Physical Factors

A simplistic theory based on circumstantial evidence is that because OS tends to occur in major weight-bearing bones adjacent to late-closing physes and heavy dogs are predisposed, multiple minor trauma and subsequent injury to sensitive cells in the physeal region may occur. This may initiate the disease by inducing mitogenic signals, increasing the probability for the development of a mutant lineage. One in vitro study comparing the incidence of microdamage in cadaver radii of small- and large-breed dogs found no difference between the groups.³⁷ OS has been associated with metallic implants used for fracture repair, with chronic osteomyelitis, and with fractures in which no internal repair was used.^38–42 OS has also been reported at the site of a bone allograft used for fracture repair 5 years previous.⁴³ Exposure to ionizing radiation can induce OS.^35,44–52 In humans exposed to plutonium, 29% and 71% of the OSs were in the appendicular and axial skeleton, respectively, with the spine having the most tumors (36%). An almost identical distribution of plutonium-induced OS was reported for dogs injected with ²³⁹Pu as young adults in experimental studies. This distribution of OS is quite different from the distributions of naturally occurring OS for both species and appears to be related to bone volume and turnover. Similar findings were seen for dogs injected with 226R (radium).⁵² A distribution favoring bone marrow volume was seen for dogs exposed to strontium-90.⁵¹ OS is a rare, late complication of radiation therapy (RT) in humans and dogs.^{44,46,48–50} Three of 87 (3.4%) spontaneous tumor-bearing dogs treated for soft tissue sarcomas developed OS within the field of radiation.⁴⁴ In another experimental study, 21% of dogs undergoing intraoperative RT (>25 Gy) followed by external-beam RT to the vertebral column developed OS following treatment.⁴⁸ Secondary OS developed between 1.7 and 5 years after radiation in that study, and the authors speculated that high dose of radiation per fraction or total dose may predispose to this serious late effect of irradiation. OS was reported in 3% of 57 dogs irradiated for acanthomatous epulis of the oral cavity in another study.⁴⁶ Postirradiation OS in humans comprised approximately 2% to 4% of all OSs reviewed in two large series.^53,54

OSs have been concurrently seen in dogs with bone infarcts, but it is not clear whether there is any causal relationship.55–59 Bone infarcts are uncommon, are of unknown etiology, and may be identified as incidental findings by radiography. Bone infarcts are probably not associated with tumor emboli and appear to be more common in smaller breeds. A single report exists of OS occurrence secondary to a bone infarct caused by total hip arthroplasty.⁶⁰ A case of OS was also reported to be associated with osteochondritis dissecans in the humoral head,⁶¹ and another report documents malignant transformation of an aneurysmal bone cyst.⁶²

Genetic Factors

Ample evidence exists implicating the involvement of genetic and heritable factors for the development of OS in dogs. Currently, the most thoroughly described gene mutation that contributes to OS formation and/or progression in dogs is p53.63–70 Initial studies performed in immortalized canine OS cell lines demonstrated that the functionality of the p53 gene was defective based on the incapacity of p53 to regulate appropriately the transcriptional expression of downstream target genes including p21 and mdm2 following genotoxic insult.⁶⁵ Furthermore, p53 mRNA and protein were overexpressed in 60% of cell lines and correlated with the presence of missense point mutations within the DNA-binding domain.⁶⁵ Corroborating in vitro cell line studies, mutations in p53 have also been demonstrated in dogs with spontaneously-arising OS. Several studies using either single-strand conformational polymorphism, polymerase chain reaction, or southern blotting, followed by nucleotide sequence analysis have identified missense mutations involving exons 4 to 8 of p53 in 24% to 47% of all spontaneously arising OS samples.^63,67,69,70 In addition to exons 4 to 8, the entire gene sequence of p53 has also been assessed by polymerase chain reaction (PCR) and single-strand conformational polymorphism from 59 spontaneously arising appendicular and axial OS samples.⁶⁴ In 41% of tumors, p53 mutations were identified, with the majority of abnormalities being point mutations (74%), which resulted in an amino acid substitution, with a lesser percentage of mutations (26%) being deletions.⁶⁴ Finally, through the implementation of targeted microarray-based comparative genomic hybridization analysis of 38 canine OS cases, similar recurrent cytogenetic aberrations classically present in human OS samples were also identified in OS specimens collected from dogs, including loss of heterozygosity (LOH) of the p53 gene in 18% of tumors.⁷¹

