tumor
P rimary adrenal tumors account for < 2% and about 0.2% of canine and feline neoplasia, respectively.1 Adrenalectomy has been associated with an overall favorable long-term outcome regardless of the be- nign or malignant nature of the disease process,2-6 with median survival times (MSTs) ranging from 270 to 844 days and low rates of recurrence (0% to 22%)5,7-10 and metastasis (5% to 24%).9-12 Periopera- tive morbidity remains generally high, with reported mortality rates ranging from 4.2% to 43% depending on the selected population.3,6,9,11,13-15
Multiple retrospective studies2-8,11-16 have de- scribed the outcome for specific tumor types, sizes, anatomic configurations, clinical presentations, or surgical approaches. However, only a few case re- ports and case series17-22 describe the outcome of dogs presenting with extracapsular adrenal gland hemorrhage secondary to spontaneous adrenal tu- mor rupture. The perioperative mortality rate has been reported as high as 50%,6,17 and studies have suggested that dogs with extracapsular adrenal gland hemorrhage are prone to developing arrhyth- mias, hypotension, and postoperative complications as well as requiring a blood transfusion and having an overall longer duration of hospitalization com- pared with nonruptured cases.6 Little information is available regarding their prognostic factors and long-term outcome.
The purpose of this retrospective study was to describe the short- and long-term outcomes of dogs and cats undergoing adrenalectomy for the treatment of adrenal gland tumors with extracapsular hemor- rhage secondary to nontraumatic rupture. Particular attention was paid to the timing of the surgical proce- dure and its association with short-term survival rate. Primary variables considered for long-term outcomes were survival, rate of local recurrence, and metastasis. The authors hypothesized that initial stabilization and delayed surgical procedure would be associated with increased short-term survival over emergent surgi- cal management and that the tumor’s recurrence and metastasis rates would be low.
Methods
Case selection
The medical records from 10 academic institu- tions and 1 private referral institution were searched to identify dogs and cats of any age, body weight, reproductive status, sex, and breed with primary ad- renal tumors that underwent adrenalectomy between January 1, 2000, and June 1, 2021. The inclusion cri- teria consisted of dogs and cats that were taken to surgery for an adrenalectomy after presenting with a spontaneously ruptured adrenal mass as suspected by the presence of retroperitoneal effusion, perito- neal effusion or hematoma detected on preoperative imaging, and with the effusion confirmed as blood by abdominocentesis (PCV ≥ 20%) or during surgery. No minimum follow-up duration was required consider- ing the rarity of the presentation. Cases were ex- cluded from the analysis if spontaneous hemorrhagic
effusion or hematoma could not be confirmed after review of the laboratory diagnostics, imaging, and/or surgery reports.
Data collection
Data extracted from medical records included signalment; history; clinical presentation; preopera- tive blood work; coagulation panels; adrenal function test results; abdominal fluid analysis results; blood pressure (BP) readings; electrocardiogram findings; preoperative management and response to treat- ment; diagnostic imaging; surgical, histopathologi- cal, anesthesia, and postoperative findings; adjuvant treatment; and long-term follow-up and survival.
Preoperative diagnostic imaging results were reviewed to record tumor lateralization, size, pres- ence of retroperitoneal and/or peritoneal fluid, he- matoma, evidence of vascular and/or surrounding tissue tumor invasion, and suspicion for metastasis. Time-interval between initial presentation and sur- gery, gross tumor findings, active hemorrhage, caval venotomy, ureteronephrectomy, other surgical pro- cedures, intraoperative complications and manage- ment, and surgery and anesthesia durations were recorded. An emergent procedure was defined as a time interval of ≤ 1 day between presentation and surgery. Intraoperative hypotension (defined as a mean arterial pressure < 60 mm Hg or a systolic BP < 80 mm Hg for ≥ 10 minutes), hypertension (defined as a systolic BP ≥ 180 mm Hg for ≥ 10 minutes), ma- jor intraoperative hemorrhage (defined as requiring a blood transfusion and/or recorded as significant by the surgeon), blood products received, and cardiac arrhythmia and associated treatment were recorded. Information retrieved from the histopathology re- port included diagnosis and confirmed metastatic disease of any organ sampled. Postoperative com- plications and treatments associated, total duration of hospitalization, and short-term survival (≤ 14 days postoperatively) were recorded. Medical records from the referring veterinarian and/or referral insti- tutions were collected to gain information regarding long-term follow-up examination and diagnostics, evidence and date of local recurrence and/or me- tastasis, adjuvant treatments and potential compli- cations, and overall survival time. Owners were con- tacted as needed to confirm the dog or cat survival status or date of death, the cause of death, and nec- ropsy results if indicated.
