Metastatic thyroid carcinoma in the appendicular skeleton and tibial plateau leveling osteotomy site of a dog

Abstract

A 13-year-old spayed female Labrador retriever cross dog was referred to the Foster Hospital for Small Animals at Tufts University for evaluation of a metastatic carcinoma discovered at the site of a previous tibial plateau leveling osteotomy (TPLO). The dog was previously evaluated at the primary care veterinarian for a complaint of lameness, and radiographs of the previous TPLO site revealed bony lysis associated with the TPLO plate. Surgical exploration of the site by the primary veterinarian provided evidence of osteolysis. The lytic area of the proximal tibia was biopsied, and a metastatic carcinoma was confirmed. The patient was referred for further evaluation. Following consultation and examination, a full body computed tomography (CT) scan was performed to determine the source of the carcinoma. A well-defined soft tissue attenuating mass effacing the right thyroid gland was located, along with 3, well-defined soft tissue attenuating nodules within the pulmonary parenchyma, consistent with metastatic disease. The previously diagnosed osteolytic, aggressive bone lesion of the proximal left tibia was visualized. Following the CT scan, palliative left hind-limb amputation via coxofemoral disarticulation was performed. Histological examination of the hind limb revealed neoplastic epithelial cells admixed with reactive bone. Neoplastic cells were arranged in packets with rare colloid-filled microfollicles consistent with a diagnosis of metastatic thyroid carcinoma. To the authors’ knowledge, this is the first clinical report of metastatic thyroid carcinoma in the appendicular skeleton and TPLO site of a dog.

Key clinical message:

Our findings emphasized that thyroid carcinoma may metastasize to the appendicular skeleton, and causes other than osteomyelitis or implant-associated osteosarcoma should be considered when evaluating osteolytic lesions at a TPLO site.

Tumors of the thyroid gland are relatively uncommon in dogs and account for 1.2 to 3.8% of all canine tumors (1–4). Carcinomas account for 88% of all cases, with as many as 35% of dogs having evidence of metastasis at the time of diagnosis (1–8). Thyroid carcinomas are more commonly unilateral (~ 67 to 75%) but may be bilateral (25 to 33%) (7,9). Normally, the bi-lobed thyroid gland is not palpable (5); however, the most common presenting complaint of dogs with thyroid neoplasia is a palpable cervical mass (5,7,10–13). Most primary thyroid neoplasms in dogs do not cause changes in thyroid hormone concentrations (5,14). Therefore, thyroid tumors tend to remain clinically undetected until either the primary neoplasm is large enough to be palpated, or if secondary clinical signs have developed (5,14,15). Clinical signs observed in patients are usually due to local invasion, with dyspnea being the most common sign, followed by coughing, gagging, retching, regurgitation, vomiting, and change in bark (6,10,14,15). The presence of metastasis has not been correlated with clinical signs (16).

Carcinomas in the thyroid arise from follicular or parafollicular (C-cell or medullary) lineages, with follicular being further subclassified as follicular, compact, or solid (4,5). The follicular compact is the most common histologic subtype of canine thyroid carcinomas (4,5). Whereas screening lungs and regional lymph nodes for metastasis in dogs is considered standard-of-care, screening for bone metastasis is rarely pursued.

Although local effects of the tumor are the most common reasons for presentation in dogs, metastasis of thyroid carcinoma is reported in up to 1/3 of dogs at time of diagnosis (4,6–8,10,17,18). Furthermore, metastasis was present in 65 to 90% of dogs at necropsy (4–7,10,12,16,17). Although adenomas are smaller, well-encapsulated nodules with slow growth (5), thyroid carcinomas have been historically characterized by rapid and invasive growth, with many ultimately metastasizing; some may be associated with less aggressive behavior (e.g., slow growth and minimal invasion into surrounding structures) (5). The lungs are the most common site of metastasis (6–8,10). Other noted sites of metastasis are retropharyngeal and mandibular lymph nodes, cardiac, renal, adrenal, and hepatic sites, and the central nervous system (4,6–8). The risk of metastasis increases in dogs with tumor volume > 20 cm³ or diameter > 5 cm, bilateral thyroid tumors, and follicular origin neoplasms (versus C-cell or parathyroid origin) (8). We present an atypical case of metastatic thyroid carcinoma in a dog that metastasized to a TPLO site in the appendicular skeleton.

Case description

A 13-year-old spayed female Labrador retriever cross dog weighing 24.4 kg was referred to the Foster Hospital for Small Animals at Tufts University to determine the origin of a left tibial metastatic carcinoma diagnosed by the family veterinarian. The dog had undergone left-sided tibial plateau leveling osteotomy (TPLO) 12 mo prior to this examination.