Substantiation for the presence of p53 mutations in sporadic canine OS has also been documented by immunohistochemical studies because a hallmark of many p53 mutations is enhanced protein stability of this normally labile protein, enabling detection of protein with methodologies such as immunohistochemistry (IHC).⁷² In one study evaluating p53 protein expressions in 106 osteogenic tumors, a greater percentage of appendicular (84%) OSs overexpressed p53 protein in comparison with OSs arising from the axial skeleton (56%) and other non-OS bone tumors (20%).⁶⁸ Finally, loss of p53 gene function in 167 osseous tumors has been characterized by p53 nuclear staining frequency and intensity expressed as a p53 index. Of 103 OS samples, 67% stained positively for p53 protein, and the p53 index was significantly greater in OS derived from the appendicular (n = 84) versus axial (n = 38) skeleton.⁶⁶ Interestingly, the p53 index of appendicular OS derived from Rottweilers was significantly higher than in Great Danes or other commonly affected breeds, supporting the notion that p53 gene mutations may be associated with breed susceptibilities to OS development.²⁴

Another tumor suppressor gene likely to be permissive for OS development is the RB gene. Based on investigations using five tumorigenic immortalized canine OS cell lines, the RB gene signaling pathway was found to be dysregulated with the persistence of hyperphosphorylated RB protein in the absence of mitogen stimulation. Despite apparent aberrant RB gene signaling, reduction in RB protein was identified in only one of five cell lines.⁶⁵ Corroborating these in vitro findings, the evaluation of 21 spontaneously arising OSs failed to identify gross RB gene alterations by Southern blotting, and protein expressions of RB were identified in all OS samples evaluated.⁶⁷

Despite normal protein expression of RB in canine OS samples, the observed translational normalcy does not exclude the possibility for allelic deletion of the RB gene because prior studies in human OS samples have demonstrated that LOH at the RB gene locus does not absolutely correlate with inactivation of RB at the protein level.⁷³ Substantiating the possibility that RB gene may have allelic deletion in spontaneously arising canine OS, analysis of 38 OS samples with comparative genomic hybridization techniques identified copy number loss in 11/38 cases (29%), resulting in a correlative reduction or absence of RB protein expression in 62% of OS samples tested.⁷¹ Based on these recent findings, it is probable that aberrations in the RB gene indeed participate in sporadic OS formation and/or progression in dogs.

In addition to p53 and RB gene abnormalities, the phosphatase and tensin homolog (PTEN) tumor suppressor gene is suspected to participate in the genetic pathogenesis of canine OS. Original in vitro studies conducted with canine OS cell lines demonstrated that the majority of cell lines (60%) harbored mutations in PTEN, resulting in the absence of gene transcription and protein translation. Corroborating the cell line findings, expression of PTEN was either absent (n = 6) or variable (n = 4) in 15 spontaneously arising OS samples.⁷⁴ Further support for the loss of PTEN gene in canine OS pathogenesis has been the identification of specific recurrent chromosome copy number aberrations (CNAs) through targeted microarray-based comparative genomic hybridization studies.^71,75 In one study utilizing 38 OS samples derived from Rottweilers and golden retrievers, deletion of a chromosomal region (CFA 26q25), which encompasses the PTEN tumor suppressor gene locus, occurred in 42% of OS samples.⁷¹ In a subsequent study analyzing 123 OS samples predominantly derived from Rottweilers, greyhounds, golden retrievers, and great Pyrenees, high-resolution comparative genomic hybridization studies similarly identified high recurrent copy number loss encompassing the PTEN gene in 30% of samples.⁷⁵ In addition to the PTEN gene, other genes identified by high-resolution comparative genome hybridization studies potentially involved in the genetic pathogenesis of OS included overexpression of RHOC and RUNX2 and underexpression of TUSC3.⁷⁵

