Bilateral Appendicular Bone Tumors in Four Dogs
Bilateral synchronous appendicular bone tumors, occurring in the same bone and same anatomic site within the bone are very rare. This report describes the clinical presentation and oncologic outcome for four dogs with this rare presentation. All cases presented to the authors following a history of unilateral lameness for several weeks. On presentation, case 1 had pain elicited in the contralateral proximal humerus but all the other cases had no abnormalities detectable on physical examination of the contralateral limb. All dogs had technetium 99m (99mTc) nuclear scintigraphy performed that identified bilateral lesions of the distal radii in two dogs, proximal humeri and distal tibiae in one dog each. Thoracic radiographs performed on all dogs showed no evidence of pulmonary metastases. Three dogs were treated with palliative radiation therapy (two dogs received concurrent bisphosphonates) resulting in survival times from initial presentation of 50 days, 193 days, and 523 days, respectively. One dog had stereotactic radiation therapy (SRT) and a surgical limb-salvage performed followed by carboplatin chemotherapy, resulting in a survival time of 926 days from initial presentation. Palliative and curative-intent treatments for the bilateral synchronous appendicular bone tumors resulted in survival times similar to those reported for treatment of a single primary appendicular bone tumor.
Introduction
Osteosarcoma (OSA) is the most common primary bone tumor in dogs, accounting for 85–98% of malignant bone tumors.1–5 Other types of primary bone tumors, including chondrosarcoma, fibrosarcoma, and hemangiosarcoma, account for < 5–10% of all primary bone tumors in the dog.6 OSA occurs most frequently in the metaphyseal location of a single long bone, with the distal radius being the most common location.1,3,7 OSA most commonly metastasizes via the hematogenous route to the lungs; however, other skeletal sites are the next most common location.6 It has been reported that 1.4–28% of dogs with primary bone tumors have secondary bone lesions at the time of diagnosis based on either survey radiographs or nuclear scintigraphy.8–11 Often, those secondary bone lesions are single (71%); however, multiple lesions occur in approximately 29% of OSA patients.8 In a study of 72 dogs, Jankowski et al. (2003) found that secondary bone lesions occurred most commonly in the appendicular skeleton, with 59 sites identified compared with only 36 sites identified in the axial skeleton.8
In humans, bone metastases of OSA are unusual at the time of diagnosis and normally present late in the disease course.12 There is a rare, multicentric form of OSA that has been reported with an incidence of 0.5–5.1%.13,14 The multicentric OSA presentation could represent either the synchronous development of multiple bone OSA lesions or metasynchronous development of a primary tumor with multiple metastatic lesions. In humans, if smaller lesions appear at different intervals after treatment of the dominant lesion, the term metasynchronous multifocal OSA is applied. Recently, support has been given to the synchronous bone lesions representing a primary tumor and multiple metastatic lesions.15–17 In one study, histopathologic response of the multiple bone lesions to chemotherapy was evaluated, and similar responses were found in the multiple bone lesions in 13 of 16 patients.17 The authors of that study concluded that their results support the hypothesis that the primary and metastatic lesions have the same chemosensitivity and provide further evidence to support the supposition that synchronous lesions are metastases. The exact pathogenesis remains uncertain.
There are only two cases reported in the veterinary literature with the unique presentation of synchronous bilateral appendicular OSA.8,18 One of those cases, which was described in a retrospective study, was presumed to have a primary tumor in the proximal humerus and a single potential secondary lesion in the contralateral proximal humerus. Those lesions were documented by nuclear scintigraphy and radiography.8 The second case had bilateral distal radial OSA.18 The purpose of this study was to describe the signalment, diagnostic and staging outcomes, treatment, and survival times of four dogs with bilateral synchronous primary bone tumors of the appendicular skeleton at the time of initial presentation.
Case Report
The primary bone tumor database at the Animal Cancer Center, Colorado State University was searched for dogs with bilateral primary bone tumors of the same bone and same anatomic location (either proximal or distal). The medical records of those dogs were reviewed, and the following information was obtained: breed, sex and neuter status, and age at presentation. Other information recorded included the following: method of diagnosis of primary bone tumor (histopathology, radiographic, or nuclear scintigraphy), bone affected, location within the bone (proximal or distal, metaphysis or diaphysis), presence/absence of pathologic fracture at diagnosis, the alkaline phosphatase (ALP) values at diagnosis, and the clinical stage of disease at presentation. A board-certified radiologist read the radiographs and nuclear scintigraphy studies, and the findings were recorded. Date of initiation of treatment and type of treatment (i.e., surgery, radiation, medical) were recorded. If radiation was performed, additional information collected included the type of radiation treatment and intent of therapy (curative versus palliative), total radiation dose, and number of fractions delivered. If chemotherapy was administered, the agent and number of doses were recorded. Patient follow-up and outcome information was obtained by the client and/or veterinarian via telephone interview, and this information was recorded. All dogs were followed until either death or euthanasia. The first date of either metastases or local recurrence and the date and cause of death/euthanasia were recorded. If a postmortem examination was performed, the findings were recorded. The survival time was calculated as the time from treatment to time of death/euthanasia.
