Australian VETERINARY JOURNAL
ASSOCIATION
EQUINE
CASE REPORT AND CLINICAL REVIEW
Acute lameness associated with osseous metastasis of a peri-renal carcinoma in a horse
AC Young,ª* KL Hoffmann,b AP Begge and DA Majord
We present a case of aggressive metastatic carcinoma in a horse that was initially presented for shoulder lameness. Although radiography and scintigraphy were useful for localising a lesion in the proximal humerus, subsequent development of non-specific signs of sys- temic disease prompted further evaluation. Haematology and blood biochemistry, urinalysis and ultrasonography were all instrumental in identifying renal involvement. A diagnosis of a peri-renal mass causing secondary renal failure prompted euthanasia of the horse because of the poor prognosis. Antemortem findings were sup- ported by necropsy, with secondary lesions also identified in the spleen, liver, 8th left rib and proximal humerus. Histological exami- nation yielded a diagnosis of undifferentiated metastatic carcinoma.
Keywords carcinoma; horses; lameness; metastasis; peri-renal mass; scintigraphy
Abbreviation ACC, adrenocortical carcinoma Aust Vet J 2010;88:346-350
doi: 10.1111/j.1751-0813.2010.00609.x
I ntraosseous metastasis of a peri-renal carcinoma is a rare finding in horses and subsequently not commonly considered as a differential diagnosis for acute onset lameness in an otherwise clinically healthy equine athlete. Differential diagnoses for primary carcinomas in this region include renal, adrenocortical and adreno- medullary carcinomas. A few cases of renal carcinoma metastasising to bone have been recorded in the literature,1,2 although this form of carcinoma is more typically reported as initially spreading to regional lymph nodes, liver and lung3,4 and is generally considered uncommon in the horse.5-8 Adrenocortical carcinoma (ACC) has been reported even more rarely9 and is characterised as a locally aggressive primary tumour with multiple metastases to abdominal and thoracic viscera and lymph nodes. In the previously reported case there was no second- ary osseous involvement. Bone metastasis has been recorded in a dog with adrenomedullary carcinoma (phaeochromocytoma), which was presented for acute lameness and subsequently found to have multiple metastasis of a locally invasive adrenal mass, including a lesion in the proximal humerus.10
We describe a case of locally invasive, undifferentiated peri-renal carcinoma in a Thoroughbred that first presented as a lameness case following metastasis to the proximal humerus. We discuss the diffi-
culties encountered in acquiring a definitive diagnosis and establish- ing a relationship between localised (lameness) and systemic disease (renal failure) both ante- and postmortem.
Case report
History
An 18-year-old Thoroughbred gelding used for eventing was pre- sented for sudden lameness of the right forelimb. The horse reportedly exhibited uncharacteristic disobedience while warming up for show- jumping, before awkwardly clearing a small cross-rail and landing with non-weight-bearing lameness (grade 5/5) of the right forelimb. No obvious areas of heat or swelling were identified and the horse received non-steroidal anti-inflammatory treatment (phenylbu- tazone: Butasyl™M Fort Dodge Animal Health, Fort Dodge, IA, USA; 4.4 mg/kg IV) from the attending veterinarian and was rested over- night before being transported to our clinic.
On presentation the next day, the horse was found to be in good body condition (score 3/5) with all vital parameters within normal limits. The lameness had improved to the point where the horse could take some weight on the right forelimb but was still reluctant to advance the leg normally and was only evaluated at the walk. The lameness worsened when turning to the right and a shortened cranial phase of the stride was observed. There was no obvious heat, swelling or pain palpable in the distal limb and the foot was negative to hoof testers and percussion. There was also no visible swelling of the shoulder region, no audible or palpable crepitus and no pain on deep palpation; however, the horse did object markedly to manipulation of the scapu- lohumeral joint.
A series of craniomedial-caudolateral radiographs of the right shoulder were taken with the horse under heavy sedation. An obvious fracture was not identified, but obtaining a full set of diagnostic images was limited by the horse’s reluctance to allow the limb to be fully protracted. The horse subsequently underwent scintigraphic eva- luation of the right and left forelimbs. After injection of 7 Gbq of 99mtechnetium methylene-diphosphonate, a ‘bone phase’ evaluation, including lateral and dorsal views of the shoulder region, was con- ducted 2.5 h later. A marked focal area of increased radiopharmaceu- tical uptake was observed in the proximal humerus of the right forelimb when compared with the left (Figure 1). A discrete area of increased uptake was also visible in the cranial thoracic cavity caudal to the shoulder region on the left lateral view (Figure 1b). This was thought to be an incidental finding, whereas the increased radiophar- maceutical uptake in the proximal humerus was considered to be highly significant and suggestive of either a non-displaced fracture of the greater or lesser tubercle or a proximal humeral stress fracture.