The dog was presented to the family veterinarian 11 mo after the TPLO was performed, with a presenting complaint of left hind limb lameness of 1 wk duration. On examination, there was pain on palpation over the implant, but the stifle was evaluated as stable, with normal range of motion. Stifle radiograph examination was performed preoperatively, and the dog was taken to surgery for TPLO plate exploration. After the plate was removed, evidence of osteolysis was detected and a bone biopsy was submitted for histopathology. Intraoperative findings prompted postoperative radiographs of the stifle to be performed and identified an area of lucency, with thinning cortex and mild periosteal reaction at the prior osteotomy site at the metaphysis of the proximal tibia. This area of lucency contrasted with an area of sclerotic bone at the level of the distal aspect of the prior TPLO plate (Figure 1). It was concluded that this finding could represent an aggressive, neoplastic osseous lesion, or implant-associated osteomyelitis. There was no evidence of pulmonary metastatic neoplasia on 3-view thoracic radiographic examination. Histopathological examination of the bone biopsies revealed dense, round to polygonal cells arranged in solid, cohesive aggregates and occasional thin ribbons separated by hyalinized, collagenous stroma. Anisocytosis and anisokaryosis were mild, and mitotic figures were rare. The neoplasm was interpreted as epithelial in origin, suggestive of metastatic carcinoma, and the dog was referred to the Tufts Foster Small Animal Hospital for further treatment recommendations.

Figure 1.

Left lateral hind limb radiograph postoperative TPLO plate explantation. Note the poorly demarcated area of lucency, with thinning cortex and mild periosteal reaction (arrow). Sclerosis was visualized at the location of the prior TPLO plate (asterisk).

At presentation, the dog exhibited moderate to severe toe-touching lameness of the left hind leg, and on physical examination incidental findings of bilateral lenticular sclerosis and a Grade II/VI systolic cardiac murmur. Complete blood (cell) count values were within respective reference ranges, but there were mild elevations in alanine transaminase, asparatate aminotransferase, and alkaline phosphatase. Abdominal ultrasound examination was performed, and a hyperechoic hepatic nodule, a gallbladder mucocele, and incidental ill-defined, hyperechoic adrenal gland nodule and hypoechoic splenic nodules were seen.

Computed tomography was recommended and revealed an ovoid, soft tissue attenuating, heterogeneously contrast enhancing mass (3.8 × 1.9 × 2.1 cm) effacing the right thyroid gland (Figure 2 A). Three, rounded, well-defined soft tissue attenuating nodules were identified within the pulmonary parenchyma (the largest nodule measured 4.6 × 5.8 mm). It was concluded that the right thyroid mass most likely represented thyroid carcinoma and the likely primary source of the pulmonary and tibial metastases in this dog.

Figure 2.

A — Transverse view of the computed tomography study at the level of the 3rd cervical vertebra. A large, ventral, and right-sided cervical mass (large arrow) was heterogeneous and contrast-enhanced to surrounding soft tissues and muscles. The mass was causing dorsal displacement of the common carotid artery (asterisk). The left thyroid gland (small arrow) measured within normal limits. B — Soft tissue (top) and bone (bottom) transverse views of the computed tomography study of the proximal tibia of the right and left hind limb. An ill-defined, irregularly marginated, soft tissue attenuating and heterogenous mass was present within the proximal left tibia (arrowheads).

The previously diagnosed, aggressive bone lesion of the proximal left tibia and stifle joint was visualized. A moderate, ill-defined, amorphous periosteal reaction and an ill-defined, irregularly marginated, soft tissue attenuating and heterogenous mass were identified (Figure 2 B). The mass was centered at the proximal tibial metaphysis but extended into the medial aspect of the stifle joint and medial to the distal femoral condyles. Moth-eaten lysis of the distal femoral condyles and trochlear ridges was noted with mild, ill-defined periosteal reaction. Lastly, moderate, diffuse muscle atrophy of the left pelvic limb was appreciated.

Palliative left hind-limb amputation via coxofemoral disarticulation was performed to provide analgesic relief.

Histological examination of the tibial lesion revealed a poorly demarcated neoplasm composed of polygonal cells in densely arranged packets with rare colloid-filled microfollicles infiltrating the medulla and disrupting the cortex. The neoplastic cells had round to oval nuclei with moderate amounts of stippled chromatin, prominent nucleoli, and moderate amounts of faintly granular to vacuolated eosinophilic cytoplasm. The cells exhibited moderate anisocytosis and anisokaryosis with 7 mitotic figures in 10, high-power (400×) fields (2.37 mm²) (Figure 3). The histologic interpretation confirmed the clinical suspicion of metastatic thyroid carcinoma.

Figure 3.

A — Photomicrograph of metastatic thyroid carcinoma in the proximal tibia of a dog. Neoplastic epithelial cells were arranged primarily in nests and fill the medulla. H&E stain; bar = 50 μm. B — Higher magnification view of the metastatic thyroid carcinoma. Rare microfollicles were visible (arrows) that contained colloid. H&E stain; bar = 10 μm.

