Regression of Hypertrophic Osteopathy in a Cat After Surgical Excision of an Adrenocortical Carcinoma
A 12-year-old, spayed, female domestic shorthair cat was diagnosed with severe and extensive hypertrophic osteopathy of the appendicular skeleton. Diagnostic ultrasound detected a mass lesion in the right adrenal gland. A right adrenalectomy was performed, and histopathological examination confirmed an adrenocortical carcinoma. No radiographic evidence of pulmonary metastasis was found on initial presentation or recheck thoracic radiographs taken 15 weeks later. Almost complete regression of periosteal new bone formation occurred 15 weeks following the successful surgical removal of the adrenal tumor.
J Am Anim Hosp Assoc 1999;35:499-505.
Timothy J. Becker, DVM, Diplomate ACVIM
Ruby L. Perry, DVM, Diplomate ACVR
G. L. Watson, DVM, Diplomate ACVP
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From the Internal Medicine Service (Becker) and Radiology Service (Perry) of the Department of Small Animal Clinical Sciences, and the Surgical Biopsy Service (Watson) of the Animal Health Diagnostic Laboratory, School of Veterinary Medicine, Michigan State University, East Lansing, Michigan 48824.
Doctor Becker’s current address is the Veterinary Referral and Emergency Center, 123 West Cedar Street, Norwalk, Connecticut 06854.
Introduction
Hypertrophic osteopathy (HO) is a polyostotic bone disease characterized by periosteal new bone formation. The periosteal new bone formation usually occurs over the diaphyses of long bones and digits. The carpal and tarsal bones can be involved, but to a lesser degree of severity. Radio- graphically, the characteristic changes include a nodular, spiculated, or palisade pattern of reactive periosteal new bone formation, leaving the bones with an irregular surface. Hypertrophic osteopathy was referred to as hypertrophic pulmonary osteoarthropathy in earlier literature and usually occurs secondary to primary or metastatic pulmonary neoplasia in dogs.1-3 Less commonly, HO has been reported to occur secondary to other intrathoracic diseases including pulmonary granulomatous disease, pulmonary abscessation, intrathoracic esophageal granuloma due to Spi- rocerca lupi, intrathoracic esophageal adenocarcinoma, and bacterial endocarditis.1-7 Rarely, HO has been reported to be associated with intra- abdominal neoplasia without intrathoracic involvement in the dog.1-3,8-11 Hypertrophic osteopathy has rarely been reported in cats.12-15 Hyper- trophic osteopathy has also been reported in humans, horses, cattle, and other species. 1-3,16-20
The pathogenesis of HO is poorly understood. Increased circulation to the extremities secondary to the underlying disease process is thought to play a major role in the new bone formation in dogs and humans.16,21-22 Neurogenic and humorally mediated mechanisms have been proposed as causes of the increased circulation to the extremities.23-26
To the authors’ knowledge, this is the first reported case of HO in a cat secondary to an adrenal gland tumor, with regression of the skeletal changes after successful surgical removal of the tumor. Long-term sur- vival and the resolution of HO from a variety of other initiating causes have been reported in humans, dogs, horses, and other species. 19,24,26-28
Case Report
A 12-year-old, 3.1-kg, spayed, female domestic shorthair cat was referred to the Veterinary Teaching Hospital at Michigan State University (VTH- MSU) with an 18-day history of decreased appetite, decreased activity, and progressive lameness with swelling and pain in all four limbs. The
cat’s condition had not been responsive to previous anti- biotic therapy. The vaccination status of the cat was current for rabies, rhinotracheitis, calici, and panleuko- penia viruses. The referring veterinarian’s evaluation one week prior to presentation included a normal com- plete blood count (CBC), serum biochemical profile, and urinalysis (UA). Serological tests for feline leukemia virus (FeLV) and feline immunodeficiency virus (FIV) were negative. Thoracic and abdominal radiographs were unremarkable. Radiographs of the appendicular skeleton demonstrated extensive periosteal reactions consistent with hypertrophic osteopathy.
On presentation to the VTH-MSU, the cat was lethar- gic and emaciated. The cat was reluctant to ambulate, wobbly in gait, and had significant diaphyseal thicken- ing in all four limbs. There appeared to be thickening of both the long bones and the overlying soft tissue, but pitting edema was absent. The limbs were also slightly tender on palpation. Rectal body temperature was nor-
mal. Cardiac auscultation detected a grade five out of six systolic murmur that was loudest at the left parasternal area of the thorax. The thyroid gland was normal on palpation. The physical examination was otherwise un- remarkable.
