To be a great veterinarian is one thing, but the ability to maintain compassion and caring sets you apart from the rest.
Signalment: 8-year-old male castrated Terrier mix (10.3 kg)
Presenting Complaint: sneezing and gagging for 1.5 weeks prior to presentation which progressed to nasal congestion.
History: Initial clinical signs included sneezing followed by gagging. At night nasal congestion was noted by owners. Initial medical management included enrofloxacin and Neo-Poly-Dex drops administered intra-nasally. No improvement noted and a nasal flush 1 week later flushed out mucoid nasal discharge. Increased frequency of sneezing and nasal discharge was noted after the nasal flush. Eating more slowly since the nasal disease started.
Medications: enrofloxacin (68 mg once every 24 hours)
Physical Exam Findings: Completely absent airflow from the left or right nostril with open mouth breathing. Bilateral mucopurulent nasal discharge.
Complete blood count: WBC 23.88 K/ul. (54.3 % Neu, 32.6 % Lym).
Thoracic Radiographs (performed by rDVM): No significant abnormalities.
Skull Radiographs (performed by rDVM): Increased soft tissue opacity within the nasal cavities bilaterally.
Assessment: Bilaterally obstructive nasal disease. Differential diagnoses included non-specific rhinitis (eg. lymphocytic-plasmascytic, suppurative, etc), nasal neoplasia, fungal rhinitis or nasal foreign body.
Recommendations: Nasal CT to be followed by rhinoscopy
Nasal CT was performed before and after intravenous administration of contrast media (Iohexol 240 mgI/ml).
There was fluid accumulation among the left and right nasal turbinates with complete occlusion of airspaces rostrally and only minimal turbinate destruction (Figure 1). A space occupying mass lesion was present in the nasopharynx just caudal to the caudal margin of the hard palate. This lesion had a hyperattenuating (bright) rim in both pre- and post-contrast images and did not demonstrate any significant contrast enhancement. Some contrast of the nasopharyngeal mucosa surrounding this structure was seen. CT findings in the rostral nasal passage were consistent with a non-specific bilateral rhinitis. Differentials for the mass lesion in the nasopharynx included a nasal foreign body, inflammatory polyp or neoplastic mass.
Figure 1. Transverse CT images viewed in bone window from rostral to caudal (A through D). Fluid is present among the nasal turbinates causing nearly complete occlusion of the airspaces within both the left and right nasal passages.
Figure 2. Transverse (A) and sagittal (B) CT images of the head viewed in a soft tissue window. A space occupying mass lesion within the nasopharynx just caudal to the caudal margin of the hard palate. The lesion is shaped like an upside down “witch’s hat” in the transverse image (A) with a hyperattenuating (bright) rim and completely occludes the lumen of the nasopharynx.
Flexible retrograde rhinoscopy was performed and with the endoscope retroflexed dorsally over the soft palate a foreign body was visible within the nasopharynx (Figure 3). A rat tooth grasper instrument was used to grasp the foreign body and retrieve it via the oral cavity. Marked circumferential swelling and bruising of the nasopharyngeal mucosa was noted in the location where the nasal foreign body had been lodged. The lumen of the nasopharynx also appeared significantly narrowed.
The patient was monitored in the hospital overnight and discharged the next day. A tapering dose of prednisone and several days of tramadol for pain were prescribed. Due to the severe nasopharyngeal inflammation and apparently narrowed lumen of the nasopharynx the owners were warned about the possibility of the patient developing a secondary nasopharyngeal stenosis. One week following retrieval of the foreign body the patient was reportedly doing well at home with minimal upper respiratory noise noted.
Figure 3. Retroflexed endoscopic view of the nasopharynx with a nasal foreign body completely occluding the lumen.
Figure 4. The retrieved nasal foreign body was determined to be the cap to an acorn.
A range of diseases can affect the nasopharynx of cats and dogs with neoplasia and inflammatory disease being most common. A variety of neoplasias recognized in the nasal cavity and nasopharynx include lymphosarcoma, carcinomas, mast cell tumor, fibrosarcoma and osteosarcoma. Multiple inflammatory diseases can also be seen including suppurative rhinitis, lymphocytic-plasmacytic rhinitis, inflammatory polyps and fungal rhinitis. While neoplastic masses and inflammatory polyps are the most common cause of nasopharyngeal obstruction, nasal or nasopharyngeal foreign bodies and nasopharyngeal stenosis must also be included on that list.
The most common presenting clinical sign in animals with nasopharyngeal disease is stertor. Repeated attempts at swallowing or “hard-swallowing” may also be noted. Nasal discharge may or may not be present. Sneezing is not typical but may be present with concurrent disease of the nasal turbinates or if the more rostral nasal passages are also involved.
