Osteosarcoma of the proximal tibia in a dog 6 years after tibial tuberosity advancement

Abstract

A 9-year-old spayed female Cane Corso dog was presented with a 1-week history of an acute right hind limb non-weight-bearing lameness. Six years previously, a right tibial tuberosity advancement (TTA) procedure had been performed. Orthogonal radiographs of the right pelvic limb taken before presentation revealed a comminuted displaced mid-diaphyseal tibial fracture. An aggressive bone lesion with osteolysis and periosteal reaction of the proximal tibia were evident that were most consistent with a primary bone tumor. The owner elected to have the dog euthanized. After euthanasia a fine-needle aspirate of the right proximal tibia was submitted for clinical pathology. Cytology and alkaline phosphatase staining of the fine-needle aspirate were consistent with osteosarcoma.

Key clinical message:

To the authors’ knowledge, this is only the second reported case of osteosarcoma at the site of a TTA. Implantassociated osteosarcoma has been associated with tibial plateau levelling osteotomy (TPLO) and fracture repair.

Osteosarcoma at the site of an orthopedic implant has been previously reported in dogs (1,2), although direct causal relationship between the orthopedic implant and bone neoplasia has not been established. Fracture-associated osteosarcoma has been associated with comminuted fractures with a history of complicated healing, implant loosening, or infection (3). One of the theories implicates corrosion of the implant as a casual factor (3,4). Orthopedic implants are mostly made of either stainless steel or titanium. A titanium implant is used for the tibial tuberosity advancement (TTA) procedure. About 100 000 TTA procedures have been performed since the procedure’s introduction in 2004 (5) and only 1 case report exists implicating a titanium implant as a causal factor for osteosarcoma.

Case description

A 9-year-old spayed female Cane Corso dog was presented to the emergency service at our hospital with a 1-week history of a non-weight-bearing right hind limb lameness. Two weeks before presentation, the dog had an episode of right hind limb lameness which resolved with administration of meloxicam. Six years previously, the dog was diagnosed with right cranial cruciate ligament rupture and a tibial tuberosity advancement (TTA) was performed. The stifle joint was stabilized using a 7-hole titanium plate and 12/24-mm titanium cage.

On presentation, the dog was noted to be bright and alert with normal vital signs. The dog was non-weight-bearing on the right pelvic limb. A splint had been applied to the limb by the primary care veterinarian just before referral. Radiographs taken by the primary care veterinarian showed that the previously placed TTA implant was in place with no evidence of implant failure (Figure 1). There was a comminuted, closed, cranially displaced mid-diaphyseal fracture of the tibia and evidence of osteolysis and osteoproduction of the proximal tibia. The radiographic appearance was most consistent with a primary bone tumor and secondary pathological fracture.

Figure 1.

Right pelvic limb radiograph (lateral view) showing comminuted, closed, cranially displaced mid-diaphyseal fracture of the tibia and evidence of osteolysis and osteoproduction at the proximal tibia.

Based on the presumptive diagnosis of a primary bone tumor, likely osteosarcoma, further diagnostic testing, including cytology of the bone lesion and staging with thoracic radiographs were recommended but declined by the owner. Treatment options such as amputation and chemotherapy, or euthanasia were discussed. The owners elected to have the dog euthanized and pentobarbital sodium injection (Euthanyl 240 mg/mL; Bimeda-MTC, Cambridge, Ontario), 40 mg/kg body weight, IV, was administered.

After euthanasia and with informed consent, a fine-needle aspirate from the proximal tibia and more detailed radiographs were taken which confirmed a pathological fracture and aggressive bone lesion of the mid tibial diaphysis at the site of the previous TTA (Figure 2). The aspirates were submitted to a clinical pathologist for cytology and alkaline phosphatase (ALP) staining (Figures 3, 4). The cytology revealed well-differentiated osteoblasts in low to moderate numbers with individual, scattered, atypical spindle-shaped cells in moderate numbers. The nuclei of these cells were round or oval, and contained clumped to granular chromatin, as well as 1 to 8 small, round, prominent nucleoli. Large cells containing a large nucleus were regularly observed, as well as mitotic figures, macro nucleoli, and bi- and tri-nucleated cells. Osteoclasts and well-differentiated osteoblasts were indicative of reactive bone and the presence of atypical stromal cells was compatible with sarcoma. The neoplastic cells were positive for ALP-staining, suggesting that they were of osteoblastic origin. Therefore, the cytology was suspicious for osteosarcoma (6,7).