A growing body of evidence in dogs supports breed-associated inheritance of OS, especially in Scottish deerhounds, Rottweilers, greyhounds, Great Danes, Saint Bernards, and Irish wolfhounds.24,30,76–79 Many domestic dog breeds have narrow genetic diversity as a consequence of selective breeding practices; this has provided the opportunity to more clearly elucidate the heritability of OS in dogs. For Scottish deerhounds in particular, the reported incidence of OS formation is 15%,^76,77 and the narrow heritability in this breed was 0.69, indicating that 69% of the cause for OS development in Scottish deerhounds is due to heritable trait, likely a Mendelian major gene with dominant expression.⁷⁷ Further studies in Scottish deerhounds using a whole genome linkage approach have mapped a novel locus (OSA1) for OS formation in this breed to CFA34 and provide the opportunity to pinpoint specific candidate genes directly involved in OS etiology for this specific dog breed.

Molecular Factors

Because of the heterogeneous and chaotic nature of OS, it has been difficult to definitively ascribe specific molecular derangements responsible for the etiopathogenesis of OS.⁸⁰ Nonetheless, substantive progress has been achieved through experimental, preclinical, and comparative investigations to identify dysregulated intracellular signaling and cell survival pathways likely to participate in the pathogenesis of OS. Significantly, the identification and tumorigenic consequences of several putative pathways have been recently characterized not only in immortalized OS cell lines but also in spontaneously arising OS samples.

The MET proto-oncogene encodes a tyrosine kinase receptor that on ligation with hepatocyte growth factor (HGF) mediates multiple cellular functions, including cell scattering, motility, and proliferation. Given its biologic activities, excessive or dysregulated MET signaling in canine OS has been demonstrated to promote tumorigenic phenotypes in cell lines.81–83 Furthermore, in a small pilot study with spontaneously arising OS samples, the expression of MET proto-oncogene was identified in the majority (5/7, 71%) of tumor specimens by northern blot analysis.⁸⁴ Additionally, a novel germline mutation that results in constitutive receptor phosphorylation and aberrant MET signaling has been identified primarily in the Rottweiler breed.⁸⁵ In a larger study of 59 primary OS samples, mRNA expressions for MET and HGF were detected by real-time PCR (RT-PCR) in all specimens and suggested the existence of a putative MET/HGF autocrine or paracrine feedback loop.⁸⁶ In a subset of OS samples, proteolytically activated HGF was identified in homogenized tumor lysates (n = 6) by western blot, and MET protein was expressed by 100% of tumors analyzed (n = 16) by IHC. Increased expression of MET mRNA correlated with regional lymph node metastases, supporting the participation of MET signaling for metastases and cell invasion.

The cellular effects of growth hormone (GH) are mediated through the hepatic production of insulin-like growth factor-1 (IGF-1). In osteoblasts, IGF-1 induces cell mitogenesis and protection from apoptosis, as well as promoting angiogenesis. Derived from experimental and preclinical investigations, aberrant or excessive IGF-1 signaling likely participates in OS pathogenesis. In three canine OS cell lines, the expression and functionality of the IGF-1/IGF-1 receptor (IGF-1R) signaling cascade has been reported.⁸⁷ In all cell lines, IGF-1R expression was confirmed by northern blot analysis and radioligand binding studies; however, despite uniform receptor expression, IGF-1–mediated promotion of anchorage independent growth and invasion appeared to be cell-line specific.⁸⁷ Furthermore, to validate IGF-1/IGF-1R as a molecular target, dogs treated with definitive surgery and systemic chemotherapy received a long-acting somatostatin analog (OncoLAR) in an adjuvant setting to attenuate the protumorigenic effects of IGF-1. Despite significant reductions in circulating IGF-1 concentrations, no clinical benefit was detected in dogs treated with OncoLAR compared to placebo.⁸⁸