*Corresponding author. Current address: Department of Large Animal Ultrasound, University of California, Davis, CA, USA; alexyoungvet@yahoo.com.au
a,dAgnes Banks Equine Clinic, Agnes Banks, NSW, Australia
bUniversity of Sydney, Diagnostic Imaging, Faculty of Veterinary Science, University of Sydney, Sydney, NSW, Australia
“Symbion Vetnostics, North Ryde, NSW, Australia
EQUINE
a
b
The owner was advised to confine the horse and administer phenyl- butazone (Butasyl™M, 4.4 mg/kg PO once daily initially then 2.2 mg/kg PO once daily), with a re-evaluation scheduled in 2 weeks.
Three weeks later the horse was re-presented with an additional com- plaint of gradual onset of anorexia and rapid weight loss. Physical examination demonstrated loss of body condition (score 2/5), a grade 3/5 right forelimb lameness and dull demeanour. All vital parameters were within normal limits and there were no significant findings on rectal palpation.
A blood sample was collected for haematological and biochemical evaluations. There was a mild leucocytosis (10.6 × 109/L, normal range: 6.0-10.5 × 109/L) with a mature neutrophilia (8.3 × 109/L, normal range: 2.5-7.0 × 109/L) and lymphopenia (1.4 × 109/L, normal range: 1.6-5.4 × 109/L). The total protein was elevated (76 g/L, normal range: 55-70 g/L) with a hyperglobulinaemia (42 g/L, normal range: 25-36 g/L). Urea was increased (12.1 mmol/L, normal range: 3.3-6.5 mmol/L), but creatinine and fibrinogen were within their normal reference ranges. The sample also showed electrolyte abnor- malities, with a moderate hypercalcaemia (3.98 mmol/L, normal range: 2.6-3.3 mmol/L) and hypophosphataemia (0.37 mmol/L, normal range: 0.80-1.40 mmol/L), with an approximate calcium to phosphorus ratio of 10:1. A follow-up blood sample was taken 4 days later, which revealed increased variation of most of the parameters from their normal reference ranges, as well as mildly elevated creati- nine (185 umol/L, normal range: 80-180 umol/L) and low fibrinogen (1.8 g/L, normal range: 2.0-4.0 g/L) levels. The horse was given a
course of combination trimethoprim-sulfadimidine (Sulfa-T oral paste™M, Equivet Pty Ltd, QLD, Australia; 5 mL/100 kg PO twice daily) and the oral phenylbutazone was discontinued because of concerns regarding renal function.
Further diagnostic procedures
Radiography of the right shoulder was repeated with the horse under heavy sedation. A circular, irregularly lucent area (approximately 7 × 11 cm in diameter), bordered by a sclerotic rim, was visible within the trabecular bone of the proximal humerus (Figure 2). The lesion was roughly 1.5 cm from the proximal articular margin, but radio- graphic evidence of articular irregularity or scapulohumeral joint osteoarthritis was not seen. A fracture was still not identified.
The horse underwent a routine general anaesthetic and was placed in left lateral recumbency to facilitate access to the right scapulohumeral joint and proximal humerus. Ultrasonographic examination of the joint showed no abnormalities and enabled sterile collection of 15 mL of moderately turbid, red synovial fluid for cytological analysis. Red blood cells were present, but as they were not phagocytosed were considered to be contaminants. Too few white cells were present to count. No bacteria were observed and the protein level was measured at 30 g/L (normal considered <20 g/L). With a low white cell count and minimally elevated protein we did not feel culture and sensitivity was indicated at this time.
An ultrasound-guided biopsy of the proximal humerus was taken from a lateral approach. An orthopaedic drill bit established access to the humerus and a 14g, Tru-Cut (Travenol Laboratories, Deerfield, IL, USA) biopsy needle was inserted. Two smooth, firm, pale grey, elon- gated pieces of tissue approximately 7 mm and 14 mm in length, respectively, were retrieved. Histological analysis showed only well- differentiated cartilage and the cytological smears contained skeletal muscle fibres, some cartilage and loose, fibrous connective tissue.
