Outcome following treatment of soft tissue and visceral extraskeletal osteosarcoma in 33 dogs: 2008–2013

Extraskeletal osteosarcoma (EOS) is a rare, highly malignant mesenchymal neoplasm arising from viscera or soft tissues characterised by the formation of osteoid in the absence of bone involvement. Owing to the rarity of these neoplasms very little information exists on treatment outcomes. The purpose of this study was to describe the outcome following surgical treatment of non‐mammary and non‐thyroidal soft tissue and visceral EOS in dogs. Thirty‐three dogs were identified; the most common primary tumour site was the spleen. Dogs that had wide or radical tumour excision had longer survival times compared with dogs that had only marginal tumour excision performed [median survival time of 90 days (range: 0–458 days) versus median survival time of 13 days (range: 0–20 days)]. The use of surgery should be considered in the management of dogs with non‐mammary and non‐thyroidal soft tissue and visceral EOS.     

Serum vascular endothelial growth factor in dogs with various proliferative diseases

Angiogenesis plays an important role in the proliferation and metastasis mechanisms of malignant tumors. Vascular endothelial growth factor (VEGF), a group of cytokines that contribute to angiogenesis and vasculogenesis. This study aimed to investigate the serum VEGF-A concentrations in dogs with various proliferative diseases. A total of 202 dogs that were histopathologically diagnosed with proliferative diseases were included in the study. Serum VEGF-A concentrations were measured using enzyme-linked immunosorbent assay. Median serum VEGF-A concentrations in dogs were as follows: healthy dogs, 4 pg/ml [0–21 pg/ml]; hepatocellular carcinoma, 30 pg/ml [0–158 pg/ml, P=<0.001]; hepatocellular adenoma, 32 pg/ml [0–49 pg/ml, P=0.003]; hepatic nodular hyperplasia, 18 pg/ml [0–51 pg/ml, P=0.595]; adrenal pheochromocytoma, 32 pg/ml [0–187 pg/ml, P=<0.001]; adrenocortical carcinoma, 32 pg/ml [3–161 pg/ml, P=0.002]; adrenocortical adenoma, 27 pg/ml [0–106 pg/ml, P=0.005]; colorectal adenocarcinoma, 36 pg/ml [0–75 pg/ml, P=0.002]; colorectal adenoma, 43 pg/ml [0–48 pg/ml, P=0.144]; inflammatory colorectal polyps, 37 pg/ml [0–111 pg/ml, P=<0.001]; pulmonary adenocarcinoma, 35 pg/ml [4–107 pg/ml, P=0.002]; pulmonary histiocytic sarcoma, 35 pg/ml [0–131 pg/ml, P=0.016]; and follicular thyroid carcinoma, 35 pg/ml [0–106 pg/ml, P=0.009]. The serum VEGF-A concentrations were significantly higher in dogs with neoplastic lesions compared to healthy dogs, except for colorectal adenoma. High serum VEGF-A concentrations were observed in dogs with proliferative diseases. The present study suggests that angiogenesis-inhibiting therapy, which targets VEGF-A, may be useful for canine neoplastic diseases.     

Serum vascular endothelial growth factor in dogs with haemangiosarcoma and haematoma

Splenic haemangiosarcomas are frequently seen in dogs. Because of their bad prognosis differentiation from other benign splenic lesions are of prognostic importance.     

Diagnostic accuracy of pre‐treatment biopsy for grading soft tissue sarcomas in dogs

Histologic grade is an important prognostic factor for both local recurrence and metastatic potential with canine soft tissue sarcoma (STS). Pre‐treatment biopsy with identification of tumour grade may aid in prognostication and determination of surgical margins necessary for local control. The purpose of this study was to evaluate the grading accuracy of various pre‐treatment biopsy techniques (wedge, punch, needle‐core) for STS in dogs. Medical records of 68 dogs diagnosed with a STS via pre‐treatment biopsy and confirmed by excisional biopsy were evaluated. The concordance in grade between excisional and pre‐treatment biopsies was 59%. Of the 41% that lacked concordance, 29% of pre‐treatment biopsies underestimated and 12% overestimated grade. The method of pre‐treatment biopsy did not significantly effect grade concordance. Based on these data, needle‐core biopsy appears to be similar in accuracy compared to open biopsy, however, grading determined by pre‐treatment biopsy in general should be interpreted with caution.     