Statistical analysis
Associations between continuous variables and binary variables were examined via Wilcoxon rank sum tests. Associations between binary variables were examined via the Fisher exact test. Associa- tions of postoperative complications, short-term survival, and duration of hospitalization with preop- erative blood work abnormalities were done with a series of Bonferroni-corrected Fisher exact tests and the Wilcoxon rank sum test. Associations between continuous variables and long-term survival were examined with univariate Cox proportional hazards models. Overall and censored (excluding short-term
mortality) MSTs were estimated across the entire study population, including dogs and cats lost to follow-up and alive at the time of study completion, and illustrated in Prism 9 (GraphPad) using a Kaplan- Meier analysis. The cause of death was not restricted to the adrenal disease in the survival analysis due to the absence of consistent necropsy. A cutoff value of 0.05 was used for significance.
Results
Clinical presentation
Fifty-nine dogs and 3 cats met the inclusion cri- teria. Clinical signs at presentation included lethargy (40/62 [64.5%]), abdominal pain (15/62 [24.2%]), collapse (13/62 [21.0%]), pale mucous membranes (12/62 [19.3%]), panting or tachypnea (10/62 [16.1%]), hyporexia (8/62 [12.9%]), abdominal dis- tension (7/62 [11.3%]), vomiting (6/62 [9.7%]), rest- lessness (5/62 [8.0%]), shaking or trembling (4/62 [6.5%]), and back pain (1/62 [1.6%]). Additionally, 14 of 62 (22.6%) dogs and cats were presented with uri- nary signs of varied chronicity. Cranial organomeg- aly was reported in 4 of 62 (6.5%) cases on physi- cal examination. In 4 of 62 (6.5%) cases, the adrenal mass was found incidentally via ultrasonography (n = 1 dog) or tomodensitometry (3 dogs). The popula- tion’s demographics and clinical presentation were summarized (Table 1).
Preoperative diagnostics and treatments
Complete preoperative blood work was per- formed in 60 of 62 cases. Anemia was evident in 22 of 62 (35.5%) cases, including 2 cats, and thrombocy- topenia was reported in 7 of 60 (11.6%) canine cases, with 2 of 7 dogs that had a confirmed platelet count < 100 X 103/ML (41 and 82 X 103/uL). Overall me- dian peripheral PCV was 38% (range, 17.3% to 57%) in dogs and 30% (range, 23% to 37%) in cats. Abdomi- nocentesis was performed in 18 of 62 (29.0%) canine cases and diagnostic of hemorrhagic peritoneal ef- fusion with a median PCV value of 41% (range, 25% to 58%). There was an increased prothrombin and/ or partial thromboplastin times ≥ 1.5 times the upper range limit in 7 of 48 (14.6%) canine cases. A hyper- coagulable state was suggested via thromboelastog- raphy in 4 of 4 (100%) dogs; elevated fibrinogen in 12 of 17 (70.6%) cases, including 1 cat; and elevated D-dimers in 4 of 9 (44.4%) dogs. Only 1 dog out of 45 dogs and cats for which noninvasive BP was mea- sured appeared hypotensive on presentation. Seven dogs and 2 cats (14.5%) were administrated packed RBCs (pRBCs), and 2 (3.2%) dogs received a whole blood transfusion preoperatively. Lower PCV (P = .001) and platelet count (P = . 047) were significantly associated with preoperative blood transfusion.
Adrenal function tests were performed in 26 of 62 (42.1%) cases, including a low-dose dexamethasone suppression test (n = 11 dogs and 1 cat), ACTH stimu- lation test (11 dogs), urine cortisol-to-creatinine ratio (8 dogs and 1 cat), serum or urine metanephrine (6 dogs), endogenous ACTH (4 dogs), and endogenous
| Variables | Species | |
|---|---|---|
| Dogs | Cats | |
| Breeds represented (n) | ||
| Crossbreed | 12 | |
| Labrador Retriever | 8 | |
| Golden Retriever | 7 | |
| German Shepherd Dogs | 5 | |
| Beagle | 4 | |
| Boxer | 2 | |
| Yorkshire Terrier | 2 | |
| Fox Terrier | 1 | |
| Bichon Frise | 1 | |
| Glen of Imaal Terrier | 1 | |
| Labradoodle | 1 | |
| Soft-Coated | 1 | |
| Wheaten Terrier | ||
| Basenji | 1 | |
| American Eskimo | 1 | |
| American Cocker Spaniel | 1 | |
| Doberman Pinscher | 1 | |
| Standard Poodle | 1 | |
| Rhodesian Ridgeback | 1 | |
| Australian Blue Heeler | 1 | |
| Collie | 1 | |
| Anatolian Shepherd | 1 | |
| Border Terrier | 1 | |
| Bassett Hound | 1 | |
| Boston Terrier | 1 | |
| Cavalier King | 1 | |
| Charles Spaniel | ||
| Pit bull-type dog | 1 | |
| Domestic shorthair | 3 | |
| Sex status | ||
| Spayed females | 29 | 1 |
| Castrated males | 28 | 2 |
| Intact female | 1 | |
| Intact male | 1 | |