A thorough visual oral and pharyngeal exam under sedation or general anesthesia is warranted in patients tentatively diagnosed with nasopharyngeal disease. The nasopharynx can also be palpated for masses through the soft palate. The use of advanced imaging such as computed tomography (CT) in combination with flexible retrograde rhinoscopy has greatly facilitated the diagnosis of nasopharyngeal disease and therefore the recognition of potentially treatable diseases. CT findings typical of foreign body rhinitis include focal nasal turbinate destruction, hyperplasia of remaining nasal mucosa, and regional accumulation of fluid or mucoid exudates. Changes are typically unilateral unless the nasopharynx is involved rather than the left or right nasal passage. The nasal foreign body itself may or may not be seen depending on both size and composition. Endoscopy additionally allows for treatment of several of these diseases as demonstrated in the above case with endoscopic retrieval of the nasopharyngeal foreign body.
Submitted by: Chris Ryan, VMD, DABVP, DACVR
In 2016, an estimated over 1.5 million new cases of cancer will be diagnosed in the United States and almost 600,000 people will die from the disease.1 On the veterinary side, there are approximately 65 million dogs and 32 million cats in the United States, with roughly 6 million new cancer diagnoses made in each dogs and cats annually.2 Although we often see ourselves in the veterinary world as “catching up” to the human side, veterinary cancer medicine has actually co-evolved with human cancer medicine. November is Pet Cancer Awareness month, which is always a good time to reflect upon our progress and standing as a profession. The following provides a (rather) abbreviated overview of where we started, where we are, and where we’ve still yet to go.
Historical accounts of human cancer date back some 5000 years ago to the scribes of Egyptian physicians.3 These records included descriptions and illustrations of uterine and breast cancers and the physical suffering they caused. Ancient physicians used a variety of terms to describe tumors, including ‘‘carcinos’’, the Greek word for crab, which alluded to the crab leg-like extensions emanating from breast tumors, and “onkos”, the Greek word for swelling.3 Obviously these terms and derivations of them are still with us today. Although their observations were astute, the early Greeks’ initial approach to cancer treatment was rudimentary. Surprisingly, this undeveloped methodology remained static over the following centuries and cancer treatment consisted of surgery, cautery, blood-letting, and herbal medicines only.3 Fortunately, science and technology advanced enormously once the 1700s came around, however, it was still not for over 200 years that chemotherapy became established as a legitimate tool of modern cancer medicine.
Paul Ehrlich, a German physician known as the “Father of Chemotherapy”, coined the term chemotherapy and was one of the earliest pioneers to screen medicinal chemicals in animals.3 In 1915, Germany – the home nation of Ehrlich – became the first country to use mustard gas on the battlefield during World War I. It is actually upon this act of war that the era of modern chemotherapy is founded. Almost 100,000 people lost their lives to this poison gas during the war. Fortunately, several autopsies were performed and found that mustard gas exposure caused severe lymphoid depletion, neutropenia, and bone marrow aplasia. Unfortunately, it took 20 more years before the idea of therapeutically using mustard compounds was realized. The chemical research that went on following the war found that nitrogen mustard, a close but less toxic derivative of mustard gas, had antitumor activity against lymphoma in mice. Then in 1943, a mustard compound was used for the first time in a patient with non-Hodgkin’s lymphoma at Yale University Medical Center. Impressive, but only temporary, regression was observed in this and subsequent lymphoma patients. Then in 1947, aminopterin, a folate analog initially used for pernicious anemia, was first used by Dr. Sidney Farber to treat pediatric patients with leukemia. His successes were met with a lot of resistance, but eventually led to expansion of cancer medicine and the discovery of several other chemotherapy agents, including methotrexate, vinca alkaloids, and procarbazine, in the 1950s-60s. 3
In many ways, veterinary medical oncology has closely followed the advances in human medical oncology. For example, the first reported use of chemotherapy in a veterinary cancer patient (a dog with lymphoma treated with urethane) was in 1947, the same year Sidney Farber treated his first pediatric patient with aminopterin. The first use of asparaginase for treatment of canine lymphoma was reported in 1967. During these early years of development of veterinary chemotherapy, single agent chemotherapy was still the standard of care in human oncology until the MOPP (Mustargen, Vincristine, Procarbazine, Prednisone) combination protocol was developed in the mid to late 60s. The first reported use of combination chemotherapy for canine lymphoma involved chlorambucil plus prednisone and was published in JAVMA in 1968. A far more sophisticated combination chemotherapy protocol for canine lymphoma using 5 different drugs was reported in 1975. The first report of doxorubicin use in dogs was published in the veterinary literature in 1976. In time, this drug became the backbone of multidrug protocols for a wide variety of canine and feline tumors. The evolution in sophistication of the drug protocols used in dogs mirrored what was transpiring in human medical oncology at about the same time. However, as in human cancer medicine, the problem of drug resistance in veterinary oncology is very real and typically the limiting factor in being able to successfully eradicate individual cancers with conventional chemotherapy alone. This problem may be even more magnified in veterinary oncology given the limits (natural and applied) on chemotherapy dose intensity.