Progression of clinical signs and renal disease
Two weeks after the presentation for anorexia and weight loss, the horse’s condition suddenly deteriorated. All physical examination
parameters were within normal limits, with the exception of an increased capillary refill time (>2 s; normal range: 1-2 s). The horse was now dull and no longer eating or drinking. A blood sample was collected for haematological and biochemical evaluations and a voided urine sample taken for urinalysis. Intravenous fluid therapy (Hartman’s Solution™M Baxter Healthcare, VIC, Australia; 50 mL/kg/24 h) was commenced and the antibiotic regimen changed from oral trimethoprim-sulfadimidine to benzyl penicillin (Ben Pen™M, CSL Ltd, VIC, Australia; 6 g IV four times daily) and ceftiofur (ExcenelTM, Pfizer Animal Health, NSW, Australia; 1 g in 20 mL IV twice daily). The horse also commenced anti-ulcer treatment with omeprazole (Gastrozol™M, Axon Animal Health, NSW, Australia; 5 mL PO once daily).
Biochemistry, haematology and urinalysis results revealed a progres- sive and marked azotaemia (urea: 32.3 mmol/L, normal range: 3.3-6.5 mmol/L; creatinine: 585 umol/L, normal range: 80-180 umol/ L), together with an isosthenuric urine specific gravity (1.012), con- firming progression to renal failure. Haematuria (erythrocyte count >100 ×106/L, normal range: < 10×106/L) and increased white cell numbers (30 × 106/L, normal range: < 10 × 106/L) were also noted on urinalysis. Other relevant changes included an increasing leucocytosis (16.4× 109/L, normal range: 6.0-10.5 x 109/L), neutrophilia (14.4 × 109/L, normal range: 2.5-7.0 × 109/L) and lymphopenia (1.3 × 109/L, normal range: 1.6-5.4×109/L), with the fibrinogen elevated to 4.4 g/L (normal range: 2.0-4.0 g/L). Electrolyte distur- bances included, persistent hypercalcaemia (4.63 mmol/L, normal range: 2.6-3.3 mmol/L) and hypophosphataemia (0.66 mmol/L, normal range: 0.80-1.40 mmol/L), all of which were consistent with renal disease or possibly a neoplastic process. Thoracic radiographs were taken to identify pulmonary or pleural metastasis, but no abnor- malities were detected. At this point, the horse was still passing a clear, full urine stream and appetite and demeanour had improved during 2 days of hospitalisation and treatment.
An ultrasound-guided biopsy sample was taken at the caudal pole of the right kidney using a 14g Tru-Cut needle. A 20 x 1 mm transverse section containing two levels of the corticomedullary junction was examined and showed the tubules as mostly intact. Occasional dilated and calcified tubules were observed, as were rare hyaline and proteina- ceous casts within some tubular blockages. A mild to moderate patchy interstitial infiltrate comprising normal lymphocytes, rare neutrophils and occasional plasma cells was also noted, leading to a tentative diagnosis of interstitial nephritis.
At this point, the horse deteriorated further, becoming pyrexic with a body temperature of 39.9℃ (normal reference range: 37.5-38.5℃) and began to pass watery diarrhoea. Treatment with ceftiofur was discontinued. The horse was referred for advanced renal and abdomi- nal ultrasonography.
On transabdominal ultrasonography, the renal medulla of both kidneys showed relatively increased echogenicity. There was bilateral pyelectasia (left 2.3 cm and right 2.6 cm in diameter), hydroureters (Figure 3) and a small hypoechoic nodule of 1.97 cm diameter located in the mid spleen. The cranial edge of a heterogeneous mass with irregular margins could be imaged just caudal to the left kidney and further evaluation by rectal palpation and transrectal ultrasonography
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RIGHT KIDNEY
URETER
identified a close association with the abdominal aorta. Hydrone- phrosis and hydroureters secondary to urinary occlusion by an intra- pelvic mass was diagnosed and neoplasia with secondary renal failure, and possible metastases to the humerus and spleen was suspected. Given the deterioration in the horse’s condition and the poor prog- nosis associated with the suspect neoplasia, the horse was euthanased.
Postmortem examination
Multiple lesions were identified at necropsy. The mass surrounding the abdominal aorta was located caudal to the mesenteric root and consisted of multiple firm, white to tan-coloured, nodules closely adhered to each other. Invasion of the aortic wall was grossly visible, as was a close association of the mass with the renal vessels and hilus of both kidneys. Both renal pelves were dilated and the proximal ureters were grossly distended. Renal architecture was otherwise intact and did not appear to have been invaded by the tumour (Figure 4). Neither adrenal gland was identifiable within the mass of fibrous tissue, adhe- sions and tumour. Multiple firm, round, white nodular masses ranging from 5 to 15 mm in diameter were present within the liver and a
9 × 9 mm nodule was identified on the surface of the spleen. A solitary nodule (15 x 25 mm) was found in the mesentery. The peripheral lymph nodes and thoracic viscera were grossly normal. Gross exami- nation of the right scapulohumeral joint and proximal humerus showed no detectable abnormalities and the articular surface appeared smooth and regular. The proximal humerus was dissected and then bisected along a craniomedial-caudolateral oblique plane. A round, irregular area of softened tissue (4 x 5 cm in diameter) was visible as close as 1.5 cm from the articular surface (Figure 5) and correlated with previous radiographic findings (Figure 2). The only other iden- tifiable osseous metastasis was located in the mid-shaft of the left 8th rib, explaining the unusual area of increased radiopharmaceutical uptake seen at the time of scintigraphy. This tissue was of similar consistency to the lesion located within the humerus.