Four dogs were identified with bilaterally symmetrical lesions (i.e., same bone and same anatomic location within individual dogs) consistent with a diagnosis of primary bone neoplasia in the appendicular skeleton. All dogs initially presented to the authors’ institution between Mar 2001 and Jan 2008. The details of the four cases are provided below.
Case 1
A 10 yr old spayed female rottweiler presented with a 1 wk history of left forelimb lameness with pain over the proximal humeri bilaterally. Radiographs were taken of the humeri and thorax by the referring veterinarian. Bilateral aggressive bone lesions of the proximal humeri were noted. There was no history of travel outside of Colorado and no history of neoplasia. Physical examination by the referring veterinarian identified a weight-bearing left forelimb lameness and pain was elicited on palpation of both proximal humeri. The referring veterinarian performed a complete blood cell count and serum biochemical analysis within 2 wk of diagnosis. There was a mild elevation of ALP at 92 IU/L (reference range, 1–60 IU/L), but no other significant abnormalities were present.
Radiographs of the humeri, three-view thoracic radiographs, and a whole body nuclear scintigraphy (with technetium 99m [99mTc]) were performed. Radiographs of the proximal humeri showed focal bone lysis in the proximal left humeral metaphysis and bone lysis in the right proximal humeral metaphysis with periosteal reaction caudally. Three-view thoracic radiographs did not show any evidence of pulmonary metastases. Nuclear scintigraphy showed increased uptake at the proximal aspect of both humeri. The right proximal humerus appeared to have a larger area of radiopharmaceutical uptake than the left.
The owner elected palliative intent radiation and medical treatment. The dog received a total dose of 16 gray (Gy) bilaterally, divided into two 8 Gy fractions administered on consecutive days. In addition, a single bisphosphonatea infusion (1 mg/kg) was administered IV over 4–6 hr between the first and second fractions of radiation therapy. The referring veterinarian administered another dose of bisphosphonate to the dog following the course of palliative radiation and the first dose of bisphosphonate. The date of administration was not recorded in the medical record. The dog was also prescribed etodolacb (10.7 mg/kg per os [PO] q 24 hr) and morphinec (1.1 mg/kg PO q 8 hr) for analgesia. No cytotoxic chemotherapy was administered. It was not recorded in the medical record whether improvement was seen following the radiation therapy or not. The dog was euthanized by the referring veterinarian 523 days after initial presentation due to the detection of a pathologic fracture of one humerus (side not recorded). No necropsy was performed, so the metastatic status was unknown at the time of death.
Case 2
A 1 yr old castrated male rottweiler presented with a 2 wk history of a progressively worsening intermittent left forelimb lameness. Prior to presentation to the authors, the referring veterinarian performed radiographs of the left distal radius that showed an aggressive bone lesion of the left distal radius. There was no history of travel outside of Colorado and no history of neoplasia. A weight-bearing left forelimb lameness was identified on physical examination. No other abnormalities were identified. A complete blood cell count and serum biochemical analysis performed by the referring veterinarian revealed no additional abnormalities.
The authors performed radiographs of the left and right distal radii at presentation. Radiographs performed of the left radius showed lysis in the distal metaphysis with cortical thinning and focal bone sclerosis. Radiographs of the right radius showed mild lysis of trabecular bone and regions of increased lucency (Figures 1A, B). Three-view thoracic radiographs revealed no evidence of pulmonary metastases. Whole body 99mTc nuclear scintigraphy showed increased uptake of the radiopharmaceutical in the left distal radius and a small focal region of increased uptake in the right distal radius (Figures 2A, B).