The proto-oncogene erbB-2 encodes human epidermal growth factor receptor-2 (HER-2), which is a tyrosine kinase receptor capable of promoting cell transformation and growth. In both dogs and humans, the overexpression of HER2 protein as a result of gene amplification is a negative prognostic factor in mammary carcinoma; however, less clarity exists for the role of HER2 overexpression in OS.89,90 To better characterize HER2 expressions in canine OS, one study evaluated HER2 mRNA transcript and protein expressions in seven cell lines and 10 OS tumor specimens.⁹¹ Based on RT-PCR, the majority of OS cell lines (6/7) and 40% of primary OS tumor samples overexpressed HER2. Similarly, the overexpression of HER2 protein was confirmed by IHC. Although not adequately powered, the results of the study suggested the possibility of HER2 overexpression as a negative prognostic factor for survival.

The mammalian target of rapamycin (mTOR) is an evolutionary conserved protein kinase downstream of Akt, which acts as a central hub for the integration of cellular signals induced by growth factors, nutrients, energy, and stress for the purposes of regulating cell cycle progression and growth. As such, aberrant signaling through the mTOR pathway contributes to growth, survival, and chemotherapy resistance in multiple tumor types. To characterize the functionality of the mTOR pathway in canine OS, one study using three canine OS cell lines investigated the expressions of mTOR and p70S6K, a downstream effector protein of mTOR.⁹² Study results indicated that the mTOR pathway was active in canine OS cells, and phosphorylation of mTOR and p70S6K could be inhibited by rapamycin, resulting in apoptosis and reduced growth of OS cells in vitro. In a complementary phase I dose-escalation study to assess the feasibility of mTOR inhibition as a treatment strategy, the pharmacokinetics and pharmacodynamics of rapamycin were investigated in dogs with primary OS.⁹³ Results from the phase I trial demonstrated that biologically effective concentrations of rapamycin were safely obtainable in dogs and that modulation of mTOR target proteins by rapamycin was achievable within the bone tumor microenvironment.

The tropomyosin-related kinase (Trk) proto-oncogenes encode for high-affinity receptor tyrosine kinases (RTKs), including TrkA, B, and C. Specifically in osteoblasts, TrkA receptor binds nerve growth factor (NGF), resulting in cellular mitogenesis and the inhibition of apoptosis. To characterize the possible involvement of TrkA signaling in OS pathogenesis, one study investigated the expression of TrkA and the functional consequences of TrkA receptor ligation in OS cell lines and tumor samples.⁹⁴ All canine OS cell lines (n = 2) and the majority of primary OS tumors (10/15) and pulmonary metastatic lesions (9/12) expressed TrkA receptors. Additionally, although TrkA signaling did not induce OS cell mitogenesis, blockade of basal TrkA signaling with either a small molecule inhibitor or blocking antibody increased serum starvation-induced apoptosis. The inhibition studies suggest that TrkA signaling participates in OS cell survival and may serve as a novel druggable target.