Over time, researchers have uncovered the fact that cancer can arise from any number of genetic aberations, and often is due to a combination of errors that ultimately lead to unregulated cell growth. Now, with dramatic improvements in DNA technology, researchers and physicians can analyze an individual patient’s tumor to determine what genetic abnormalities are present. Using genomic profiling, instead of simply applying the broad-brush approach of surgery, radiation, and one-size-fits-all chemotherapy protocols for specific cancers, physicians can now more accurately match targeted treatments to individual patients. For some cancers, the protein products of genetic mutations are identifiable targets in cancer cells that can be “blocked” with specific drugs. Such molecularly targeted drugs have provided patients, in particular those with advanced disease, an option to help control cancers that have failed traditional chemotherapies and radiation. This is what personalized medicine is all about, and this is also becoming more readily applicable in veterinary medicine. A still fairly recent and no doubt exciting development in veterinary chemotherapy was the introduction of toceranib phosphate, also known as Palladia, by Pfizer (now Zoetis) in 2009. This drug was the first targeted chemotherapy agent developed specifically for dogs and is FDA-labeled for the treatment of advanced canine mast cell tumors, although its current application in veterinary oncology spans several tumors types in both dogs and cats.4 Although molecularly targeted drugs are certainly a step forward, they too are not a cure-all, as there are mechanisms of resistance and evasion by cancer cells to these drugs as well.
Potentially the most promising approach in clinical cancer medicine is immunotherapy. This modality incorporates a patient’s own immune system into the fight against the tumor, oftentimes along with radiation, chemo, and targeted molecular therapies. Immune-based therapies involving monoclonal antibodies, checkpoint inhibitors, cytokines, and many others, have already transformed the treatment for several human cancers. These are therapies that we are now evaluating in companion animals and gradually adding to our arsenal for veterinary cancers. In veterinary medicine, we have Merial’s Oncept®, a USDA-approved vaccine against malignant melanoma that has significantly improved outcomes for dogs with this highly aggressive cancer.5 While initial attempts at developing monoclonal antibodies against canine B-cell and T-cell lymphoma have thus far fallen short, several companies have gone back to the drawing board and are working on second-generation monoclonals with the intent of developing the veterinary version of rituximab (Rituxan®), the monoclonal antibody that has revolutionized the treatment of B-cell lymphoma in people.
Other areas of interest in veterinary cancer research include bone marrow transplantation, complementary and alternative therapies such as herbals like Yunnan Baiyou and polysaccharopeptide (PSP), an extract from the mushroom coriolus versicolor and the key ingredient in I’m Yunity®,7 acupuncture, and diet therapy.
Undoubtedly, light years of progress has been made since mustard gas was first used in World War I, yet as we all know, we still have so much further to go in the war against cancer.
Submitted by Christine Mullin, VMD, Diplomate ACVIM (Oncology)
- National Cancer Institute. Cancer Statistics. https://www.cancer.gov/about-cancer/understanding/statistics
- National Cancer Institute Center for Cancer Research. Comparative Oncology Program, For Pet Owners. https://ccr.cancer.gov/comparative-oncology-program/pet-owners/what-is-comp-onc
- Morrison WB. Cancer Chemotherapy: An Annotated History. J Vet Intern Med 2010;24:1249–1262. http://onlinelibrary.wiley.com/doi/10.1111/j.1939-1676.2010.0590.x/full
- London CA, Malpas PB, Wood-Follis SL, et al. Multicenter, Placebo-controlled, Double-blind, Randomized Study of Oral Toceranib Phosphate (SU11654), a Receptor Tyrosine Kinase Inhibitor, for the Treatment of Dogs with Recurrent (Either Local or Distant) Mast Cell Tumor Following Surgical Excision. Clin Cancer Res 2009;15(11):3856-3865. http://clincancerres.aacrjournals.org/content/15/11/3856.long
- Bergman PJ and Wolchok JD. Of Mice and Men (and Dogs): development of a xenogeneic DNA vaccine for canine oral malignant melanoma. Cancer Ther 2008; 6:817-26.
- Griffin MM and Morley N. Rituximab in the treatment of non-Hodgkin’s lymphoma – a critical evaluation of randomized controlled trials. Expert Opin Biol Ther 2013;13(5):803-11. https://www.ncbi.nlm.nih.gov/pubmed/23560506
Brown DC and Reetz J. Single agent polysaccharopeptide delays metastases and improves survival in naturally occurring hemangiosarcoma. Evidence-based complementary and alternative medicine 2012; Article ID 384301:1-8. https://www.hindawi.com/journals/ecam/2012/384301/
A 7-year-old female spayed 14-kilogram mixed breed dog was presented to HOPE Veterinary Specialists for a surgical consult after a recent diagnosis of a right auricular mass. She initially presented to her local emergency clinic for an acute episode of lethargy, pale mucous membranes and increased respiratory effort. Radiographs at that time showed a characteristic “globoid” heart shape and a focal thoracic ultrasound revealed pericardial effusion causing cardiac tamponade. Pericardiocentesis was performed, she was evaluated the following morning by a cardiologist and an echocardiogram revealed a 3 x 4 cm right auricular mass. Bloodwork showed mild hypoalbuminemia but no evidence of anemia. Cytology of the pericardial fluid was consistent with hemorrhage and no neoplastic cells were noted. Pericardiocentesis was required three additional times over the next few days.