The dog was started on toceranib phosphate (Palladia; Zoetis, Kalamazoo, Michigan, USA), 2.5 mg/kg BW, PO, 3 times/wk, 2 wk after surgery. In addition, the dog was started on carprofen, 2 mg/kg BW, PO, q12h, as an anti-inflammatory and analgesic, and gabapentin, 12 mg/kg BW, PO, q24h, as an anxiolytic. The dog has been seen every 4 to 6 wk through the Oncology Service to monitor baseline diagnostics (blood pressure, blood work, and urinalysis). The dog has had thoracic radiographs performed every 6 to 8 wk for monitoring progression of metastatic disease. Palladia was discontinued after 6 mo due to gastrointestinal side effects (diarrhea) that did not resolve with probiotic therapy. The dog is reportedly still alive 12 mo after surgery, with no radiographic changes of metastasis progression.

Discussion

In humans, osseous metastases (OM) occur in only 2 to 13% of thyroid cancer patients but are associated with higher morbidity and mortality (19–21). Most OM are osteolytic in nature, rather than osseous invading (19,22). Unsurprisingly, bone metastasis in humans is documented to increase mortality rate, shorten survival rate, and compromise patient quality of life (22–24). Prophylactic screening for bone metastasis is not commonly done in human medicine, and in ~84% of thyroid cancer patients, osseous metastases diagnosis was pursued only following complaints of bone pain, masses, nerve compression, or pathologic fracture (22). Most patients presenting with bone metastases present prior to their thyroid carcinoma diagnosis, which is identified following further diagnostic imaging (22). Histological type has been identified as a reliable prognostic factor when considering thyroid carcinoma in humans (22). Follicular and papillary forms are the most common, with a higher survival rate than medullary carcinoma (22).

The most common sites of thyroid osseous metastasis in humans are the vertebrae (52%), followed by the femur (20%), skull (16%), pelvis (16%), and clavicle (13.6%) (22). The incidence of primary bone tumors affecting the proximal tibia and fibula in dogs is noted to be < 1% (25). Tibial Plateau Leveling Osteotomy (TPLO) is a common procedure for treatment of ruptured anterior cruciate ligament in dogs (26,27). Osteosarcoma, at the site of an orthopedic implant, has been reported in dogs (28–32). The prevalence of TPLO-associated osteosarcoma is 4 times higher than that of primary neoplasia affecting the proximal tibia and fibula (29). Although sarcomas have been associated with TPLO sites, the authors could not find any previous report of metastatic thyroid carcinoma at the site of an orthopedic implant. A direct relationship between the orthopedic implant and bone neoplasia has not been established. Several theories have been postulated as the inciting cause, including but not limited to, chronic inflammation, corrosion of the implant, and decreased vascularity of bone following fracture (33). Chronic inflammation, either incited by the implant or corrosion of the implant, has been theorized to cause uncontrolled cell growth, immunosuppression, and production of reactive cytokines and metalloproteinases that amplify the inflammatory process (34). Inflammation also results in production of angiogenic factors that can augment tumor growth and progression (34). The authors believe that these same mechanisms could contribute to development of metastatic neoplasia. The exact pathophysiology leading to cancer development, however, remains poorly understood. Identification of metastatic disease in our patient was detected 1 y following its original TPLO procedure. In comparison, OSA at previous TPLO sites occurred typically 5 to 6 y after the procedure (28–30). The authors could not find any previous reports of implant-associated thyroid metastasis in humans.

The most important factor in determining the best treatment option for a primary thyroid carcinoma in dogs is whether the tumor is mobile or fixed. The use of surgery alone for mobile, non-metastatic thyroid tumors is associated with a median survival time (MST) > 36 mo (9). In the present case, neither surgery nor radiation were recommended for the primary tumor, due to evidence of distant metastatic disease in the thorax, as well as the tibia. In the metastatic setting, surgery plus chemotherapy did not significantly increase survival (8). Surgical treatment of human osseous metastasis of thyroid neoplasia is performed in approximately half of reported cases, not to improve prognosis, but rather to provide better functional outcomes and improve overall morbidity in patients (22). Similarly in this case, left hind limb amputation was performed to improve quality of life, rather than to improve prognosis. Conventional and/or novel chemotherapies have not significantly improved survival outcome in dogs with metastatic thyroid disease; however, toceranib phosphate, a multikinase inhibitor, has provided clinical benefits, either with a complete or partial response, or stable disease (35,36).

The toceranib phosphate label indicates dosing should be initiated at 3.25 mg/kg BW, every other day, which is the maximum tolerated dose, and be reduced as needed to mitigate clinical side effects. In the present case, a dose of 2.5 mg/kg BW, Mon/Wed/Fri, was chosen. Lower doses of toceranib phosphate at 2.5 to 2.75 mg/kg, every other day, have provided clinical benefits in up to 80% of in dogs with thyroid carcinoma, with fewer adverse events (36).

The median overall survival time for dogs treated for metastatic thyroid carcinoma with toceranib phosphate alone is reported at 563 d and as high as 1082 d if prior therapy, surgical or chemotherapeutic, had been initiated (35).

To the best of the authors’ knowledge, this is the first reported case of bone metastasis of a dog with thyroid carcinoma. In addition, this case reports orthopedic implant-associated disease metastasis, as the ultimate cause for detection of primary disease. Differential neoplasms at a TPLO site should not be limited to osteosarcoma, and importantly should include metastatic tumors.