The use of novel lymphatic endothelial cell‐specific immunohistochemical markers to differentiate cutaneous angiosarcomas in dogs

Lymphangiosarcomas are uncommon vascular neoplasms that arise from lymphatic endothelial cells (LECs). They efface and replace normal subcutaneous tissue and are characterised by arborising, vascular channels lined by a single layer of pleomorphic endothelial cells and a paucity of erythrocytes. Lymphangiosarcomas are architecturally similar to hemangiosarcomas, a common malignancy of vascular origin arising from blood vascular endothelial cells. Common immunohistochemical markers for vascular endothelium, such as Factor VIII‐related antigen (F8RA) and CD31, have traditionally been used to confirm the diagnosis of tumours of vascular origin. However, these markers fail to differentiate between lymphangiosarcoma and hemangiosarcoma, which often show overlapping morphologic features, disparate clinical behaviour and require different treatment modalities. Here we describe the use of two novel LEC‐specific markers, lymphatic vessel endothelial receptor‐1 (LYVE‐1) and prospero‐related homeobox gene‐1 (PROX‐1), to further differentiate between vascular tumours of lymphatic (lymphangiosarcoma) and blood (hemangiosarcoma) endothelial cell origin in the dog.     

Outcome in dogs with advanced (stage 3b) anal sac gland carcinoma treated with surgery or hypofractionated radiation therapy

Stage 3b anal sac gland carcinoma (ASGC) can be life‐threatening. A surgical approach is not always possible or may be declined. Dogs with stage 3b ASGC treated with surgery or conformal radiation therapy (RT) with 8 × 3.8 Gy (total dose 30.4 Gy, over 2.5 weeks) were retrospectively evaluated. Patient characteristics, median progression‐free interval (PFI) and median survival time (MST) were compared. Twenty‐eight dogs were included; 15 underwent surgery, 13 underwent RT. At the time of presentation, 21% showed life‐threatening obstipation and 25% showed hypercalcaemia. PFI and MST for surgery cases were 159 days (95% CI: 135–184 days) and 182 days (95% CI: 146–218 days), both significantly lower than for RT cases with 347 days (95% CI: 240–454 days) and 447 days (95% CI: 222–672 days), (P = 0.01, P = 0.019). Surgery as well as RT led to a fast relief of symptoms. PFI and survival of surgical patients were significantly inferior to that of a comparable patient group treated with conformal hypofractionated RT.     

Ultrasound and computed tomography of the iliosacral lymphatic centre in dogs with anal sac gland carcinoma

In this prospective study, we hypothesized that computed tomography (CT) would identify more normal and abnormal iliosacral lymph nodes (LNs) than abdominal ultrasound in dogs with anal sac gland carcinoma (ASGC). Twelve client‐owned dogs with ASGC but without distant metastasis were enrolled. Abdominal ultrasound and contrast‐enhanced CT scans of the abdomen were obtained. Iliosacral LNs were counted and assessed for location, laterality and size. Significantly (P < 0.00001) more iliosacral LNs were identified with CT (61) than ultrasound (30), including significantly (P = 0.00012) more medial iliac LNs with CT (33) than ultrasound (19). There was no difference in number of internal iliac LNs identified with CT versus ultrasound. Significantly (P = 0.000061) more sacral LNs were identified with CT (15) than ultrasound (0). Ultrasound identified slightly more (7) abnormal iliosacral LNs than CT (5). Contrast CT was able to identify more normal but not more abnormal LNs than ultrasound.     