Based on the presentation, echocardiogram findings, and repeated hemorrhagic pericardial effusion, cardiac hemangiosarcoma was suspected. She was transferred to a referral center at which time she was hospitalized and received a dose of Doxorubicin. After discharge from the referral center, the owners presented to HOPE for discussion of surgical options. The treatment for the tamponade component of this disease has historically been repeated pericardiocentesis or a pericardial window/subtotal pericardiectomy via thoracotomy in combination with adjuvant chemotherapy. However, due to the poor prognosis with cardiac hemangiosarcoma, many owners are reluctant to pursue surgical intervention because of the invasiveness and postoperative morbidity of a thoracotomy.
Instead of an open thoracotomy, the owners were offered minimally invasive thoracoscopy and after a discussion about the prognosis and the options for treatment, they elected to proceed with the procedure. In this procedure, three small incisions are made in the thorax to allow placement of ports for passage of a rigid endoscope and thoracoscopic instruments. Through this approach, the pericardium is able to be grasped, elevated and resected to create a pericardial window. The goal is to allow the pericardial effusion to drain into the pleural cavity thereby avoiding cardiac tamponade in the future. A sample of pericardium can also be obtained for biopsy.
A: Pericardium grasped and elevated.
B: Mild amount of pericardial effusion visible.
Figure 2: Portion of pericardial window completed.
D: Thoracostomy tube.
Video 1: Pericardial window
Because of the small size of the incisions, local blocks with bupivacaine were used at each of the sites to provide multimodal analgesia. The patient recovered well from anesthesia and within two hours of surgery was able to stand and go for a walk outside. She was maintained on intravenous doses of methadone overnight, her chest tube was removed the following day, and she was transitioned off intravenous narcotics at that time.
Although it is relatively new in veterinary medicine, thoracoscopy has been used in humans for over 100 years. It was initially used for lysis of pleural adhesions due to tuberculosis and in the 1990’s, started to be used to perform video-assisted procedures1. In veterinary medicine, this approach is currently used for a variety of thoracic procedures including pericardial window, subtotal pericardiectomy, lung lobectomy, and to obtain pleural, mediastinal or lung biopsies2,3,4. There are several disadvantages to thoracoscopy including the initial cost of the equipment and steep learning curve. However, there are numerous advantages including decreased postoperative pain, a faster return to activity and a decreased hospital stay which results in a lower cost for the client. Additionally, the small incision size allows us to provide local anesthetic blocks at the incision sites which results in a decreased need for intravenous opioids. Especially in cases where the surgical treatment is palliative, the advantages of thoracoscopy make it a good choice for our patients.
While cardiac tumors in dogs are uncommon in comparison to other tumors, hemangiosarcoma is the most common type of cardiac neoplasia in dogs. The initial presentation is often for signs related to acute cardiac tamponade including lethargy, pale mucous membranes, and collapse. These patients may be anemic however the anemia may not be as profound as it is in cases of splenic hemangiosarcoma because the amount of hemorrhage needed to cause cardiac tamponade is relatively small. Thoracic radiographs show a globoid cardiac silhouette and identification of the mass is achieved via echocardiography. Although it can occur in any region of the heart, the right auricle is the most common location.
Treatment options for this disease are limited. Mass excision, pericardial window, subtotal pericardiectomy and chemotherapy have all been reported and all of these are intended to be palliative as there is no effective long-term treatment for hemangiosarcoma.
Due to the aggressive nature of the disease (the median survival time is often reported as 3-4 months) and reported presence of distant metastasis in up to 75% of cases of cardiac HSA5, owners are often reluctant to pursue open thoracotomy for mass excision, subtotal pericardiectomy or pericardial window. These owners often decline surgery because of the concern of prolonged postoperative morbidity during the relatively short expected survival time. A recent retrospective study6 evaluated the effectiveness of Doxorubicin alone in the treatment of cardiac hemangiosarcoma and found a median survival time of 116 days compared to 42 days for dogs that were not treated with chemotherapy. Based on these results, this appears to be an appropriate option for patients who do not have recurrent episodes of cardiac tamponade. However, for patients with recurrent tamponade, short term treatment of the pericardial effusion is necessary through repeated pericardiocentesis or a pericardial window. With the introduction of thoracoscopy, we are now able to provide a long-term solution to eliminate recurrent tamponade with minimal postoperative morbidity. In the future, the combination of minimally invasive thoracoscopy and adjuvant chemotherapy may provide a more effective approach for the palliative treatment of this disease than previously available.