Figure 2.

Right pelvic limb radiograph (lateral and anteriopalmer view) showing comminuted, closed, cranially displaced mid-diaphyseal fracture of the tibia and evidence of osteolysis at proximal tibia.

Figure 3.

Cytology of the fine-needle aspirate of the proximal tibia showing stained osteoblast cells and spindle cells (© IDEXX Laboratories, Markham, Ontario. Used by permission) [Hematoxylin and eosin (H&E) staining].

Figure 4.

Alkaline phosphatase (ALP) staining of the fine-needle aspirate from the proximal tibia showing neoplastic cells stained with ALP, suggestive of osteoblasts (© IDEXX Laboratories. Used by permission).

Discussion

Osteosarcoma is the most common primary malignant tumor of the skeletal system in dogs (8). It is locally aggressive with high metastatic potential (9). Spontaneously occurring osteosarcoma is most commonly seen in older large breed dogs with the distal radius and proximal humerus shown to be the most common sites (8).

Osteosarcoma has previously been reported secondary to fracture fixation in dogs (3,4). Fracture-associated osteosarcoma has been associated with comminuted fractures with a history of complicated healing, implant loosening, or infection (3). It has also been reported that fracture-associated osteosarcomas tend to occur on average 5 to 6 y after the primary fracture in dogs (3,10). Implant-associated osteosarcomas have been previously reported both in human (11) and animal studies (2,12,13). It was previously believed that Jonas pins, the spring-loaded pins used for intramedullary fixation, which are known to be corrosion susceptible, were related to implant associated osteosarcoma (1). The Jonas pins are no longer available, but implant associated osteosarcoma continues to be reported in dogs (2,13). It has been hypothesized that chronic inflammation, corrosion of implants, and decreased vascularity of bone after fracture might contribute to the formation of fracture-associated or implant-associated osteosarcoma (4,10).

Tibial plateau levelling osteotomy (TPLO) is a common procedure for the treatment of ruptured anterior cruciate ligament in dogs (14,15) and has been implicated as a potential cause of implant-associated OSA (2). Primary bone tumors affecting the tibia and fibula are rare (9). In a large study of about 400 000 insured Swedish dogs, the incidence of primary proximal tibial or fibular neoplasia was only 0.017% (9). The prevalence of TPLO-associated osteosarcoma is noted to be about 4 times higher than the frequency of spontaneous bone tumor affecting the proximal tibia and fibula (13). In preceding studies, osteosarcoma at the previous TPLO site has been shown to occur 5 to 6 y after the procedure (2,13,16). There is limited evidence to prove the causal relationship between the orthopedic implant and the development of osteosarcoma, but the association has been noted in both humans and dogs (8). Several theories have been postulated such as metal implants inciting chronic inflammation leading to neoplasia development (10) or corrosion at the implant site leading to a neoplastic process (17). Corrosion at the implant site can incite chronic inflammation and tissue necrosis (18) and can negatively affect osteoblast proliferation and differentiation (19) which hypothetically could result in a neoplastic process. It has been hypothesized that chronic inflammation and necrosis can lead to cancer as a result of processes such as uncontrolled cell growth, cell transformation, and immunosuppression leading to lack of response from the growing cells (20). Chronic inflammation leads to production of reactive oxygen, nitrogen species, cytokines, metalloproteinases and PGE2, which amplify and perpetuate the inflammatory cascade (20). These inflammatory mediators can lead to transformation of normal cells via activation of oncogenes or lack of anti-oncogenic activity. Some inflammatory mediators such as reactive oxygen and nitrogen species primarily attack infectious agents and foreign bodies by nitration and oxidation. However, these mediators can induce DNA damage and mutations in the host cells by the same mechanism (20). Inflammation also results in the production of angiogenic factors such as vascular endothelial growth factor which can lead to tumor growth and progression (20). The exact pathway leading to cancer development, however, remains poorly understood.