| Median age (y) | 11 (range, | 8.4 |
| 5-13) | (range, 8.2-12.9) | |
| Median body weight (kg) | 26.8 (range, | 5.6 (range, 5.5-6.0) |
| 5.1-63.9; 23/59 [38.9%] ≤20 kg) | ||
| Clinical signs (n) | ||
| Lethargy | 37 | 3 |
| Abdominal pain | 13 | 2 |
| Collapse | 12 | 1 |
| Pale mucous membranes | 12 | |
| Panting or tachypnea | 9 | 1 |
| Hyporexia | 6 | 2 |
| Abdominal distension | 7 | |
| Vomiting | 5 | 1 |
| Restlessness | 4 | 1 |
| Shaking or trembling | 3 | 1 |
| Back pain | 1 | |
| Polyuria-polydipsia | 12 | |
| Inappropriate urination | 2 | 1 |
| Physical examination | ||
| findings (n) | ||
| Cranial organomegaly | 3 | 1 |
| Palpable fluid wave | 4 | |
steroid hormone levels (1 cat). A primary cortisol- secreting adrenal tumor was suspected in 8 of 21 (38.1%) cases tested for hyperadrenocorticism, and 1 of 8 dogs received preoperative oral trilostane at 1.4 mg/ kg once daily (for an unknown duration). A pheochro- mocytoma was suspected in 20 of 62 (32.2%) canine
cases based on adrenal function test (n = 8), systemic hypertension (12), vascular invasion (5), cardiac ar- rhythmia (2), and/or syncopal episode (1). a-Blockers were administrated preoperatively in 27 of 62 (43.5%) canine cases; 25 dogs received phenoxybenzamine at a mean oral dose of 0.47 mg/kg twice daily (range, 0.085 to 1.4 mg/kg) for a mean duration of 9.2 days (range, 2 to 34 days), and 2 dogs received prazosin at a mean total oral daily dose of 0.38 mg/kg for 12 and 23 days. Phenoxybenzamine use was not associated with the diagnosis of pheochromocytoma (P = . 136) but was associated with a nonemergent surgery (P = . 016). Oth- er specific preoperative medications in dogs included amlodipine (n = 2), aminocaproic acid (2), diltiazem (1), and heparin at a rate of 10/IU/kg/h (1). There was no specific pretreatment administered in cats.
Fifty-nine of 62 (95.2%) dogs and cats had imag- ing with abdominal ultrasonography (n = 19 dogs and 1 cat), CT (6 dogs), or a combination of both (31 dogs and 2 cats) preoperatively. Three dogs did not have comprehensive abdominal imaging but had evidence of free fluid on FAST (focused assessment with so- nography for trauma) scan, which was confirmed as hemorrhagic on abdominocentesis in 2 of 3. Of the 62 cases that received complete abdominal imaging and/or a FAST scan, peritoneal effusion was noted in 29 dogs (46.7%), retroperitoneal effusion was noted in 39 dogs and 1 cat (64.5%), and both were noted in 16 dogs and 1 cat (27.4%). A retroperitoneal hema- toma was suspected in 34 of 59 (57.6%) cases that had complete abdominal imaging, including 1 cat. Other significant imaging findings included splenic (n = 10 dogs) and hepatic nodular lesions (8 dogs), gastric and intestinal foreign bodies (2 dogs), urocystoliths (1 dog), and diffuse small intestinal layer changes (1 cat). Three dogs of 57 (5.2%) dogs and cats that re- ceived thoracic imaging preoperatively had suspect- ed pulmonary metastasis (none sampled), and 1 dog had a right caudal lung lobe mass.
Surgical procedure
The overall median time between presentation and surgery in dogs and cats was 3 days (range, 0 to 210 days), with 21 of 62 (33.9%) surgical procedures per- formed emergently (n = 20 dogs and 1 cat). No sig- nificant relationship was found between surgery timing and peripheral PCV (P = . 317), lactate (P = . 153), plate- let count (P= . 383), prothrombin time (P= . 453), partial thromboplastin time (P = 1), systolic BP (P = . 169), and imaging identification of peritoneal effusion (P = . 128), retroperitoneal effusion (P = . 82), and/or hematoma (P = . 053) on presentation. Surgical approach consisted of ventral midline celiotomy (n = 57 dogs and 3 cats),
right paracostal approach (1 dog), or combined ap- proach (1 dog). Active adrenal hemorrhage was noted in 15 of 62 (24.1%) cases, including 1 cat. Vascular in- vasion was confirmed in 15 of 62 (24.1%) canine cases, with a tumor thrombus invading the caudal vena cava (n = 10), phrenicoabdominal (4), and renal (1) vein. Cases with right-sided tumors (n = 28 dogs) had odds of vascular or surrounding tissue invasion that were 2.8 times as high as those in left-sided tumors (30 dogs and 3 cats; OR, 3.35; 95% CI, 1.04 to 10.93; P = . 047). Retroperitoneal hematoma (n = 39 dogs and 2 cats), adrenal gland disruption (29 dogs and 1 cat), and tu- mor adhesions to the ipsilateral kidney (8 dogs) or hyp- axial musculature (1 dog) were documented at surgery.