The minimum database collected included a CBC, serum biochemical profile, UA, thyroid hormone profile, and radiographs of the thorax and extremities. The CBC was normal except for a mature neutrophilia (13.62 x103/ ul; reference range, 2.5 to 12.5 x103/ul). Abnormalities on the serum biochemical profile included a low total calcium (8.2 mg/dl; reference range, 8.4 to 11.5 mg/dl) and an elevated alkaline phosphatase (105 IU/L; refer- ence range, 4 to 81 IU/L). The UA was within reference ranges. The thyroid hormone profile (i.e., total and free tetraiodothyronine [T4] and triiodothyronine [T3]) was normal.
Radiographs of the thorax, including left and right lateral views and a ventrodorsal view, were unremark- able. Radiographs of the limbs revealed extensive peri- osteal new bone formation demonstrating a “palisade” pattern involving the scapula, humerus, radius, ulna, dig- its of the front limbs [Figure 1], and pelvis, femur, tibia,
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fibula, tarsus, and digits of the hind limbs [Figure 2]. There was sparing of the carpus and the first digit in the front limbs. Soft-tissue swelling was pronounced over the distal femur, proximal tibia, distal humerus, and proximal radius and ulna.
Since the thoracic radiographs did not demonstrate signs of intrathoracic disease, an abdominal ultrasound examination was performed to search for an intra-ab- dominal cause of the HO. Diagnostic abdominal ultra- sonography demonstrated a well-marginated hypoechoic mass with mineralization between the caudate lobe of the liver and the cranial pole of the right kidney in the area of the right adrenal gland. The mass measured 2.1 by 1.1 cm [Figure 3]. The differential diagnoses for the adrenal mass included adrenal gland hypertrophy, an adrenocortical tumor, or a pheochromocytoma.
An ultrasound-guided fine-needle aspiration of the mass was performed. Cytological examination demon- strated a very cellular sample with large sheets of cohe-
sive cells [Figure 4]. These cells had abundant, foamy cytoplasm with occasional multinucleated cells, a highly variable nuclear to cytoplasmic ratio, anisokaryosis, and a fine chromatin pattern. Nucleoli were prominent, vari- able in size and number, and occasionally enlarged. The cytological impression was a carcinoma, most likely of endocrine origin.
To screen for a functional adrenocortical tumor, urine was submitted for a cortisol:creatinine ratio, and plasma was submitted for a resting cortisol concentration. The urine cortisol:creatinine ratio was five (reference range for this ratio is not well-defined in the cat; however, there is evidence to suggest that reference ranges for the cat are probably similar to those of the dog [canine reference range at VTH-MSU, eight to 24]).29 The rest- ing plasma cortisol concentration was normal (18 nmol/L; reference range, 15 to 97 nmol/L). These endo- crine tests were not suggestive of active cortisol secre- tion by the adrenal tumor.
In order to evaluate for intraocular signs of current or previous systemic hypertension, a complete ophthalmic examination was performed. Abnormalities on the oph- thalmic examination were limited to the posterior seg-
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ment. Numerous, deep, intraretinal and choroidal hemor- rhages were evident in the tapetal and nontapetal fundus. Distinct alterations in the retinal vasculature included numerous, focal constrictions of the retinal arterioles resembling a “box-car” effect, and mild, focal widening and compression of retinal venules at arteriovenous cross- ings (“arteriovenous nicking”). Degeneration of the peri- papillary retina in both eyes (OU) and peripapillary exudate in the right eye (OD) was also evident. The retinal hemorrhages and vascular changes were sugges- tive of systemic hypertension. Other differentials for the intraretinal hemorrhages included coagulopathies, ehrlichiosis, and severe anemia. The hematocrit and platelet counts were within reference ranges. A coagula- tion profile and serology for Ehrlichia spp. were not performed.