Angiofibroma of the nasal cavity in 13 dogs

This case series describes a rare entity, nasal angiofibroma, in 13 dogs that were presented to the University of Wisconsin, School of Veterinary Medicine from 1988 to 2000. All dogs in this case series presented with clinical signs and radiographic changes that were strongly suggestive of a locally invasive neoplasm. However, histopathology completed on transnostral core biopsy samples revealed benign appearing vascular proliferation with secondary lymphosuppurative inflammation was established despite cytologic criteria of malignancy present in five dogs. On the basis of the outcomes in this case series, nasal angiofibroma should be considered a differential for dogs presenting with clinical signs consistent with a malignant nasal tumour.     

Plasma vascular endothelial growth factor concentrations in healthy dogs and dogs with hemangiosarcoma

Vascular endothelial growth factor (VEGF) is a dimeric glycosylated polypeptide growth factor with potent angiogenic, mitogenic, and vascular permeability-enhancing properties specific for endothelial cells. In humans, VEGF seems to play a major role in tumor growth, and plasma concentrations correlate with tumor burden, response to therapy, and disease progression. This study compared plasma VEGF concentrations in healthy client-owned dogs (n = 17) to dogs with hemangiosarcoma (HSA; n 16). Dogs with HSA were significantly more likely to have detectable concentrations of plasma VEGF (13/17) compared to healthy dogs (1/17; P < .001). The median plasma VEGF concentration for dogs with HSA was 17.2 pg/mL (range, < 1.0-66.7 pg/mL). Plasma VEGF concentrations in dogs with HSA did not correlate with stage of disease or tumor burden, but 1 dog had undetectable VEGF during chemotherapy that subsequently increased with disease progression.     

Inter‐ and intra‐rater reliability and agreement in determining subcutaneous tumour margins in dogs

The objective of this prospective study was to evaluate agreement and reliability of calliper‐based measurements of locally invasive subcutaneous malignant tumours in dogs. Four raters measured the longest diameter of 12 subcutaneous tumours (7 soft tissue sarcomas and 5 mast cell tumours) from 11 client‐owned dogs during 3 randomized, blinded measurement trials, both pre‐ and post‐sedation. Inter‐ and intra‐rater reliability was evaluated using intra‐class correlation coefficient (ICC) and agreement was evaluated using Bland‐Altman plots. Inter‐ and intra‐rater reliability was good (ICC range of 0.8694‐0.89520) and excellent (ICC range of 0.9720‐0.9966), respectively. For agreement calculations, an a priori clinically relevant limit of agreement of 10 mm was set. Inter‐ and intra‐rater agreement was unacceptable with inter‐rater limits of agreement ranging from 15.9 to 55.6 mm and intra‐rater limit of agreement ranging from 11.9 to 28.1 mm. Review of the measurement trial photographs revealed that calliper orientation changes were frequent, occurring in 9/12 (75%) and 8/12 (67%) pre‐ and post‐sedation cases. No significant correlation was found between inter‐rater measurement standard deviations and calliper orientation changes or dog body condition score. These findings suggest veterinarians may have poor agreement in determining the gross edge of tumours, which is expected to introduce bias and inconsistency in tumour staging, assessing response to therapy, and surgical margin planning. Due to the potential consequences for veterinary cancer patients, future studies are needed to validate the present findings.     

Serum vascular endothelial growth factor concentrations and postsurgical outcome in dogs with osteosarcoma

Vascular endothelial growth factor (VEGF) is a key angiogenic growth factor, playing putative roles in both tumour growth and metastasis. The purpose of this study was to correlate pretreatment serum concentrations of VEGF in dogs with osteosarcoma (OSA) with disease‐free interval (DFI) and overall survival (OS). Additionally, the effect of serum from dogs with OSA on ex vivo canine endothelial cell (EC) growth was determined. Pretreatment platelet‐corrected serum VEGF levels correlated significantly with DFI. No other examined variable predicted outcome. The ability of sera from dogs with OSA to stimulate canine EC proliferation did not correlate with VEGF concentration or outcome. These data support a role for VEGF in the development or progression of metastatic disease in dogs with OSA. The VEGF concentration in tested sera was not a major determinant of ex vivo canine EC proliferation in this study.     