Left, right, and bilateral adrenalectomy were completed in 33 of 62 (53.2%), 28 of 62 (45.2%), and 1 of 62 (1.6%) cases, respectively. Caval venotomy was performed in 10 (16.1%) dogs to retrieve a tumor thrombus, and 12 (19.4%) dogs underwent an ipsilat- eral ureteronephrectomy. The retroperitoneal hema- toma was reportedly removed in 13 (21.3%) dogs and a nephropexy performed in 4 (6.5%) dogs. Additional procedures included liver biopsy (n = 20 dogs), sple- nectomy (9 dogs), abdominal lymph node extirpation (3 dogs and 1 cat), gastrointestinal biopsy (3 dogs and 1 cat), liver lobectomy (3 dogs), omental nod- ule excision (2 dogs), gastrotomy (3 dogs), pancre- atic nodule excision (1 dog), lung lobectomy (1 dog), typhlectomy (1 dog), renal biopsy (1 dog), cystotomy (1 dog), gastropexy (1 dog), ovariohysterectomy (1 dog), pancreatic and mesenteric nodule excision (1 dog), and excisional biopsy of skin tag (1 dog), peri- anal mass (1 dog), and facial mass (1 dog).
Thirty-seven of 62 (59.6%) dogs and cats experi- enced adverse events during anesthesia, including hypo- tension in 23 dogs and 3 cats (41.9%), hypertension in 5 dogs and 1 cat (9.6%), and cardiac arrhythmia in 16 dogs (25.8%). There was no significant impact of phenoxy- benzamine pretreatment on the occurrence of hypoten- sion, hypertension, or cardiac arrhythmia, whether this was considered for the entire study population (P = . 566, P= 1, and P = . 088, respectively) or pheochromocytoma cases exclusively, according to histopathology (P = . 203, P = 1, and P = 1, respectively). Intraoperative hemor- rhage upon dissection of the adrenal gland was reported in 22 of 54 (40.7%) canine cases, with major hemorrhage recorded in 8 of 22 (36.3%) dogs. Nineteen of 62 (30.6%) dogs and cats received intraoperative blood transfu- sions, including pRBCs (n = 16 dogs and 1 cat), fresh frozen plasma (2 dogs), and whole blood (1 dog). In 3 dogs and 1 cat, the transfusion was continued from be- fore the operation. Factors associated with intraopera- tive transfusion are illustrated (Table 2).
| Variables | No. of patients | Intraoperative blood transfusion | P value, Fisher exact test | |
|---|---|---|---|---|
| Timing of surgerya | Emergent | 21 | 10/21 (47.6%) | .002 |
| Delayed | 41 | 9/41 (21.9%) | ||
| Intraoperative hemorrhage | Yes | 22 | 12/22 (54.5%) | .003 |
| No | 32 | 5/32 (15.6%) |
aTime from presentation to emergent surgery of ≤ 1 day versus median time of 7 days (range, 2 to 210 days) for delayed surgery.
The overall median duration of the surgical pro- cedure and anesthesia was 120 minutes (range, 60 to 350 minutes) and 210 minutes (range, 113 to 480 minutes), respectively. Shorter procedures were sig- nificantly associated with emergent surgery and ab- sence of vascular invasion (P < . 001 and P = . 034, respectively). Overall, 57 dogs and 3 cats (96.7%) re- covered from surgery and anesthesia. One dog was euthanized intraoperatively due to uncontrolled ad- renal hemorrhage. The second remained comatose postoperatively after an episode of cardiopulmonary arrest and was eventually euthanized. Both under- went surgery within 1 day of presentation.
Postoperative period
Of the 60 cases that survived the surgical pro- cedure, 14 dogs and 2 cats (26.6%) received a blood transfusion postoperatively, including pRBCs (n = 11 dogs and 2 cats), fresh frozen plasma (4 dogs), and whole blood (1 dog); in 6 dogs and 1 cat, the trans- fusion was continued from intraoperative administra- tion. Twenty-three of 60 (38.3%) dogs and cats re- ceived glucocorticoid treatment immediately before and/or after surgery in the form of injectable dexa- methasone sodium phosphate (n = 20 dogs and 1 cat) and/or prednisone (15 dogs) or prednisolone (1 cat). For 15 dogs, hypoadrenocorticism was confirmed postoperatively, and 9 continued long-term glucocor- ticoid treatment (> 14 days postoperatively).
Postoperative complications were reported in 25 of 60 (41.6%) cases, including acute kidney injury (AKI; n = 7 dogs), aspiration pneumonia (5 dogs), disseminated intravascular coagulation (5 dogs), hemoperitoneum (3 dogs), suspected pulmonary thromboembolism (2 dogs), suspected pancreatitis (2 dogs), neurologic signs including seizures (2 dogs), cardiovascular complications such as cardiac arrhythmias (3 dogs), hypo- (3 dogs) or hypertension (1 dog), and tachycardia (2 dog). Of the 7 dogs that developed an AKI, 5 of 7 had a ureterone- phrectomy and 3 of 7 developed other postoperative
complications, including aspiration pneumonia (n = 2), suspected pancreatitis (1), hemoperitoneum (1), and seizure (1) leading to their death (1) or euthanasia (2). A significant association was noted between ureterone- phrectomy and postoperative AKI (P = . 003), but not with other variables, including intraoperative hypotension (P = . 672). Additionally, there was no significant associa- tion between intraoperative hypotension and postopera- tive AKI within the subpopulation that underwent a ure- teronephrectomy (P = . 222).