Citation: Journal of the American Animal Hospital Association 49, 2; 10.5326/JAAHA-MS-5828
Citation: Journal of the American Animal Hospital Association 49, 2; 10.5326/JAAHA-MS-5828
Treatment of the right radial lesion involved administration of 1 dose of curative intent stereotactic radiation therapy (SRT), total dose was 30 Gy to the 80% isoline).19 The left radial lesion was treated with surgical limb-salvage and endoprosthesis.20 The SRT and surgical limb-salvage treatments were performed at the University of Florida Veterinary Teaching Hospital. Histopathology performed on the resected left radius bone specimen confirmed the diagnosis of OSA, and clean surgical margins were noted. Ten days postoperatively the dog re-presented to the authors for nonweight-bearing lameness of the left forelimb and focal swelling of the surgical site. The dog had been examined 2 days earlier (8 days postoperatively) by the referring veterinarian, and enrofloxacind (11 mg/kg PO q 24 hr) was prescribed due to the suspicion of a surgical site infection. On presentation to the authors, a fine-needle aspirate of the tissue at the level of the surgery site was performed but this was nondiagnostic. At that time, gabapentine (4 mg/kg PO q 8 hr) was initiated to improve analgesia. Limb swelling decreased with the prescribed treatments and IV carboplatinf (300 mg/m2) was administered q 4 wk for a total of four doses. Enrofloxacin (11 mg/kg PO q 24 hr) was continued throughout the chemotherapy.
The dog underwent a revision of the limb-sparing procedure 4 mo postoperatively due to plate fracture. Seven mo after the SRT, the dog re-presented with a pathologic fracture of the right distal radius. The irradiated bone was stabilized using a transcarpal 3.5 mm 20 hole locking plate with screwsg that engaged the proximal radius, radiocarpal bone, and the third metacarpal using a minimally invasive approach to avoid creating skin incisions in the irradiated field. Following surgery, the dog experienced chronic draining tracts on the operated (right) limb, and cultures identified a resistant Klebsiella spp. infection. Ten mo after the original limb-sparing surgery on the left forelimb, the plate fractured at the level of the metal/bone interface. That surgery was revised with an allograft stabilized with a 4.5 mm broad dynamic compression plateh. Three weeks following that revision, the dog was nonweight-bearing lame, and a draining tract was present over the middle of the left surgical limb-spare incision in addition to a draining tract on the caudal aspect of the right radius. An aerobic and anaerobic culture showed evidence of a Staphylococcus intermedius infection that was widely sensitive to antimicrobials. The dog suffered complications of infection associated with the both the right stereotactic radiation limb-sparing surgery and the left radial limb-sparing surgery. Throughout treatment, multiple organisms were isolated, including a resistant Klebsiella spp. from the right forelimb and Staphylococcus intermedius and Proteus spp. from the left forelimb. Fourteen mo after the original treatments, radiographs showed loosening of the distal third metacarpal screws in the right forelimb. A revision was performed in which the distal aspect of the plate was moved laterally, and the screws engaged the fourth metacarpal. At that time, a significant wound was present over the left proximal antebrachium. Both the wound and the right radial surgical site were cultured, but no growth was found. Fifteen mo after the original treatment, loosening of the left radial proximal screw was identified in addition to infection at that site. The screws were replaced with 5.5 mm screws and amikacin impregnated calcium phosphate beadsi were placed. Eighteen mo following the original treatment, plate fracture of the right antebrachial plate was identified. The 3.5 mm locking plate was replaced with a 3.5 mm broad dynamic compression platej. Twenty-two days, later some incisional dehiscence occurred, the wound was cultured, debrided, and closed with placement of polymethylmethacrylate amikacin impregnated beadsk,i. A culture taken at the time of that surgery yielded Escherichia coli. Twenty-one mo after the original treatment, the dog developed exposure of the right radial plate, the wound was closed, and polymethylmethacrylate antibiotic impregnated beadsk,i were implanted.
Throughout the treatment period, limb use was generally good; however, each time a significant complication occurred, increased lameness occurred. Complete resolution of the infections was never achieved.
Thoracic radiographs performed 862 days after diagnosis showed no evidence of pulmonary metastases. The dog was euthanized 926 days after initial presentation due to dyspnea. A necropsy examination revealed pulmonary metastases from OSA and dilated cardiomyopathy. Evaluation of the right and left radius did not show any evidence of residual OSA.
Case 3
A 6.5 yr old castrated male mastiff presented with a 2 wk history of left forelimb lameness and swelling at the left distal antebrachium. Radiographs of the left radius performed by the referring veterinarian revealed an aggressive bone lesion of the left distal radius. There was no history of travel outside of Colorado, and no history of neoplasia.