Submitted by: Brian Bretz, DVM, DACVS
2.Skinner OT, et al. Pericardioscopic Imaging Findings in Cadaveric Dogs: Comparison of an Apical Pericardial Window and Sub-phrenic Pericardectomy. Vet Surg 2014; 43(1):45-51. https://www.ncbi.nlm.nih.gov/pubmed/?term=Pericardioscopic+Imaging+Findings+in+Cadaveric+Dogs%3A+Comparison+of+an+Apical+Pericardial
3.García F, et al. Examination of the Thoracic Cavity and Lung Lobectomy by Means of Thoracoscopy in Dogs. Can Vet J. 1998; 39(5):285-91. https://www.ncbi.nlm.nih.gov/pubmed/?term=Examination+of+the+Thoracic+Cavity+and+Lung+Lobectomy+by+Means+of+Thoracoscopy+in+Dogs
4.Atencia S, et al. Thoracoscopic Pericardial Window for Management of Pericardial Effusion in 15 dogs. J Small Animal Prac. 2013; 54(11):564-9. https://www.ncbi.nlm.nih.gov/pubmed/?term=Thoracoscopic+Pericardial+Window+for%E2%80%89Management+of+Pericardial+Effusion+in+15+dogs
5.Yamamoto S, et al. Epidemiological, Clinical and Pathological Features of Primary Cardiac Hemangiosarcoma in Dogs: A Review of 51 Cases. Journal of Veterinary Medical Science 2013; 75(11):1433–1441. https://www.ncbi.nlm.nih.gov/pubmed/?term=Epidemiological%2C+Clinical+and+Pathological+Features+of+Primary+Cardiac+Hemangiosarcoma+in+Dogs
6.Mullin CM, et al. Doxorubicin Chemotherapy for Presumptive Cardiac Hemangiosarcoma in Dogs. Veterinary and Comparative Oncology 2014; Dec 18. https://www.ncbi.nlm.nih.gov/pubmed/?term=Doxorubicin+Chemotherapy+for+Presumptive+Cardiac+Hemangiosarcoma+in+Dogs
- Signalment: 12-year-old female spayed Yorkshire terrier (4.1 kgs)
- Presenting complaint: Progressively worsening periods of inspiratory dyspnea with mild coughing
- Pertinent history: 3-year history of collapsing trachea and mild chronic valvular disease; Failed medical management with Theophylline ER, Butorphanol, Diphenhydramine, Enrofloxacin, and/or Acepromazine
- Medications: Prescription diet w/d (Hill’s Pet Nutrition), Hydrocodone (2.5mg orally very 6 hours), Prednisone (2.5mg orally every 12 hours)
- Physical examination findings: Bright, alert, and responsive; body condition score 6/9; Grade 2/6 holosystolic heart murmur, intermittent inspiratory dyspnea with mild cyanosis, inducible cough upon tracheal palpation, profound increased inspiratory respiratory effort (suggesting upper airway involvement) with moderately increased expiratory effort as well (suggesting intrathoracic tracheal and/or bronchial involvement)
- Hemoglobin Saturation: 94%
- Complete blood count: Mils stress leukogram
- Serum chemistry profile: ALT 79, AST 39, ALP 420
- Thoracic and cervical radiographic and fluoroscopic examination: (See Figure 1)
- Cardiology Consult: Mild chronic valvular disease
Figure 1: Lateral thoracic and cervical static fluoroscopic image demonstrating cervical and thoracic inlet tracheal narrowing (black arrows) and open intrathoracic tracheal lumen and carina (white arrows).
This patient had received various medications with little improvement in clinical signs. Historical cardiology consultation reported no need for cardiac medications needed at that time. Presentation 2 weeks earlier resulted in final attempt at medical management including antibiotics, steroids, and anti-tussives. No major improvement in clinical signs led to consideration for more aggressive interventions. Discussion with the owner included extraluminal tracheal ring placement and intraluminal stent placement. While the primarily inspiratory clinical signs suggested more severe extrathoracic tracheal collapse, physical examination and fluoroscopic evaluation suggested concurrent intrathoracic tracheal and bronchial collapse. Tracheal stenting was chosen to treat both the extrathoracic and intrathoracic tracheal collapse. Under general anesthesia and using fluoroscopic guidance, positive pressure (Figure 2; 20cm H2O) and negative pressure (Figure 3; -15cm H2O) ventilation tracheal measurements were made in order to determine the maximal tracheal diameter and determine the extent of the tracheal and/or bronchial collapse. A self-expanding metallic tracheal stent was placed through the endotracheal tube (Figure 4) and the patient was recovered in 40% oxygen in the ICU and until awake and ambulatory.