Telomeres are highly conserved nucleoprotein complexes at the ends of linear chromosomes that safeguard against harmful recombination events. The maintenance of telomere length and thus prevention of cellular senescence is through the activity of telomerase, a ribonucleoprotein complex that catalyzes the addition of telomeric sequences to the 3′ ends of chromosomes. Telomerase endows cells with infinite replicative capacity, and given its protumorigenic potential, telomerase has been investigated in canine OS. In an exploratory study, telomerase activity was identified in 100% of OS cell lines (5/5) and in the majority of primary tumors (5/6, 83%).⁹⁵ In a larger corroborative study using 67 OS tumors, telomerase activity was identified in 73% of OS samples and supported the hypothesis that the majority of OSs possess the enzymatic machinery required for infinite replicative capacity.⁹⁶

In addition to various growth and survival pathways that potentially contribute to OS pathogenesis, the ability of OS cells to interact with their immediate microenvironment found in bone and lung tissues likely influences OS progression and metastases. Tissue invasion and focal osteolysis are hallmark characteristics of OS, and local disease progression is promoted by several OS-associated proteins, including matrix metalloproteinases (MMPs), receptor activator of NF-κB ligand (RANKL), and lysosomal cathepsin K.97–100 Similar to the ability of OS cells to invade local tissues, specific proteins have been identified to participate in the progression of canine OS metastases, including ezrin,¹⁰¹ a cytoskeletal linker protein, as well as CXCR4,¹⁰² a chemokine receptor.

Systemic Alterations

Alterations in energy expenditure, protein synthesis, urinary nitrogen loss, and carbohydrate flux have been documented in dogs with OS, similar to results documented in humans with neoplasia. Changes were documented in resting energy expenditure and protein and carbohydrate metabolism in dogs with OS. These changes were evident even in dogs that did not have clinical signs of cachexia.¹²⁵ Systemic, metabolic derangements reported for dogs with OS include lower chromium and zinc levels, lower iron and iron-binding capacity, and increased ferritin levels as compared to normal dogs.¹²⁶ Hypercalcemia is extremely rare. The impact of these changes on patient treatment, response, or outcome is unknown.

Radiology

Initial evaluation of the primary site involves interpretation of good quality radiographs taken in lateral and craniocaudal projections. Special views may be necessary for lesions occurring in sites other than in the appendicular skeleton. The overall radiographic abnormality of bone varies from mostly bone lysis to almost entirely osteoblastic or osteogenic changes (see Figure 24-1, B). There is an entire spectrum of changes between these two extremes, and the appearance of OS can be quite variable. There are some features, however, that are commonly seen. Cortical lysis is a feature of OS and may be severe enough to leave obvious areas of discontinuity of the cortex leading to pathologic fracture. There is often soft tissue extension with an obvious soft tissue swelling, and new bone (tumor or reactive bone) may form in these areas in a palisading pattern perpendicular or radiating from the axis of the cortex (i.e., “sunburst”). As tumor invades the cortex, the periosteum is elevated and new bone is laid down by the cambium layer providing a triangular-appearing deposition of dense new bone on the cortex at the periphery of the lesion. This periosteal new bone has been called “Codman’s triangle,” but this is not pathognomonic for OS. OS does not directly cross articular cartilage, and primary lesions usually remain monostotic. The tumors may extend into periarticular soft tissues, however, and adjacent bones are at risk because of extension through adjacent soft tissue structures. Other radiographic changes that can attend OS are loss of the fine trabecular pattern in the metaphysis, a vague transition zone at the periphery of the medullary extent of the lesion (rather than a sharp sclerotic margin), or areas of fine punctate lysis. Any one or combinations of these changes may be seen, depending on the size, histologic subtype, location, and duration of the lesion. The radiographic appearance of OS is similar to osteomyelitis, specifically of fungal etiology.¹²⁷ In cases in which the travel or clinical history might support the possibility of osteomyelitis, a biopsy with submission for histology and culture may be warranted.

Based on signalment, history, physical examination, and radiographic findings, a presumptive diagnosis of OS can be made. Differential diagnoses of lytic, proliferative, or mixed pattern aggressive bone lesions identified on radiographs include other primary bone tumors (chondrosarcoma, fibrosarcoma, hemangiosarcoma); metastatic bone cancer; multiple myeloma or lymphoma of bone; systemic mycosis with bony localization; bacterial osteomyelitis; and, albeit rare, bone cysts.