Development of a questionnaire assessing health-related quality-of-life in dogs and cats with cancer

Health-related quality-of-life (HRQoL) has been studied extensively in human medicine. There is currently no standard HRQoL evaluation for veterinary oncology patients. The aim of this study was to assess the practicality, usefulness and robustness, from a pet owner and clinician perspective, of a questionnaire for the assessment of HRQoL in canine and feline cancer patients. A HRQoL assessment entitled 'Cancer Treatment Form' and two questionnaires entitled 'Owner Minitest' and 'Clinician Minitest' were designed. The first and second were completed by owners of patients presenting to a veterinary oncology referral service and the third by attending clinicians. The 'Cancer Treatment Form' was well received by owners and clinicians and provided a valuable assessment of HRQoL with 98% (82/84) of owners reporting an accurate reflection of their pet's quality-of-life. Following this, minor improvements to the form could be suggested prior to regular use in evaluation of clinical oncology patients.     

Endostatin and vascular endothelial growth factor concentrations in healthy dogs, dogs with selected neoplasia, and dogs with nonneoplastic diseases

To evaluate the relationship between endostatin and vascular endothelial growth factor (VEGF) in cancers of dogs, circulating concentrations of these 2 tumor-associated markers were measured prospectively in healthy dogs (n = 44), dogs with tumors (n = 54), and dogs with nonneoplastic diseases (n = 42 for endostatin; n = 16 for VEGF). A canine-directed enzyme-linked immunosorbent assay kit was used for determination of endostatin, and a human-directed kit was validated for detection of canine VEGF. Concentrations of endostatin for all dogs were 28-408 ng/mL. Increasing serum endostatin concentration was associated with increasing age (P = .0396). Concentrations of endostatin were not different among groups of dogs (P = .1989) when adjusted for age. Mean endostatin concentrations for all dogs were higher in dogs (P = .0124) with detectable VEGF concentrations. Endostatin concentrations, when corrected for age, were related to decreasing PCV (P = .032) but not white blood cell count (P = .225) or platelet count (P = .1990). Measurable VEGF (> or = 2.5 pg/mL) was detected in 3 (7.0%) of 43 healthy dogs. Dogs with tumors had detectable VEGF in 24 (44%) of 54 dogs, with concentrations ranging from 2.5-274 pg/mL; only 1 dog with a nonneoplastic disease process had detectable VEGF. VEGF concentrations for all dogs after correcting for age, endostatin, and disease categories were associated with increased white blood cell count (P = .0032) and platelet counts (P = .0064) and decreased PCV (P = .0017). Linkage between increased endostatin and VEGF concentrations suggests that similar factors may influence concentrations of these markers. Further evaluation of endostatin and VEGF associations in dogs with tumors may provide information on the extent and progression of the disease.     

Bilateral removal of the mandibular and medial retropharyngeal lymph nodes through a single ventral midline incision for staging of head and neck cancers in dogs: a description of surgical technique

Currently, there is no standard protocol for removal of regional lymph nodes for the staging of head and neck cancers in dogs. Palpation and fine needle aspiration of mandibular lymph nodes are most commonly performed for staging of head and neck cancers. Although cytology is commonly performed for staging of head and neck, cancers histopathology is required for definitive lymph node staging. When regional lymph node biopsy is performed, mandibular lymph nodes are most commonly sampled due to their accessibility. The medial retropharyngeal lymph nodes may be the most relevant draining lymph node of the head and neck, but they are not routinely sampled due to their anatomic location medial to the salivary glands. The technique described here will allow for a standardized surgical approach for the efficient removal of both mandibular and medial retropharyngeal lymph nodes for staging of head and neck tumours via a single ventral midline approach.     