Figure 2: Lateral thoracic and cervical static fluoroscopic image obtained at 20cm H2O positive pressure ventilation (PPV) demonstrating maximal tracheal diameter. A marker catheter (black arrows) is in place in the esophagus for measurement purposes. The carina is open (white block arrow). Line 3 is 10mm and used to calibrate the image in order to determine the diameter of the trachea (Line 4).
Figure 3: Lateral thoracic and cervical static fluoroscopic image obtained at -15cm H2O negative pressure ventilation (NPV) demonstrating diffuse tracheal collapse (black arrows) as well as carina and mainstem bronchial collapse (white block arrow) not previously apparent without NPV.
Figure 4: Lateral thoracic and cervical static fluoroscopic image immediately following intraluminal stent placement demonstrating re-established tracheal lumen patency (white arrows).
This patient was discharged from the hospital the following day with resolution of the dyspnea. A mild dry cough persisted. Discharge medications included a 3-week tapering dose of corticosteroids (prednisone 2.5mg orally twice daily to start), hydrocodone (2.5mg orally every 6 hours), and a 10-day course of enrofloxacin (40mg compounded orally once daily). Follow-up phone calls each week confirmed she continued to do well. Recheck examination 4 weeks later showed dramatically improved respiration with progressive resolution of the dry cough. Occasional periods of excitement-induced coughing episodes continued but dramatically improved compared to pre-stent episodes. Re-examination at 3 months, 6 months, and 1 year demonstrated similar clinical signs; Every other day prednisone remained necessary as well as daily hydrocodone therapy.
Tracheal collapse is a progressive, degenerative disease of the cartilage rings in which hypocellularity and decreased glycosaminoglycan content lead to dynamic tracheal collapse during respiration. More recently, tracheal ring malformations have been found to also contribute to tracheal lumen obstruction and respiratory compromise. Tracheal collapse is a condition of predominantly middle-age, small and toy-breed dogs that develop a wide and varying range of symptoms varying from a mild, intermittent “honking” cough to severe respiratory distress from dynamic upper-airway obstruction. Many of these patients (like the example above) are successfully palliated for years with conservative treatments (weight loss, management of comorbidities, etc.) and medications including anti-inflammatories, cough suppressants, and bronchodilators. Once medical management fails to provide an acceptable quality of life, more aggressive interventions are considered.
The two most commonly performed treatment options include extraluminal tracheal rings and intraluminal tracheal stenting. Tracheal ring surgery involves placing extraluminal support rings around the trachea during an open cervical approach and has a reported 75%-85% overall success rate in 90 dogs for reducing clinical signs.1 This procedure is limited to those patients with collapse limited to the cervical trachea (primarily inspiratory dyspnea) and is not without complications. The same study reported that 5% of animals died peri-operatively, 11% developed laryngeal paralysis from the surgery, 19% required permanent tracheostomies, and ~23% die of respiratory problems with a median survival of 25 months. More importantly, only 11% of the dogs in this study had intra-thoracic tracheal collapse (all dogs had extrathoracic tracheal collapse).
The advantages of intraluminal self-expanding metallic stent (SEMS) placement include minimal invasiveness, shorter anesthesia times, and access to the entire cervical and intrathoracic trachea. Disadvantages include misplacement, choosing the inappropriate stent size, and an unknown but relatively low risk of stent fracture. Two studies report clinical improvement rates in 75%-90% of animals treated with intra-luminal SEMS.2,3 Immediate complications were typically minor although there was a reported peri-operative mortality rate of approximately 10%, a rather high figure compared to the author’s experience. Late complications included stent shortening, excessive granulation tissue, progressive tracheal collapse, and stent fracture. Complications are often due to inappropriate stent placement or sizing which is reduced with experience.
For stent placement, the patient is placed under general anesthesia, tracheal measurements are made, and an appropriately sized stent is placed through an endotracheal tube and deployed during direct visualization using fluoroscopy. The stenting procedure is fairly short and the patients are typically discharged from the hospital the following day. Medical management with corticosteroids and anti-tussives continues initially and most dogs will need continued anti-tussive medications for life. Those with concurrent low-airway disease will often benefit from continued corticosteroid therapy as well.
Submitted by Dr. Chick Weisse
1 Buback JL, Boothe HW, and Hobson HP. Surgical treatment of tracheal collapse in dogs: 90 cases (1983-1993) Journal of the American Veterinary Medical Association 1996; 208(3):380-384.
2 Norris JL, Boulay JP, Beck KA, et al. Intraluminal self-expanding stent placement for the treatment of tracheal collapse in dogs (abstr), in Proceedings, 10th Annual Meeting of the American College of Veterinary Surgeons 2000.
3 Moritz A, Schneider M, and Bauer N. Management of advanced tracheal collapse in dogs using intraluminal self-expanding biliary wallstents. Journal of Veterinary Internal Medicine 2004; 18:31-42.