Other primary bone tumors are far less common but may be suspected, especially in dogs with unusual signalment or tumor location. Metastatic cancer can spread to bone from almost any malignancy. A careful physical examination is important, including a rectal examination, with special attention paid to the genitourinary system to help rule out the presence of a primary cancer. Dogs with a history of cancer in the past should have their original biopsy reviewed and should be restaged for the original disease. Common sites for metastatic bone cancer are lumbar and sacral vertebrae, pelvis, and diaphyses of long bones. There are usually other clues for the diagnosis of multiple myeloma, such as hyperproteinemia, and both multiple myeloma and lymphoma of bone are usually attended by radiographic lesions that are almost entirely lytic. Two classic radiographic appearances of myeloma bone lesions are described: “punched-out” areas of lysis or a generalized osteoporotic thinning of cortices.

Tissue Biopsy

A diagnosis of primary malignant bone tumor may be suggested by signalment, history, physical examination, and radiographic findings. Cytology has not been thought to be definitive for diagnosis; however, it may support the tentative diagnosis, and enough confidence in the diagnosis, combined with clinical features and radiographic appearance, may exist to facilitate a discussion of treatment options. Consistent cytologic criteria of OS has recently been described, and with repeated evaluations, dependent on experience, cytopathologists may be more definitive in making a diagnosis from cytology alone.128,129 Alkaline phosphatase staining of cytologic samples has been shown to differentiate OS from other vimentin-positive tumors.¹⁰³ However, in most cases, a definitive diagnosis lies in procurement and interpretation of tissue for histopathology. With new treatments such as limb sparing (see subsequent sections), knowledge of the specific tumor type may avoid overextension or inappropriate treatment of bone tumors thought to be OS (e.g., chondrosarcoma, myeloma, or lymphoma). It is crucial to the success of a limb-sparing surgery that the biopsy procedure is planned and performed carefully with close attention to asepsis, hemostasis, and wound closure.¹³⁰ The skin incision for the biopsy must be small and placed so that it can be completely excised with the tumor at limb sparing without compromising the procedure. Transverse or large incisions must be avoided. It has been recommended that the surgeon who is to perform the definitive surgical procedure (especially if limb sparing) should be the person to perform the preoperative bone biopsy.¹³¹

Bone biopsy may be performed as an open incisional, closed needle (Figure 24-2), or trephine biopsy. The advantage of an open technique is that a large sample of tissue is procured, which presumably improves the likelihood of establishing an accurate histologic diagnosis. Unfortunately, this advantage may be outweighed by the disadvantages of an involved operative procedure and risk of postsurgical complications such as hematoma formation, wound breakdown, infection, local seeding of tumor, and pathologic fracture.^132,133 Although biopsy with a trephine yields a diagnostic accuracy rate of 93.8%, there is the increased risk of creating pathologic fracture when compared with using a smaller gauge needle.¹³⁴ This underscores some of the advantages of a closed biopsy using a Jamshidi bone marrow biopsy needle (Jamshidi bone marrow needle, American Pharmaseal Co, Valencia, CA; bone marrow biopsy needle, Sherwood Medical Co, St. Louis, MO) or similar type of needle. Jamshidi needle biopsy has an accuracy rate of 91.9% for detecting tumor versus other disorders and an 82.3% accuracy rate for diagnosis of specific tumor subtype.¹³⁵ Accuracy of diagnoses from needle core samples can depend on the pathologist’s experience and comfort level with examining small samples. Histology reports indicating the presence of reactive bone should not rule out the presence of a primary bone tumor or other pathology, especially if the radiographic changes suggest tumor. In some cases, it can be very difficult to get the diagnosis by preoperative biopsy (i.e., repeated biopsy attempts yield “reactive bone”) and yet the pathologist has no trouble identifying tumor when the entire specimen is available for histopathologic analysis (e.g., postamputation), This is likely a result of the heterogeneity of the tumor tissue itself and the large amount of reactive bone present within the tumor.