At the time of presentation, a full physical examination was performed, and a painful boney swelling at the left distal antebrachium was identified. Radiographs of the left radius showed loss of trabecular bone and periosteal reaction of the distal metaphysis. Radiographs of the right radius showed multiple areas of punctate lysis in the distal radial metaphysis, with periosteal reaction on the dorsocaudal and medial aspect of the radius. Whole body 99mTc nuclear scintigraphy showed increased uptake in the distal radii bilaterally. There was also mildly increased radiopharmaceutical uptake in the right tarsocrural joint consistent with degenerative joint disease.
The owner elected palliative intent treatment. The dog received a total dose of 16 Gy bilaterally divided into two 8 Gy fractions administered on consecutive days. In addition, a single bisphosphonate (1 mg/kg) infusion was administered IV over 4–6 hr, between the first and second fractions of radiation therapy. The dog was prescribed piroxicaml (0.15 mg/kg PO q 24 hr) and doxycyclinem (5 mg/kg PO q 24 hr). Initially, the owner reported improvement following radiation therapy, but significant local pain recurred. The dog was euthanized approximately 193 days following initial presentation.
Case 4
A 10 yr old castrated male greyhound presented to the authors with a 4 wk history of right hind limb lameness and swelling of the medial aspect of the tarsus. Prior to presentation, radiographs that were taken by the referring veterinarian revealed an aggressive bone lesion of the right distal tibia.There was no history of travel outside of Colorado, and no history of neoplasia. On the initial physical examination at presentation, a swelling was identified on the medial aspect of the right tarsus and a weight bearing right hindlimb lameness was detected. The only abnormality noted on a complete blood cell count and serum biochemical analysis was an elevated ALP (903 IU/L; reference range, 20–142 IU/L). A whole body 99mTc nuclear scintigraphy showed increased uptake in both distal tibiae. Left tibial radiographs revealed a loss of trabecular bone detail within the distal tibial metaphysis with periosteal reaction on the medial plantar aspect of the lesion. Right tibial radiographs revealed an osteolytic and osteoproductive lesion within the distal tibial metaphysis. Thoracic radiographs did not show any evidence of pulmonary metastases.
The owner elected palliative radiation treatment. The dog received a total dose of 16 Gy bilaterally divided into two 8 Gy fractions administered on consecutive days. The dog had an epidural catheter placed and was administered morphinen (0.3–0.5 mg/kg q 24 hr for 2 days). Additional analgesia included a fentanyl patcho (100 μg/hr), carprofenp (2.2 mg/kg PO q 12 hr), and morphine (1 mg/kg PO q 12 hr). Oral pain medications were continued following discharge. No cytotoxic chemotherapy was administered.
An initial improvement was seen in the comfort level of the dog within the first mo after radiation therapy, but due to increasing bone pain the dog was euthanized 50 days after presentation to the authors. At the time of euthanasia, no further radiographic evaluation of the limbs were performed, and pathologic fracture could not be excluded.
Discussion
Bilateral synchronous primary bone tumors of the appendicular skeleton are rare in dogs. Based on a review of the primary bone tumor database at the authors’ institution, only 4 cases were identified from the 1,134 cases (0.4%) of primary bone tumors that were treated between 1997 and 2010. Bilateral primary bone tumors have been described in two dogs in the veterinary literature.8,18 None of the four dogs in the cases described herein had radiographic evidence of pulmonary metastases at the time of diagnosis. Each dog had a whole body nuclear scintigraphy performed for staging purposes that identified increased uptake in bilateral metaphyseal areas consistent with primary multifocal bone neoplasia. No other metastatic foci within the skeleton were identified in any dog.