Early-generation TPLO plates had inhomogeneous structure with differences in chemical composition, not only between plates but also between regions of the plate (17,20). Cast plates have larger grain boundaries than the wrought counterparts and are more prone to intergranular corrosion (17). Previous case reports have mostly implicated Slocum TPLO plates in relation to the development of neoplasia. Two contradicting studies are available regarding corrosion of the Slocum plate (21,22). One study found evidence of corrosion at the implant site and postulated that compounds produced secondary to corrosion can incite neoplastic change (21). The other study found no evidence of corrosion at the implant site (22). However, TPLO-associated osteosarcomas have also been associated with newer generation TPLO plates (13,16). Another case report showed osteosarcoma at the TPLO implant site, but the bone plate in that report was manufactured from 316LVM surgical steel rather than the Slocum TPLO plate (13). Tibial tuberosity advancement (TTA), another surgical procedure used to stabilize a cranial cruciate deficient knee joint (23), was also associated with osteosarcoma in a single case report (24). The report herein is the second case report to document presence of osteosarcoma at the site of a previous TTA. The first case was reported in an Alaskan malamute that underwent the TTA procedure to stabilize a stifle joint with a deficient cranial cruciate ligament (24). The dog made an excellent recovery and no post-operative complications were reported. Twenty months after the procedure, the dog was diagnosed with osteosarcoma at the site of the TTA implants.

The TTA procedure is not performed as often as the TPLO, likely because of surgeon preference and experience (25) as well as initially TTA could not be used in the large breed dogs as tuberosity advancement was limited to 12 mm (25,26). This may be part of the reason that TTA-associated osteosarcoma is so rarely reported in the literature. A recent study showed that the TTA procedure has a worse outcome than TPLO (27), which may further reduce its popularity and therefore the incidence of TTA-associated osteosarcoma.

In in-vitro studies (28), animal models (29) and human studies (30) titanium implants have been shown to be less prone to biofilm formation compared with stainless-steel implants. Titanium alloy is also more inert than stainless steel, causing less soft tissue reaction and less bone loss during the remodelling phase of fracture healing (31). It is, therefore, possible that the titanium implant itself, as opposed to the stainless steel implant, is less likely to cause chronic inflammation and subsequent transformation to a sarcoma.

In the present report, the fracture was at the mid-diaphysis at the junction of the tumor and non-tumor bone. This is likely due to a stress-riser created at the transition between lytic tumor bone and normal density bone. In contrast to the usual metaphyseal location in cases of spontaneously occurring osteosarcoma, an implant-associated osteosarcoma can occur at diaphyseal locations (4).

A histopathological diagnosis was not available in this case. In human medicine, fine-needle aspirate is becoming more common for diagnosis of bone tumors (32,33). Although histopathology is the gold standard for diagnosing bone neoplasia, 1 human study reported a sensitivity of 86% and a specificity of 94.7% for cytology of bone tumors (33). A recent canine study has shown that accuracy of diagnosis of a malignant bone tumor is similar between cytology and histology (34). Cytology offers faster results with less complications but there are limitations such as difficulty in differentiating reactive bone from neoplastic bone or differentiating osteosarcoma from other sarcomas such as chondrosarcoma or fibrosarcoma (35). Furthermore, this case was positive for ALP staining, which is noted to be 100% sensitive and 89% specific for the diagnosis of osteosarcoma (7). Other tumors such as amelanotic melanoma, multilobular tumor of bone, and chondrosarcoma occasionally also express ALP, but this is uncommon (6). In this case report, in addition to the positive ALP staining, cytologic evidence supported sarcoma. Although not 100% confirmatory it is considered likely that this is a case of osteosarcoma.

Tibial plateau leveling osteotomy associated osteosarcoma has been repeatedly reported in the literature (13,16,36), but TTA-associated osteosarcoma has only been reported once (24). This case report documents a pathological fracture due to osteosarcoma at the site of a previous TTA. Implant-associated osteosarcoma is rare but may occur after TTA. Although, in contrast to a TPLO, the TTA procedure utilizes a titanium plate, implant-associated osteosarcoma remains possible. CVJ