The biopsy site is selected carefully. Radiographs (two views) are reviewed, and the center of the lesion chosen for biopsy. Biopsy at the lesion periphery will often result in sampling the reactive bone surrounding the tumor growth without a resulting diagnosis.¹³⁵ The skin incision is made so the biopsy tract and any potentially seeded tumor cells can be completely removed at the time of definitive surgery. Care is used to avoid major nerves, vessels, and joint spaces. A 4-inch, 8- or 11-gauge needle is used. With the dog anesthetized, prepared, and draped for surgery, a small stab incision (2 to 3 mm) is made in the skin with a #11 scalpel blade. The bone needle cannula, with the stylet locked in place, is pushed through the soft tissue to the bone cortex. The stylet is removed, and the cannula is advanced through the bone cortex into the medullary cavity using a gentle twisting motion and firm pressure. The opposite cortex is not penetrated. The needle is removed, and the specimen is gently pushed out of the base of the cannula by inserting the probe into the cannula tip. One or two more samples can be obtained by redirecting the needle through the same skin incision so that samples of the transition zone may also be obtained. Ideal specimens should be 1 or 2 cm in length and not fragmented. Biopsy is repeated until solid tissue cores are obtained. Material for culture and cytology may be taken from the samples prior to fixation in 10% neutral buffered formalin. Diagnostic accuracy is improved when samples are evaluated by a pathologist thoroughly familiar with bone cancer. Fluoroscopy or advanced imaging (CT) can assist in obtaining needle-core biopsy samples of suspected bone lesions, especially for axial sites.¹³⁶

After tumor removal (amputation or limb sparing), histology should be performed on a larger specimen to confirm the preoperative diagnosis. If the clinical and radiographic features are typical for OS, especially when there is little possibility of fungal or bacterial infection, confirmation of histologic diagnosis following surgical treatment of local disease (amputation or limb sparing) can be considered. Few diseases causing advanced destruction of the bone can be effectively treated without removal of the local disease. If the owners are willing to treat aggressively, surgical removal of local disease with biopsy submission following surgery may be acceptable.

Staging and Patient Assessment

Anatomic Location and Signalment

In a multiinstitutional study of 162 dogs with appendicular OS treated with amputation alone, dogs younger than 5 years of age had shorter survival than older dogs.¹⁵ Additional studies have related large tumor size^13,152,153 and humerus location^154,155 to poor outcome. Large tumor size has been reported to be a negative prognostic factor for humans with OS.¹⁵⁶ For OS originating from flat bones, small dog size and completeness of excision were positive prognostic indicators.¹⁵⁷ Although there are differences in disease distribution and prevalence, documentation of improved survival for small dogs with OS is lacking.¹⁵⁸ A negative prognosis can also be predicted by a higher tumor grade and mitotic index, based on the results of one study.¹⁰⁶