Indirect systolic Doppler blood pressure was mea- sured from both the palmar metacarpal and plantar meta- tarsal areas. Three consecutive systolic readings of 160 mmHg were obtained from both sites sampled (normal value for cats at VTH-MSU is less than 160 mmHg systolic). Diastolic blood pressure readings were not obtained. Systolic blood pressure was rechecked several times during the cat’s hospitalization period and was found to range from 120 to 160 mmHg. Systemic sys- tolic hypertension was ruled out on the basis of these blood pressure readings.
An echocardiogram was performed to determine the cause of the heart murmur. Mild left atrial enlargement was noted. The echocardiogram was suggestive of mitral regurgitation, but the heart rate was too rapid to clearly document regurgitation with color-flow Doppler. Vigor- ous left-ventricular wall and septal motion was detected; however, left-ventricular wall thickness and septal thick-
ness were within normal limits. There was no evidence of hypertrophic cardiomyopathy nor vegetative lesions on the aortic or mitral valves.
Surgery was performed to remove the affected adre- nal gland. At surgery, the left adrenal gland was deter- mined to be normal in size and shape. The right adrenal gland was enlarged, the capsule was intact, and it was not adhered to adjacent structures. A right adrenalec- tomy was performed, and the tissues were submitted for histopathological examination. The right adrenal gland and the associated tumor weighed 3.8 grams and mea- sured 25 mm in length, 19 mm in width, and 10 mm in depth [Figure 5]. Additionally, bone biopsies were ob- tained from the lateral surface of the proximal tibia and submitted for histopathological examination. The cat re- covered quickly and was discharged from the hospital two days after surgery.
Histopathological findings of the bone biopsies dem- onstrated multifocal necrotic foci and trabecular bone, but were otherwise unremarkable. Histopathological ex- amination of the right adrenal gland mass documented the presence of an adrenocortical carcinoma. The carci- noma had compressed the normal adrenal gland to a minute rim of cortical and medullary cells and a rare focus of cortical cells. There was relatively mild atypia, with variability in nuclear size and in the nuclear to cytoplasmic ratio, with occasional mitoses. The mass was primarily expansile and was within the capsular margins. Immunohistochemical staining of the adrenal gland carcinoma was performed to determine the cell origin. Staining was negative for the medullary markers chromogranin A, neuron-specific enolase, and syn- aptophysin, and was also negative for the cortical marker cytokeratin. The immunohistochemical staining ruled out a diagnosis of pheochromocytoma, as the results deter- mined the tumor was not of medullary origin.
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Eight weeks postoperatively, the owner reported that the cat was much more active, was jumping onto high surfaces as it had in the past, and showed no evidence of lameness or discomfort when running around the house. On the follow-up physical examination, all four limbs were normal on palpation. Follow-up radiographs of the extremities were obtained [Figure 6]. There was a marked change in the appearance of the bone formation. The generalized periosteal bone formation was of a “lamel- lar” pattern and smoothly marginated. There was no evidence of reactive new bone growth.
On the 15-week postoperative recheck examination, the owners reported that the cat was doing very well at home and did not exhibit any abnormalities. There was no evidence of pulmonary metastasis on thoracic radio- graphs. Radiographs of the limbs demonstrated that the remodeled “lamellar” periosteal pattern was less obvious and remained smoothly marginated. An ophthalmologi- cal recheck examination was performed, and the fun- dic examination was normal. The intraretinal and choroidal hemorrhages were resolved OU, and the retinal vasculature appeared normal. The peripapil- lary exudate OD had resolved.
Discussion
Although numerous cases of HO have been reported in dogs, only a few cases in the domestic cat have been reported in the veterinary literature.1-3,13,16-18 In dogs, the majority of HO cases occur in association with pri- mary or metastatic pulmonary neoplasia. Rare cases of HO in the dog have been associated with intra-abdomi- nal neoplasia without pulmonary involvement.2,8-11 In the few reported canine cases of HO with intra-abdomi- nal neoplasia, none were associated with an adrenal tu- mor. 2,8-11
All four previously reported cases in domestic cats were associated with neoplasia.12-15 Two of these were associated with bronchiolar carcinoma; one was diag- nosed with benign thymoma; and one was associated with a renal papillary adenoma with no reported in- trathoracic involvement.13,16-18 Three of the cats were euthanized at the time of diagnosis, and the fourth cat died during a radiographic procedure. The cat presented in this paper was confirmed to have an adrenal gland carcinoma with no apparent intrathoracic lesions. The bony changes associated with HO progressively resolved following surgical removal of the adrenal gland carci- noma. There was no radiographic evidence of intratho- racic metastasis on initial presentation and 15 weeks postoperatively.