Overall, postoperative complications led to death or euthanasia in 4 and 7 dogs, respectively, with an overall short-term mortality rate of 20.9% (13/62). Me- dian duration of hospitalization was 2 days (range, 1 to 7 days), and 46 dogs and 3 cats survived the post- operative period. There was no significant impact of phenoxybenzamine pretreatment (P = . 326 for the en- tire study population, P = . 347 for pheochromocytoma exclusively), ureteronephrectomy (P = . 107), postop- erative AKI (P = . 125), and overall postoperative com- plications (P = . 504) on short-term survival. Variables significantly associated with postoperative AKI and short-term mortality are reported (Tables 3 and 4).
Histopathology results
Histopathology results were available in 60 of 62 (96.7%) cases, and diagnoses included adrenocortical carcinoma (n = 25 dogs [41.7%]), pheochromocytoma (22 dogs and 1 cat [38.3%]), adrenocortical adenoma (6 dogs and 1 cat [11.6%]), undetermined adrenocor- tical neoplasia (2 dogs and 1 cat [5.0%]), and 1 (1.7%) canine case each of adrenal fibrosis and hemorrhage and of hemangiosarcoma with metastasis to the pan- creas and kidney. Histopathology was not submitted for 1 of the 2 dogs euthanized under general anes- thesia and could not be found in the medical record system of another dog. In the second case, the sur- gery report indicated an adrenal mass associated with a 5 X 8-cm hematoma, moderate peritoneal hemor- rhagic effusion, and no other significant lesion apart
| Prognostic factors | No. of patients | Postoperative acute kidney injury | P value, Fisher exact test | |
|---|---|---|---|---|
| Ureteronephrectomy | Yes | 12 | 5/12 (41.6%) | .003 |
| No | 48 | 2/48 (4.2%) | ||
| Prognostic factors | No. of patients | Short-term mortality | P value, Fisher exact test | |
|---|---|---|---|---|
| Timing of surgeryª | Emergentb | 21 | 6/21 (28.5%) | .015 |
| Delayed | 41 | 7/41 (17.0%) | ||
| Additional surgical procedure | Yes | 43 | 13/43 (30.2%) | .006 |
| No | 19 | 0 (0%) | ||
| Intraoperative hypotension | Yes | 23 | 9/23 (39.1%) | .011 |
| No | 39 | 4/39 (10.3%) |
bWithin the subpopulation receiving an emergent surgery, there was also a significant association between hypotension and short-term mortality (P = . 012); this was not true for the subpopulation receiving nonemergent surgery (P = 1). See Table 2 for remainder of key.
from a small liver nodule. Other concurrent histopath- ologic diagnoses included hepatocellular carcinoma (n = 2 dogs); splenic, hepatic, and metastatic splenic and hepatic hemangiosarcoma unassociated with a pri- mary adrenal hemangiosarcoma (1 dog each); pulmo- nary carcinoma; oral melanoma; facial carcinoma with mixed squamous and chondroid differentiation (1 dog each); and small intestinal small cell lymphoma (1 cat).
Long-term follow-up
Thirty-nine of 49 (79.5%) dogs and cats that survived the perioperative period had follow-up examinations, with the last visit reported at a median interval of 100 days (range, 4 to 2,466 days) after surgery. Repeated diagnostics at these appointments included blood work (n = 28 dogs and 2 cats), abdominal imaging (20 dogs and 1 cat), and thoracic imaging (18 dogs and 1 cat). Local recurrence (n = 1 dog) and/or metastasis (3 dogs) of neuroendocrine carcinoma to the omentum, liver, spleen, contralateral adrenal gland, and kidney were con- firmed on histopathology in a total of 3 dogs at 314, 490, and 510 days postoperatively, including 1 dog that was initially diagnosed with adrenocortical adenoma. Non- sampled suspected metastasis and/or de novo tumors were reported in 7 other dogs and 1 cat, including sus- pected hepatic metastasis of splenic hemangiosarcoma (n = 1 dog), novel hepatic mass with liver and pulmonary nodules (1 dog), cranial abdominal mass (1 cat), mesen- teric nodules (1 dog), thyroid and pulmonary nodules (1 dog), contralateral adrenal mass with pulmonary nodules
(1 dog), urothelial cell carcinoma (1 dog), and metasta- sis of oral malignant melanoma (1 dog).