Often the pathology report is a source of frustration for both the submitting clinician and the pathologist. It is important to better understand the roles and responsibilities of both surgeon and pathologist in order to promote a better dialogue between the two.
Most tumor related biopsies yield a diagnosis, however, in cases in which tumors are poorly differentiated, the use of special stains or immunohistochemistry can aid in determining tumor type.
- Signalment (age, breed, sex)
- History including duration, prior diagnosis or therapy, etc.
- Physical examination, bloodwork, imaging findings
- Mass: Gross appearance, size, location/source, duration of growth, invasiveness, etc
- Type of biopsy (incisional or excisional)
- Ink margins and label which margins are colored, etc.
- Clinical impression of the case
- Submit all tissue removed en bloc
- Label lids and container and ensure proper amount of formalin
- Margin information (if excisional)
- “narrow”, incomplete, clean
- Should be quantified (mm or cm)
- Histologic grade
- MCT I,II,III or low grade/high grade
- Sarcomas, carcinoma
- Vascular/lymphatic invasion
- Mitotic index (soft tissue sarcoma, MCT, Melanoma)
- Final diagnosis
- Should contain negative findings
- Meaning “no vascular invasion noted”
There are three situations where more information is needed including:
- When the histopathologic diagnosis does not fit clinical presentation
- When crucial information missing on report
- When all information present, but not detailed enough.
Use of Immunohistochemistry (IHC):
In veterinary oncology, the main use of IHC has been to aid the pathologist in determining the origin of the neoplastic cell population. The importance of which can’t be overstated as often poorly differentiated tumors can be very difficult to determine the exact cell of origin with routine light microscopy alone. The identification of specific antigens on the surface of cells can provide further information regarding the cell type and in some cases aggressiveness. The ever increasing number of available antibodies is growing and is becoming commonplace in veterinary oncology.
Examples whereby IHC is important for diagnosis and therapy
- Amelanotic melanoma of the oral cavity (PNL2, Melan-A, TRP-1, TRP-2) vs. Sarcoma
- Melanoma: systemic control with the Oncept® melanoma vaccine
- Sarcoma: systemic control with chemotherapy (Doxorubicin)
- Synovial sarcoma (cytokeratin+, CD18-) vs. histiocytic sarcoma (cytokeratin-, CD18+)
- Synovial cell: if low or moderate grade local control only, if high grade Doxorubicin
- Histiocytic sarcoma: Lomustine (CCNU)
- Gastrointestinal stromal tumor (CD117+) vs leiomyosarcoma
- If high grade; tyrosine kinase inhibitor if a GIST vs chemotherapy (Doxorubicin) if a leiomyosarcoma
- Osteosarcoma (osteocalcin+) vs. fibrosarcoma (osteocalcin-)
- Fibrosarcoma: no therapy if low or moderate grade or Doxorubicin if high grade
- Osteosarcoma: Carboplatin
- Nasal carcinoma (cytokeratin+, round cell markers-) vs. lymphoma (cytokeratin+, round cell markers+)
- Round cell tumor
- Toluidine Blue, Chymase, Tryptase (MCT)
- CD3 (T cell lymphoma)
- CD20, CD79a (B cell lymphoma)
- Lymphoma high grade vs. Indolent
- Histopathology and IHC may make the difference in treatment vs not (indolent) and protocol
Tumor Markers/Panels for Prognosis
The importance of use the use of “panels” containing a several markers of malignancy is best illustrated in canine mast cell tumors. There is general consensus that the pathology and behavior of a MCT depends substantially on the histologic pattern of the tumor, which is associated with the tumor grade. However, there is variation within the grading scheme used among pathologists that lends itself to subjectivity in assigning a tumor to a particular category. Traditionally, these categories are grade I (well-differentiated or low grade), grade II (intermediate grade), and grade III (poorly-differentiated or high grade). Subsequently, guiding the appropriate therapy and providing prognostic information based on the traditional grading scheme has become complicated and unpredictable. The introduction of a two tier system (Kiupel) of low and high grade designed to minimize the subjectivity was introduced several years ago and has since been further validated. In a study of 137 surgically resected cutaneous MCTs, the relationship between grade and survival was evaluated. All grade I MCTs were low grade in the Kiupel system, and all grade III were deemed high grade. Among grade II, 71 (85.6%) were low grade, and 12 (14.4%) were high grade, with a 1-year survival probability of 94% and 46%. Per this study, the 2-tier system had a high prognostic value and was able to correctly predict the negative outcomes of some grade II MCTs. Currently pathologists are reporting both grading schemes.
To assist in more objectively categorizing a grade II MCT, which account for 70% of all MCTs, various immunohistochemical and molecular tests of tumor cell proliferation are now recommended in addition to routine histopathology. These markers of proliferation are now clinically available and are readily performed on tissue biopsy samples in the form of MCT panels (www.dcpah.msu.edu/Sections/Immunohistochemistry/FAQ.php#08).