Microscopically, the caudodorsal peri-renal mass surrounding the aorta and ureters was identified as a high-grade anaplastic carcinoma. Positive immunoperoxidase staining of the neoplastic cells for pancytokeratin confirmed a carcinoma, but inhibin A and Melan A immunoperoxidase stains failed to stain either a control adrenal cortex from a normal horse or the patient’s neoplastic cells. The sample was composed of large pleomorphic cells exhibiting epithelial features and arranged in tubules and solid clusters. Marked anisocytosis and anisokaryosis with multinucleated cells were noted, as was megakaryo- cytosis together with bizarre nuclear shapes. There was also a high mitotic rate. Infiltrating cords were accompanied by intense fibrosis and secondary inflammation with large areas of necrosis evident. Hepatic, splenic, mesenteric and osseous lesions all showed similar infiltrations of anaplastic epithelial cells; however, the epithelial tissue was not sufficiently characterised to facilitate identification of the tissue of origin. Given that the mass surrounding the aorta appeared the most advanced, the differential diagnoses included adrenal or renal carci- noma, but the primary source remained undiagnosed.
Discussion
Lameness arising from the shoulder region is considered to be rela- tively rare in the older horse without evidence of direct trauma such as
a fall or collision with a solid object.11 Primary diseases such as fracture, bone cyst and sub or complete luxation were considered when this horse first presented for lameness examination, because of the absence of trauma in the history. The severity and localised nature of the pain elicited on shoulder manipulation was considered to be sufficient to warrant proceeding to radiographic evaluation without performing perineural blocks. Intra-articular anaesthesia was thought to be contra- indicated because of the possibility of exacerbating a fracture.
In retrospect, the source of the acute onset of pain remains unclear. Although the horse had successfully completed the dressage compo- nent the day before, the rider reported an uncharacteristic reluctance of the horse to jump, suggesting there was a degree of pain already present prior to the acute onset of grade 5/5 lameness. Severe pain has been associated with osseous neoplasia in small animals, although acute onset lameness has more often been attributed to the presence of a pathological fracture,12 which was not evident in the present case radiographically or at postmortem. It is possible that unidentifiable microfractures in the trabecular bone surrounding and involving the lesion may have been present.
Retrospective review of the original craniomedial-caudolateral radiographs showed a faint lucency, which later became the more visible lesion within the trabecular bone (Figure 2). This may be either attributable to the rate at which the humeral metastasis developed (illustrating the aggressive nature of the carcinoma) or a result of the difficulties encountered when trying to radiograph patient with an acutely painful condition. Scintigraphy was invaluable in this case because it confirmed the source of pain, negating the need to anaes- thetise a patient with a possible non-displaced or radiographically unidentifiable fracture. Once the osseous lesion was visible and evi- dence of renal disease was apparent, however, gaining further infor- mation from a biopsy sample warranted a general anaesthetic.
Biopsy of intramedullary bone tumours presents challenges in both humans and animals. Fine-needle aspiration may be used in soft bony lesions, although biopsy needles or surgically obtained wedge sections are also options. However, the risk of exposing a malignant tumour and possibly seeding cancerous cells along other tissue planes and/or weakening an already compromised bone structure should be consid- ered. Although techniques using either a Michele trephine or Jamshidi bone marrow biopsy needle have been described in small animal textbooks,12 little information on biopsy techniques in horses exists, aside from those used for bone harvest in areas such as the sternum, tuber coxae and rib. All of the aforementioned techniques would still have been challenging in this case, mostly because of the depth of the lesion and the ambiguity of its location within the trabecular bone. Ultrasound was used in an attempt to localise a biopsy site; however, placement of the needle still had to be somewhat estimated from the radiographs because of the absence of a sonographically identifiable cortical surface lesion. Subsequent histopathological evaluation sug- gested the biopsy needle was unlikely to have penetrated the lytic area seen radiographically.