Seven of 49 (14.2%) dogs and cats received ad- juvant chemotherapy at a median interval of 31 days (range, 10 to 545 days) after surgery. Treatment was targeted toward the adrenal neoplasia in 2 dogs and included doxorubicin therapy for metastatic adrenal hemangiosarcoma (30 mg/m2, IV, 1 dose total) and combination therapy with docetaxel and cyclospo- rine for metastatic adrenocortical carcinoma (1.625 mg/kg and 5 mg/kg orally, respectively, 2 doses at a 1-week interval). Other adjuvant chemotherapy treat- ments included doxorubicin (n = 2 dogs), carboplatin (1 cat), vinorelbine (1 dog), and chlorambucil (1 dog) for splenic and/or hepatic hemangiosarcoma, gastro- intestinal lymphoma, suspected pulmonary carcinoma, and urothelial cell carcinoma, respectively. No dog or cat underwent adjuvant radiation therapy.
Of the 49 cases that survived the perioperative pe- riod, 15 dogs and 2 cats (34.7%) were lost to long-term follow-up. Of the remaining 32 cases, 13 dogs (26.5%) were still alive at the time of data collection, and 18 dogs and 1 cat (38.8%) were deceased, leading to overall and censored MSTs of 574 days and 900 days, respectively (range, 0 to 2,466 and 8 to 2,466 days). Long-term cause of death or euthanasia was suspected related to the ad- renal neoplasia in 4 of 19 cases, including 1 cat; unrelated in 9 of 19 cases; and unknown in 6 of 19 cases. Case sum- mary and compared Kaplan-Meier survival estimates by tumor types are presented (Table 5; Figure 1).
| Adrenal tumor diagnosis | Adrenocortical carcinoma | Pheochromocytoma | Adrenocortical adenoma | Undetermined adrenocortical neoplasm | Hemangiosarcoma | |
|---|---|---|---|---|---|---|
| Study population | ||||||
| Canine | 25 | 22 | 6 | 2 | 1 | |
| Feline | — | 1 | 1 | 1 | — | |
| Preoperative diagnostic imaging | ||||||
| Median maximum tumor axis | 5.6 (2-11.5) | 5.7 (1.8-10) | 5.4 (0.8-11) | 6.2 (4.5-7.4) | 5.2 | |
| (range [cm]) | ||||||
| Suspected vascular invasion | 5/25 (20.0%) | 9/23 (40.9%) | 3/7 (42.8%) | 1/3 (33.3%) | — | |
| Peritoneal effusion | 12/25 (48.0%) | 12/23 (52.1%) | 2/7 (28.5%) | 1/3 (25.0%) | 1/1 (100%) | |
| Retroperitoneal effusion | 16/25 (64.0%) | 19/23 (86.0%) | 2/7 (28.5%) | 3/3 (100%) | — | |
| Retroperitoneal hematoma | 16/25 (64.0%) | 8/23 (36.3%) | 4/7 (57.1%) | 3/3 (100%) | 1/1 (100%) | |
| Preoperative treatment | ||||||
| Phenoxybenzamine | 7/25 (28.0%) | 12/23 (52.1%) | 4/7 (57.1%) | 1/3 (33.3%) | ||
| Blood transfusion | 5/25 (20.0%) | 2/23 (8.6%) | 1/7 (14.3%) | 1/3 (33.3%) | — | |
| Surgical procedure | ||||||
| Adrenalectomy (L/R) | 16/10 | 10/13 | 3/4 | 3 L | 1R | |
| Caval venotomy | 3/25 (12.0%) | 7/23 (30.4%) | — | — | — | |
| Ureteronephrectomy | 2/25 (8.0%) | 7/23 (30.4%) | — | 1/3 (33.3%) | 1/1 (100%) | |
| Additional procedures | 16/25 (64.0%) | 15/23 (65.2%) | 5/7 (71.4%) | 3/3 (100%) | 1/1 (100%) | |
| Anesthesia | ||||||
| Systemic hypotension | 11/24 (45.8%) | 9/21 (42.8%) | 3/7 (42.8%) | 1/3 (33.3%) | — | |
| Systemic hypertension | 2/24 (8.3%) | 5/21 (23.8%) | — | 1/3 (33.3%) | — | |
| Cardiac arrhythmias | 8/24 (33.3%) | 5/21 (23.8%) | 1/7 (14.3%) | — | 1/1 (100%) | |
| Postoperative period (≤ 14 d) | ||||||
| Glucocorticoid treatment | 14/24 (58.3%) | 7/23 (30.4%) | 1/7 (14.3%) | 1/3 (33.3%) | — | |
| Complications | 8/24 (33.3%) | 14/23 (60.8%) | 2/7 (28.5%) | — | 1/1 (100%) | |
| Short-term mortality | 6/24 (25.0%) | 6/23 (26.0%) | — | — | — | |
| Long-term follow-up | ||||||
| Local recurrence | 1/19 (5.2%) | — | — | — | — | |
| Distant metastasis | 2/19 (10.5%) | — | 1/7 (14.3%) | — | 1/1 (100%) | |
| Targeted adjuvant chemotherapy | Docetaxel and cyclosporine (n = 1) | — | — | — | Doxorubicin (n = 1) | |
| Targeted adjuvant radiation therapy | — | — | — | — | — | |
| Median or overall survival time (d) | 555 (0-1,443) | 580 (1-2,466) | 490 (17-987) | 942 (479-1,150) | 190 | |
| Censoreda median or overall | 855 (17-1,443) | 1,471 (8-2,466) | 490 (17-987) | 942 (479-1,150) | 190 | |
| survival time (d) | ||||||
aExcluding short-term mortality (≤ 14 days postoperatively).