It is impossible to determine if the occurrence of bilateral suspected primary bone tumors in the metaphyseal regions in these four cases represents either synchronous/metasynchronous primary tumor development or a primary bone tumor with metastasis. In the human literature, multifocal OSA is thought to be a distinct and rare form of OSA. There is a single dominant tumor, and other multiple smaller bone lesions are present.17 When additional lesions are simultaneously present at the time of diagnosis, the tumor is referred to as synchronous multifocal OSA. If smaller lesions appear at different intervals after treatment of the dominant lesion, the term metasynchronous multifocal OSA is applied. There is debate about the classification of those tumors (multicentric disease versus multiple primary metastases); however, the prevailing opinion seems to be that synchronous multifocal OSA represents only one extreme of a vast spectrum of metastatic OSA.15,16 There is some speculation that metasynchronous OSA in humans may occur due to other underlying predisposing conditions, such as retinoblastoma, Li-Fraumeni syndrome, Paget’s disease, Fanconi’s anemia, or Rothmund-Thomson syndrome.21
Detection of any bone metastases at the time of initial diagnosis of primary bone tumors is uncommon, reported in 1.4–28% of cases in the veterinary literature.8–11 A recent publication identified metastatic bone lesions in 7.8% of 399 dogs with OSA that underwent whole body nuclear scintigraphy.8 Nuclear scintigraphy is a very sensitive imaging exam for detecting bone pathology and can be helpful in detecting early bone metastases.8–11 To increase specificity of scintigraphic findings, radiographs of the regions of increased uptake provide spatial resolution to verify aggressive bone lesions consistent with primary bone neoplasia. Within this case series, the areas of increased radiopharmaceutical uptake in both bilaterally symmetrical metaphyseal bone regions were thought to be consistent with an aggressive bone lesion and most likely a neoplastic process. Radiographs of the affected bones were taken and were consistent with the presence of an aggressive bone lesion with a mixed lytic and productive appearance. The differential diagnoses for aggressive bone lesions include primary bone tumor (OSA, chondrosarcoma, fibrosarcoma, hemangiosarcoma), osteomyelitis (fungal and bacterial), lymphoma, multiple myeloma, metastatic bone neoplasia, and bone cysts. OSA represents up to 98% of all primary malignant bone tumors in the dog and is the most common primary bone tumor in the dog.1–4 Based on the patient signalment, anatomic location, physical examination findings, and characteristic radiographic and scintigraphic appearance, a presumptive diagnosis of primary bone neoplasia, most likely OSA, was made in all four dogs.
Core needle biopsy of bone was offered to all four cases included in this report; however, due to the poor prognosis offered, all of the owners elected not to pursue this option. Only one dog (case 2) had histopathology performed following the surgical limb-salvage of the left distal radius. Those histopathology results confirmed OSA. The lack of histopathologic confirmation of the presumptive diagnosis in the other cases is a limitation to this case series.
Because of the presence of bilateral aggressive bone lesions and suspected primary bone tumors, all owners were advised of a poor prognosis, and the majority of the owners chose to pursue palliative treatment. With palliative treatment alone, the survival times in this case series were widely variable and, in some cases, long. The median survival reported for dogs with bone metastases alone (with no pulmonary metastases) is 132 days.22 The median survival time for dogs with bone metastases alone is significantly greater than metastases to the lungs, lymph nodes, or other distant sites.22 The six dogs in the study by Boston et al. (2006) that survived the longest had metastases to long bones (survival was 359–1,583 days).22 Of the 90 dogs that had bone metastases, only 36 underwent treatment, including surgery and chemotherapy and radiation and chemotherapy.22Palliative radiation and chemotherapy offered the longest median survival time (130 days).22
Three of the cases in this report survived for 193 days, 523 days, and 926 days, which are all longer than the median survival of 132 days reported by Boston et al. (2006).22 Two of the dogs included in this report were not treated with chemotherapy, yet survived for prolonged periods. Case 2 had the longest survival. That dog underwent limb-sparing surgery and stabilization of a pathologic fracture following SRT and single agent carboplatin chemotherapy (four doses). Improved survival has been reported with the use of carboplatin chemotherapy in the adjuvant or neoadjuvant setting (in combination with amputation) for treatment of canine OSA.23,24 In addition, the dog described in case 2 experienced chronic infections of both limbs that may have lead to increased survival. Improved survival has been reported in dogs that underwent limb-sparing surgery. The underlying pathogenesis for this observation has not yet been fully elucidated.20,25
Conclusion
Bilateral synchronous appendicular primary bone tumors at the time of initial presentation are rare in dogs. Diagnostic and staging tests including lesion radiographs, thoracic radiographs, whole body nuclear scintigraphy, and needle core biopsy are recommended to characterize the bone lesions and establish clinical stage. Based on the four cases described in this report, treatment outcomes and overall prognosis for dogs that present with synchronous primary bone tumors does not appear to be different to dogs that present with nonmetastatic primary bone tumors. As such, standard of care (either palliative or curative-intent treatment options) should be offered to patients presenting with bilateral synchronous appendicular primary bone tumors.
Lateral radiographs of the left (A) and right (B) radii of the dog in case 2. In the left forelimb, lysis in the distal metaphysis with cortical thinning and focal bone sclerosis are obvious. In the right forelimb, regions of lucency and slight lysis of the trabecular bone are noted.
Nuclear scintigraphy of the left (A) and right (B) radii of the dog in case 2. Increased uptake is seen in the left distal radius, and a small, focal region of increased uptake is obvious in the right distal radius.
Contributor Notes
L. Selmic's updated credentials since article acceptance are BVetMed (Hons), DACVS.