The caudodorsal location of the intra-pelvic mass, as well as its close association with the aorta and renal vessels, made fine-needle aspiration or biopsy technically difficult, so a tissue sample for histopathological evaluation was not available until postmortem.
Ultrasonography was, however, particularly useful in identifying and characterising the mass and its mechanical affect on the renal system, thus supporting previous haematological, biochemical and urinalysis findings. Although its location within the abdominal cavity prevented complete ultrasonographic visualisation, the irregular margins and locally invasive nature of the mass were consistent with malignancy and hence warranted the poor prognosis. Significantly, it was not found to invade the adjacent renal cortices (Figure 4), a common finding with renal carcinomas.8,13 Instead, the mass was seen to par- tially invade the abdominal aorta, as well as obstructing both ureters, causing subsequent dilation of both renal pelves and bilateral hydro- nephrosis. This mechanical obstruction would explain the progressive post-renal and then renal azotaemia, as well as the isosthenuria. The observed persistent hypercalcaemia and hypophosphataemia are also considered indicators of primary renal disease, although in this case could also be attributed to a paraneoplastic process.7 However, para- neoplasia is not a commonly recognised syndrome in the horse and there is very little information in the literature. Most reports in horses are described in relation to hypoglycaemia, which was not a finding in this case. The leucocytosis, neutrophilia, hyperfibrinogenaemia and hyperglobulinaemia were interpreted as a response to chronic inflam- mation associated with the primary and metastatic lesions and were the reason for the empirical antibiotic therapy commenced at the time of re-presentation.
Primary neoplasia of epithelial origin in the peri-renal area is rarely reported in the horse5,7 and differentiation of poorly differentiated adrenal cortical carcinomas from renal carcinomas by immuno- histochemistry is often not possible (Dr Matti Kiupel, Associate Pro- fessor, Anatomic Pathology, Michigan State University, personal communication). Although the tissue of origin was not sufficiently characterised to allow definitive diagnosis, the peri-renal mass was considered to be the most aggressive and established of the lesions found at postmortem and hence likely to be the primary tumour. Although differential diagnoses would therefore include renal or adrenal carcinoma, a review of the literature would suggest the latter to be more likely.
In comparison with cases of renal cell carcinoma recorded spora- dically in the literature,1-4,6,8,13 equine ACC appears to have been reported only once recently,9 but that case displayed some pertinent similarities. The authors described the primary ACC as multilobu- lated, firm, white to yellow-tan and invading the adjacent caudal vena cava (as opposed to the aorta in the present case). Similarly, the mass was closely adhered to the kidney, but did not invade the renal capsule (a notable difference to the renal carcinomas described in the litera- ture) and appeared to have obliterated one of the adrenal glands, with the other being closely attached. Although the adrenal glands in our patient were unidentifiable at postmortem it is possible that the tissue was missed within the fibrosis and adhesions associated with the peri- renal mass. As in the present case, multiple metastatic nodules in the liver and spleen were also described and hypercalcaemia was a notable feature on blood biochemistry.9
Renal cell carcinoma in the horse most often originates in the renal cortex, usually occurring unilaterally from one pole of the kidney and growing by expansion into the local and surrounding tissues.13 Metastasis most frequently involves the lungs, peripheral lymph nodes
and liver,3,4 two of which were not identified radiographically or at postmortem of the horse in this case. To the best of our knowledge, two cases of osseous metastasis from a primary renal cell carcinoma have been reported in the literature, one involving the maxilla in a 14-year old gelding2 and the other the olecranon in a 21-year old Arab gelding.1 The Arab showed many similarities to this case, initially presenting for lameness and weight loss, as well as exhibiting non- specific signs on haematological, blood biochemical and physical examination. Azotaemia was not observed, however, and is not gen- erally considered to be a common finding with renal carcinoma, because of the unilateral nature of the disease and the compensatory work of the unaffected kidney.1 Subsequently, difficulties in diag- nosing renal malignancy have been acknowledged,4,8 with reported cases often presenting with either vague, non-specific signs or disease related to the structures affected by metastasis.
Metastatic peri-renal carcinoma is extremely rare in horses and diag- nosis can often be complicated by the presence of metastatic disease prior to obvious clinical signs. The challenges faced while trying to establish a relationship between acute onset lameness and progressive renal failure in this case should highlight the usefulness of the various diagnostic tools used and prompt practitioners to consider metastatic neoplasia as a highly uncommon, but possible diagnosis in the acutely lame horse.
Acknowledgments
The authors thank the practitioners and staff of Agnes Banks Equine Clinic involved in this case for their time and their patience, as well as Symbion Vetnostics, Sydney, for assistance with the pathology work.
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(Accepted for publication 15 February 2010)