L = Left. R = Right.
100
Pheochromocytoma (n = 23)
Proportion Surviving (%)
Adrenocortical tumors (n = 35)
CLUJJ.
50
0
0
500
1000
1500
2000
2500
Time (days)
Discussion
This study investigated a unique population of dogs and cats presenting with acute spontaneous adrenal hemorrhage and demonstrated that, in this cohort, a delayed surgical treatment was superior to emergent surgical treatment. Additionally, local recurrence and metastasis appeared to occur rarely.
The results confirmed our clinical impression that medical management may allow for acute he- mostatic control, potentially because of the enclosed nature of the retroperitoneal space. Interestingly, some dogs and cats presenting with peritoneal effu- sion also responded favorably to initial conservative treatment despite the larger spaced cavity. There- fore, if cardiovascular stabilization can be achieved, results of the study suggested the procedure should be delayed, which might allow for improved surgi- cal visibility and hemodynamic control. Most previ- ous case reports6,17,18,20-22 include dogs receiving emergent surgical stabilization due to cardiovascu- lar decline despite medical management. A guarded outcome with a 50% perioperative mortality rate was also reported for 8 dogs receiving emergent adre- nalectomy.6 Overall, limitations in anesthesia, critical care, and surgical support on emergency may play a role in the poorer outcome. It is also possible that cases selected for emergent surgery were more un- stable on presentation in our cohort. However, the absence of association between surgery timing and preoperative peripheral PCV, lactate, platelet count, coagulation parameters, BP, or imaging evidence of rupture seems to indicate that the decision to per- form the procedure on an emergent basis would rather have been related to institution and/or sur- geon preferences. The retrospective nature of the study precludes further conclusion regarding the
clinical reasoning behind this surgical decision. The ideal timeline at which surgery should occur remains unclear, and the present study along with our clini- cal impression seems to suggest that a few days to a week would suffice. Finally, the study reinforces the importance of preoperative diagnostic imaging in identifying the source of hemorrhage in cases of hemoperitoneum, and adapting surgical timing and preparation accordingly.
Spontaneous adrenal tumor rupture is also a rare condition in human medicine, and reported mortality rates of 45% for emergent adrenalectomy have led to delayed surgical treatment when hemodynamic stabil- ity can be achieved.23 Marti et al23 established a treat- ment algorithm based on a patient’s hemodynamic stability and endocrine testing and recommended in- terval imaging at 3 and 6 months to monitor hematoma resolution and allow time for inflammation to subside. Emphasis on patient stabilization and pretreatment appears critical in cases of functional tumors. In se- lected cases of nonfunctional tumor, adrenalectomy might ultimately not be elected.23 Additionally, arte- rial embolization is frequently implemented preoper- atively to help control hemostasis, with success rates of up to 82% reported in the acute settings.24 It has also shown satisfactory efficacy as the sole treatment for inoperable tumors or to obtain tumor size reduc- tion, functional resolution, and alleviate pain with no serious adverse reactions.25 Case reports26,27 of arte- rial embolization demonstrate effective hemodynam- ic stabilization of veterinary patients presented with continuous epistaxis or hemoperitoneum secondary to ruptured liver mass. However, its use remains an- ecdotal in veterinary medicine and has not been in- vestigated to our knowledge in cases of spontaneous adrenal hemorrhage.
Adrenal tumor types represented in the current study were similar to those previously reported for nonruptured cases in dogs and cats, excluding a rare case of primary adrenal hemangiosarcoma. Pri- mary adrenal hemangiosarcoma or angiosarcoma has rarely been reported in human medicine and displays an aggressive behavior and overall poor prognosis28,29 characterized by a high propensity for local recurrence and metastasis. Intraoperative de- tection of abdominal metastases in this particular case aligns with the general rapid progression of the cancer. Overall, there was a preponderance of adre- nocortical (60%) over medullary tumors (36%); this fact corroborates the findings of Lang et al,6 who de- tail 8 cases of spontaneous adrenal hemorrhage, 7 of which had a tumor of adrenocortical origin. Interest- ingly, pheochromocytoma has been most commonly associated with adrenal rupture in people23,30; other etiologies include carcinoma, adenoma, and myeloli- poma.31 Previous veterinary studies have speculated that tumor size > 2 cm,6,8,24,32 vascular invasion,8 and high percentage necrosis32 could represent underly- ing predisposing factors of rupture. Mean tumor size on CT was 5.8 cm in the current study, which appears subjectively larger than commonly reported.2,4,8,10 Vascular invasion was documented in 37% of his- topathology reports, and percentage necrosis was
inconsistently evaluated to support further conclu- sions. Comparison with a nonruptured adrenal tumor population would be required to investigate predis- posing factors of spontaneous adrenal rupture.