A prospective evaluation of the impact of second‐opinion histopathology on diagnostic testing,cost and treatment in dogs and cats with cancer

Second‐opinion histopathology is a common practice in human medicine to avoid unnecessary procedures, costs and to optimize therapy. Histopathology review has been recommended in veterinary oncology as well. In this prospective evaluation of 52 tumours over a 1‐year period, there was diagnostic agreement between first and second opinions in 52% of cases. Twenty‐nine percent of cases had partial diagnostic disagreement, most often a change in grade, tumour subtype or margin status. Nineteen percent had complete diagnostic disagreement, including a change in cell of origin or a change from benign to malignant. Minor disagreements, which would not affect treatment or prognosis, were present in 21% of cases. Major disagreements, which would affect either treatment or prognosis, were present in 37% of cases. Costs of ideal staging and treatment recommendations were considerably different between first and second opinions.     

PCNA and grade in 13 canine oral squamous cell carcinomas: association with prognosis

This study evaluated the prognosis factors of age, tumour size, anatomic location, histological grade and proliferating cell nuclear antigen (PCNA) expression in 13 dogs with oral squamous cell carcinoma (OSCC) with bone invasion and without signs of lymph node or distant metastasis. All animals were treated with radical excision performed with at least 1 cm margin, based on computed tomography images. In the 2‐year follow‐up, median disease‐free survival was 138 days for dogs with grade 3 tumours and was not reached for those with grade 2 tumours. Grade 3 tumours and PCNA labelling index ≥65% were related with a shorter disease‐free survival time and consequently poor prognosis (p = 0.003 and p = 0.034, respectively). Mean PCNA labelling index was significantly higher in recurrent cases (p = 0.011). Histological grade and PCNA expression may be important prognosis factors in canine OSCC.     

Comparison between L-CHOP and an L-CHOP protocol with interposed treatments of CCNU and MOPP (L-CHOP-CCNU-MOPP) for lymphoma in dogs

An L-CHOP protocol with interposed treatments of CCNU and MOPP (L-CHOP-CCNU-MOPP) was evaluated in 66 dogs with stages III-V lymphoma. Results were compared with a historical group of 71 dogs treated with an L-CHOP protocol. Complete remission (CR) rates (85 and 80%, respectively) did not differ significantly between protocols (P = 0.48). First CR duration for dogs treated with L-CHOP-CCNU-MOPP was significantly longer: median, 317 days; 2-year CR rate, 35% versus median, 298 days; 2-year CR rate, 13%, P = 0.05). For the L-CHOP-CCNU-MOPP protocol, dogs in substage-b had a 4.3 times greater hazard of having a relapse than dogs in substage-a (P = 0.002). Frequency of adverse chemotherapy-associated gastrointestinal effects did not differ between protocols (P = 0.77). Neutropenia (primarily after CCNU) occurred more frequently in dogs treated with L-CHOP-CCNU-MOPP (P < 0.001). In summary, the L-CHOP-CCNU-MOPP protocol showed an improved duration of first CR as compared with an L-CHOP protocol, but the relevance of this finding might be subject to clinical judgement.     

Quality of life assessment in dogs and cats receiving chemotherapy – a review of current methods

This study aimed to review currently reported methods of assessing the effects of chemotherapy on the quality of life (QoL) of canine and feline patients and to explore novel ways to assess QoL in such patients in the light of the experience to date in human pediatric oncology. A qualitative comparative analysis of published papers on the effects of chemotherapy on QoL in dogs and cats were conducted. This was supplemented with a comparison of the parameters and domains used in veterinary QoL‐assessments with those used in the Pediatric Quality of Life Inventory (PedsQL^?) questionnaire designed to assess QoL in toddlers. Each of the identified publications including QoL‐assessment in dogs and cats receiving chemotherapy applied a different method of QoL‐assessment. In addition, the veterinary QoL‐assessments were mainly focused on physical clinical parameters, whereas the emotional (6/11), social (4/11) and role (4/11) domains were less represented. QoL‐assessment of cats and dogs receiving chemotherapy is in its infancy. The most commonly reported method to assess QoL was questionnaire based and mostly included physical and clinical parameters. Standardizing and including a complete range of potentially relevant parameters in future QoL assessments may benefit owner decision making.