Adrenal cortical tumors can be highly aggressive and may metastasize in spite of minimal cellular atypia.30,31 In this case, there was no evidence of pulmonary me- tastases, intra-abdominal metastases on diagnostic ultrasound, or gross metastases during abdominal ex- ploratory surgery. At surgery, the capsule of the right adrenal gland was still intact. There was concern regard- ing the presurgical ultrasound-guided fine-needle aspi- rate, in that it might increase the risk of spreading the malignancy along the needle tract. Needle biopsy or aspiration may not be recommended in cases where sur- gical excision is contemplated, since the potential for iatrogenic metastasis may exist. However, needle-tract seeding with malignant cells is a rare complication fol- lowing percutaneous fine-needle aspiration of abdomi- nal tumors in human clinical case reports.32-34
The retinal changes were suggestive of current or previous systemic hypertension; however, serial indirect Doppler systolic blood pressure measurements were within reference ranges. Indirect diastolic blood pressure and direct arterial blood pressure were not measured. The pathophysiology of HO is thought to result in part from hyperperfusion of the appendicular tissues. Arterial vasodilatation in the extremities could have resulted in indirect blood pressure measurements that were not rep- resentative of what was occurring systemically or dia- stolic hypertension, but this is speculative. The retinal hemorrhages and vascular changes had resolved by the 15th week postoperatively.
Since the retinal changes were suggestive of hyper- tension, despite the normal indirect systolic blood pres- sures, an evaluation for potential causes of systemic hypertension was undertaken as part of the authors’ pre- operative work-up. Differential diagnoses for systemic hypertension include renal secondary hypertension, hy- perthyroidism, hyperadrenocorticism, pheochromocy- toma, and essential hypertension.
Renal values, urinalysis, and electrolyte concentra- tions were normal. A presurgical thyroid hormone pro- file was normal, and there was no palpable thyroid nodule. The cat did not have the characteristic dermato- logical findings of feline hyperadrenocorticism, and the urine cortisol: creatinine ratio and resting plasma cortisol concentration were not suggestive of hyperadrenocorti- cism. Basal serum cortisol concentrations are not consid- ered a valid screening test for hyperadrenocorticism since serum cortisol concentrations vary considerably over
time. Ideally, a low-dose dexamethasone suppression test should have been performed preoperatively to screen for hyperadrenocorticism.35 Intermittent hypertension due to a pheochromocytoma was one distinct possibil- ity.36 A 24-hour urine collection for catecholamines and their metabolites was not performed. However, the corti- cal location of the tumor, its histopathological appear- ance, and special immunohistochemical stains for specific biochemical markers ruled out a pheochro- mocytoma. The initial retinal changes suggestive of hy- pertension remain an enigma.
The referring veterinarian reported that the cat had the systolic heart murmur prior to the current presenting condition. There was no echocardiographic evidence of cardiomyopathy or endocarditis. Bacterial endocarditis is rarely reported in cats but has been reported to be associated with HO and arterial hypertension in one canine case.4,37-39 The HO in the cat reported here is thought to be related to the adrenal tumor and not sec- ondary to cardiac disease.
There are extensive and detailed discussions on the proposed pathophysiology of HO reported in the veteri- nary and human medical literature. Various mechanisms
have been proposed to attempt to explain how the pri- mary lesions can mediate the skeletal changes observed in HO. Neurogenic and humoral theories have been pro- posed as possible explanations.23-26 The proposed neuro- genic mechanism underlying hypertrophic osteopathy suggests that a nervous reflex exists, with afferent fibers originating in the thorax and efferent pathways affecting the connective tissue and periosteum of the limbs.25
Production of a humoral or toxic factor from the neoplastic cells leading to the HO seems a more plau- sible explanation in cases of HO without intrathoracic lesions.24 The location of the tumor in the adrenal gland cortex and the absence of pulmonary involvement in this case raise the question of a possible humoral factor as an inciting cause of the bony changes.
Serum and plasma samples were obtained prior to surgery for future analysis for a possible humoral factor. At the time of this publication, the authors have no evidence that the tumor was actively secreting a humoral factor.
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