The biologic behavior for nonappendicular sites of OS appears to be similar (aggressive) with the exception of the mandible and possibly the rest of the calvarium.122,123,159–162 OS affecting the head (mandible, maxilla, and skull) is locally aggressive but has a lower metastatic rate (37%) than appendicular OS.¹⁶² Reported median disease-free intervals (DFIs) and survival times for skull OS are 191 days and 204 days, respectively. Dogs with OS of the mandible treated with mandibulectomy alone had a 1-year survival rate of 71% in one study.¹²² In contrast, maxillary OSs have demonstrated a median survival of 5 months following maxillectomy.^159,160 A study evaluating response to treatment for orbital OS reported long-term survival following complete surgical excision.¹⁶³ Similar behavior is seen for OSs of flat bones in humans.¹⁶⁴ Median survival for rib OS lesions is reported to be 3 months for dogs treated with rib resection alone and 8 months for dogs treated with resection and adjuvant chemotherapy.^165–168 OS of the canine scapula has been reported to have a poor prognosis when treated with subtotal scapulectomy surgery and chemotherapy.^157,169,170 DFI and MST in dogs diagnosed with scapula OS was 210 days (range 118 to 245 days) and 246 days (range 177 to 651 days), respectively.¹⁷¹ Use of adjunctive chemotherapy was prognostic for both increased DFI and survival. Limb function after subtotal scapulectomy is good to excellent.¹⁷¹ Survival of dogs with OS distal to the antebrachiocarpal or tarsocrural joints was somewhat longer (median: 466 days) than survival of dogs with OSs of more common appendicular sites; however, OS in these sites is aggressive, with a high potential for metastasis.²⁶ Vertebral OS is uncommon; however, reported cases indicate aggressive local and systemic behavior.^22,172 In 15 dogs treated with a combination of surgery, radiation, and chemotherapy, the median survival was 4 months.¹⁷² The biologic behavior of OS in other nonappendicular bone sites (e.g., pelvis) has not been thoroughly evaluated.

Extraskeletal OS is rare and most commonly affects visceral sites (gastrointestinal tract, spleen, liver, kidney, urinary bladder), skin or subcutaneous tissue, or mammary glands. Extraskeletal (soft tissue) OS sites also appear to have aggressive systemic behavior with a high metastatic rate. In one report, extraskeletal OS treated with surgery alone had a median survival of only 1 month, and a median survival of 5 months was obtained for cases treated with surgery and adjuvant chemotherapy.³¹ In a larger study, soft tissue OSs were separated from mammary gland OSs; median survival of nonmammary gland soft tissue lesions was 1 month and mammary gland lesions 3 months following primarily surgical resection alone.³² The major cause of death was local recurrence (92%) in the soft tissue OS cases and pulmonary metastasis (62.5%) in the mammary gland OS cases.

Dogs presented with stage III disease (measurable metastases) have a very poor prognosis.¹¹⁵ MST of 90 dogs with stage III disease at presentation was 76 days, with a range of 0 to 1583 days. No significant differences in survival times on the basis of age, sex, breed, or primary site were observed. Dogs with bone metastases (132 days) had a longer survival time than dogs with lung (59 days) or lung and other soft tissue (19 days) metastases. Dogs with lymph node metastasis had short survivals with a median of only 57 to 59 days, compared to 318 days for dogs without nodal spread.^114,115 Dogs with stage III disease treated palliatively with RT and chemotherapy had a significantly longer survival time (130 days) than dogs in all other treatment groups.

Serum Alkaline Phosphatase

Elevated alkaline phosphatase (AP) has been clearly associated with a poorer prognosis for dogs with appendicular OS in several studies.114,154,173–175 A preoperative elevation of either total (serum) or the bone isoenzyme of AP (>110 U/L or 23 U/L, respectively) is associated with a shorter DFI and survival (Figure 24-4). Likewise, dogs that have elevated preoperative values that do not return to normal within 40 days following surgical removal of the primary lesion also develop earlier metastasis. One study substantiated the predictive nature of elevated preoperative AP levels; however, no association was found for elevated postoperative serum levels.¹⁷³

Figure 24-4 A, Disease-free interval (DFI) outcome of dogs treated for OS comparing bone alkaline phosphatase levels above and below 23 U/L preoperatively. B, Survival outcome of dogs treated for OS comparing serum alkaline phosphatase levels above and below 110 U/L preoperatively. BALP, Bone alkaline phosphatase; TALP, total alkaline phosphatase. Rights were not granted to include this figure in electronic media. Please refer to the printed book. (Reprinted with permission from Erhart N, Dernell WS, Hoffmann WE, et al: Prognostic importance of alkaline phosphatase activity in serum from dogs with appendicular OS: 75 cases (1990-1996), J Am Vet Med Assoc 213:1003, 1998.) J Am Vet Med Assoc

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