These assays provide clinicians with the ability to make more sound recommendations regarding the appropriate adjuvant therapy. This particular panel evaluates argyrophilic staining nucleolar organizing regions (AgNOR), proliferation cell nuclear antigen (PCNA), Ki-67, c-kit pattern assessment, and PCR for c-kit gene mutation. AgNOR frequency is an indirect measure of tumor cell proliferation and may be equally or even more important as the tumor grade in terms of predicting the biologic behavior of the MCT. PCNA and Ki-67 are also indirect measures of tumor cell proliferation and are most useful when interpreted in conjunction with one another. c-kit is the protein receptor for stem cell factor found in many cells including mast cells. A genetic mutation of the c-kit gene, which encodes for the c-kit receptor itself, has been identified in some MCTs. When mutated, the receptor is constitutively active and promotes the malignant process within the cells. Mutations within the c-kit gene are associated with a more aggressive phenotype. With the new two tier system, ideally this should decrease the need for further panels, as low grade tumors for the most part are associated with longterm survival.
If the new grading scheme may become standard of care, then the data suggest 5-15% of “low grade” tumors will behave more aggressively. Ideally, a MCT panel, may help differentiate these patients and thereby guide the clinician to either a more aggressive surgery or adjuvant therapy that could benefit that patient. To run MCTs panels on all “low grade” tumors seems overkill to help identify the 5% of atypical cases, it also takes away the validity of grading scheme if it is being suggested to be run in conjunction with grading. Ideally, the MCT panel should be reserved for cases in which the biopsy results do not fit the clinical picture; ie a more aggressive site (muzzle), fast growing tumor, severely ulcerated, large tumor, lymph node involvement, etc.
For high grade tumors, performing portions of the panel may be useful for treatment decision. Knowing a kit mutation status in a high grade tumor may change the treatment choice from purely chemotherapy to a combination of chemotherapy and a TKI, whereby a higher response rate is noted in kit mutation positive patients. Currently studies are underway utilizing mutation status to help logically guide treatment decision for a more personalized medicine approach, albeit on a very basic level.
The Use of Tumor Markers for Targeted Therapies
On a basic level, this is being performed with kit mutation analysis in which results may play a role in the use of tyrosine kinase inhibitor. In the future assessment of HER-2/Neu expression in dogs with osteosarcoma could influence the decision to utilize targeted immunotherapy (listeria based). Similarly, the use of are COX-1/COX-2 and vascular endothelial growth factor (VEGF) receptor analysis may aid not only in prognosis but the use NSAIDs and tyrosine kinase inhibitors.
Understanding the responsibilities of both clinician and pathologist is needed to ensure that we, as clinicians obtain the information needed to best serve our client and patients. We are entering a new era in veterinary pathology in which panels of markers may help us better predict prognosis for a variety of neoplasias.
Submitted by Craig A Clifford DVM, MS, DACVIM (Oncology)
- Kamstock DA, Ehrhart EJ, Getzy DM, et al. Recommended Guidelines for Submission, Trimming, Margin Evaluation, and Reporting of Tumor Biopsy Specimens in Veterinary Surgical Pathology. Veterinary Pathology January 2011;48:19-31.http://vet.sagepub.com/content/48/1/19.short
- Smedley RC, Lamoureux J, Slefhe DG, et al. Immunohistochemical Diagnosis of Canine Oral Amelanotic Melanocytic. Vet Pathol 2011; 48:32-40.http://vet.sagepub.com/content/48/1/32.short
- Fernandez NJ, West KH, Jackson ML, et al. Immunohistochemical and Histochemical Stains for Differentiating Canine Cutaneous Round Cell Tumors. Veterinary Pathology 2005;42:437-445
- McCaw DL. Tumors of the skin, subcutis, and other soft tissues: Section D – Mast cell tumors. In: Henry CJ, Higginbotham ML, eds. Cancer Management in Small Animal Practice, St. Louis: Elsevier, 2010:317–321.http://vet.sagepub.com/content/42/4/437.short
- Kiupel M, Webster JD, Bailey KL, et al. Proposal of a 2-tier histologic grading system for canine cutaneous mast cell tumors to more accurately predict biological behavior. Vet Pathol. 2011;48:147-55.http://vet.sagepub.com/content/48/1/147.short
- Sabattini S, ScarpaF, Berlato D, et al. Histologic Grading of Canine Mast Cell Tumor Is 2 Better Than 3? Vet Pathol 2014.http://vet.sagepub.com/content/52/1/70.short
- Smith J, Kiupel M, Farrelly J, et al. Recurrence rates and clinical outcome for dogs with grade II mast cell tumours with a low AgNOR count and Ki67 index treated with surgery alone. Veterinary and Comparative Oncology 2015 Feb 3. doi: 10.1111/vco.12140