Overall, short- and long-term outcomes appeared similar to those previously reported for nonruptured primary adrenal tumors, with a relatively high short- term mortality rate (21%) but low recurrence and metastasis rates leading to prolonged survival with adrenalectomy alone.2,7,9,10,33,34 Few cases under- went adjuvant chemotherapy, considering it is not the standard of care for primary adrenal tumors, and for most cases, treatment was targeted to other tumor sites, which did not allow us to draw clear conclusions regarding its benefit in rare cases of metastasis. Ad- ditionally, only 1 case of local recurrence of adreno- cortical carcinoma was confirmed histologically and may have been related to diffuse metastatic disease. Although nonsignificant statistically, some distinc- tions in outcomes were observed between etiologies. An overall higher postoperative complication rate was noted with pheochromocytoma, which has pre- viously been described as a risk factor for short-term mortality.10 Perioperative mortality, however, was not impacted by the tumor type in the present study. Long- term prognosis appeared overall less favorable for ad- renocortical tumors, with a higher metastatic rate and shorter MST than pheochromocytoma. This survival trend was shared between malignant, benign, and undetermined adrenocortical tumors, which could challenge the reliability of histopathology to rule out a malignant process. In fact, 1 case of adrenocortical adenoma was later diagnosed with metastatic neuro- endocrine carcinoma to the liver based on necropsy and histopathology findings without evidence of an- other primary neuroendocrine tumor. Overall, the low number of cases and the absence of comprehensive long-term follow-up and necropsy related to the ret- rospective nature of the study preclude further con- clusions in that regard. An association between carci- noma and development of metastasis has previously been reported, with compared MSTs of 360 days ver- sus 953 days for the entire study population.8 Other specific retrospective studies13,35 have documented metastatic rates of up to 36% for dogs that presented with adrenocortical tumors. Similar observations have been made in human medicine, with up to 22% meta- static rate on presentation and an increased risk of lo- cal recurrence leading to an overall guarded long-term prognosis with adrenocortical carcinoma.36 Altogeth- er, metastatic rates in the present study remained low compared with those of previous studies,2,7,9,10,33,34 but may have been underestimated owing to the lack of routine necropsy. Size of the tumor, presence of a tumor thrombus, or microscopic metastasis was not associated with survival, in contrast to other stud- ies. 3,8,9,33 Finally, although this study includes a mixed population of dogs and cats, the low number of feline cases does not support separate conclusions regard- ing their outcome.
A significantly lower short-term survival rate (75%) was found in dogs and cats that received additional sur- gical procedures, compared with those cases strictly
limited to adrenalectomy (100%). Other studies9,10 have found concurrent nephrectomy to be a negative prog- nostic factor with an increased risk of acute renal injury postoperatively. This association was confirmed in this study without impacting the short-term survival. Cer- tain procedures appear inevitable, such as performing a ureteronephrectomy in cases of adhesions to the ipsi- lateral kidney or addressing a gastrointestinal obstruc- tion via gastrotomy/enterotomy. However, these re- sults along with those reported previously suggest that any additional procedure that could be avoided should be postponed. Additionally, intraoperative hypotension was significantly associated with increased short-term mortality, particularly within the group that received an emergent procedure. Interestingly, no association was found between hypotension and AKI, although this could reflect a type II error. Finally, preoperative phenoxybenzamine administration was not associ- ated with a more favorable immediate outcome, com- pared with findings in a previously published study.32 This finding of the present study was validated in the entire study population and when cases confirmed as pheochromocytoma on histopathology were selected. The absence of pretreatment in the group that received emergent surgery and had an overall poorer outcome could have induced a bias in the analysis; however, no protective effect was observed in the group that had a delayed procedure and received pretreatment. These findings reinforce ongoing debates regarding the valid- ity of such treatment.9,34
Limitations inherent to this study are related to its retrospective multi-institutional nature, including absence of standardization and incomplete medi- cal records, lack of histopathology and necropsy to confirm metastasis, local recurrence, and cause of death. The role of adjuvant therapy for ruptured ad- renal tumors cannot be fully established due to the small number of patients involved, and concurrent neoplasia could have affected survival times.
In conclusion, the findings of the present study did not support the need for emergency adrenalec- tomy in cases of spontaneous adrenal rupture, and delayed adrenalectomy can be attempted while maximizing patient hemodynamic stability, as pre- emptive hemostasis might reduce the short-term complication rate. Low reported recurrence and metastatic rates do not provide clear evidence of the need for adjuvant therapy.
Acknowledgments
The authors thank James B. Robertson, biostatistician at the North Carolina State University College of Veterinary Medicine, for his assistance with the statistical analysis.
Disclosures
The authors have nothing to disclose. No AI-assisted technologies were used in the generation of this manuscript.
Funding
The authors have nothing to disclose.
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