Aortic Body Tumor in Full-Sibling English Bulldogs
A 10-year-old, neutered male English bulldog died acutely from respiratory distress after a short history of progressive dyspnea. Less than 2 months later, a spayed female full sibling of that dog died suddenly during a nail trim. An aortic body tumor was the cause of death in both dogs based on postmortem and histological examinations. A pheochromocytoma was also diagnosed in the neutered male. Neither dog had a history of brachycephalic airway syndrome, and the implication for a genetic predisposition toward the development of paraganglioma is discussed. This is the first case report of aortic body tumors in sibling dogs, although the condition may not be an uncommon phenomenon.
Introduction
Aortic body tumors, carotid body tumors, and pheochromocytomas arise from the paraganglia, which are neuroendocrine cells with components of either the sympathetic or parasympathetic nervous system.1–4 When tumors of the paraganglia arise within the adrenal gland, they are termed pheochromocytomas; however, they are termed paragangliomas when they occur elsewhere, regardless of whether they are sympathetic or parasympathetic in origin. Although paraganglioma is the preferred terminology for aortic and carotid body tumors, the terms chemodectomas and glomus cell tumors have also been used.
Pheochromocytomas and paragangliomas of sympathetic origin usually are composed of chromaffin cells, which have secretory granules containing norepinephrine and/or epinephrine.1,2 These granules stain positive with potassium dichromate.2 Aortic and carotid body tumors and other, less well-defined paragangliomas of the head and neck typically arise from the parasympathetic nervous system and are usually negative for chromaffin cells. Chromaffin-positive tumors are more likely to have systemic effects related to the release of catecholamines, while chromaffin-negative tumors are more likely to demonstrate clinical signs related to their space-occupying nature.1
Chromogranin A is a secretory protein of neuroendocrine cells and is routinely produced by chromaffin cells.5 Immunohistochemistry for chromogranin A varies for paragangliomas and pheochromocytomas, with some nonchromaffin paragangliomas staining positive for chromo-granin A. Staining for chromogranin A typically is present in benign aortic body tumors and absent in those that are poorly differentiated or have metastasized.5,6 Immunohistochemistry to identify the expression of neuron-specific enolase and synaptophysin in paragangliomas helps identify tumors as paragangliomas, and determination of the Ki-67 proliferation score can help establish tumor grade.5,6
Clinical signs reported with aortic body tumors are often related to cardiac decompensation as a result of pressure from the expanding mass on the atria, vena cava, or both.1,4 Common clinical signs of aortic body tumors include dyspnea, coughing, cyanosis, ascites, and edema of the head, neck, and forelimbs. In dogs with carotid body tumors, the most common reasons for presentation include a palpable mass in the neck, dyspnea, and difficulty swallowing.1,7
In a study that evaluated the prevalence of cardiac tumors in dogs, aortic body tumors accounted for 5% (69 of 1383) of all cardiac tumors.8 While carotid body tumors are the most common type of paraganglioma in humans, aortic body tumors are reported to occur four to five times more frequently than carotid body tumors in dogs.3,4 Chronic hypoxia has been implicated as a potential risk factor for the development of paragangliomas in dogs, based on the results of retrospective studies that showed a high prevalence in brachycephalic breeds.3,9 One author emphasized the lack of brachycephalic breeds (other than boxers and English bulldogs) in a study of dogs with paragangliomas and suggested the need for reassessment of the role of chronic hypoxia as an important etiological factor.4 The possibility that hereditary factors play a role (in association with or independently from chronic hypoxia) in the development of paragangliomas needs to be considered. This report describes full-sibling English bulldogs that died within a 2-month period of each other and were each diagnosed with an aortic body tumor by postmortem examination. Treatment options and outcomes are not reviewed in this report.
Case Reports
Case No. 1
A 10-year-old, neutered male English bulldog was presented to an emergency clinic on June 25, 2006 for labored breathing. The dog had been seen by the primary care veterinarian 3 weeks earlier for a routine examination. No problems associated with the respiratory tract were reported at that time, and the results of a complete blood count and serum biochemical profile were within normal limits. The dog began coughing intermittently 1 week prior to presentation to the emergency clinic after choking on a rawhide chew bone, which had to be removed manually by the owner. The cough persisted and progressively worsened over the course of 1 week, at which time labored breathing developed. At the emergency clinic, the dog was reportedly panting and appeared dyspneic. The tongue and gingiva were cyanotic, and the capillary refill time was 2 seconds. Rectal temperature was 101.5°F, femoral pulse quality was poor, and a heart rate could not be obtained. An audible wheeze was ausculted in all lung fields, and the abdomen was distended. The dog was placed in an oxygen cage where temporary improvement occurred; however, the dog would decompensate quickly when removed from oxygen, so no additional diagnostics were performed. Four hours after admission, the dog became agonal and died. The body was submitted for necropsy.
On gross examination, a 3 cm-diameter, firm, nodular mass was found within the pericardium at the heart base, surrounding the ascending aorta and compressing the trachea. The mass appeared to originate in the region of the sinoatrial node. On cut section, the mass was variegated (red and yellow) with multifocal, blood-filled cysts measuring <1 mm. A 1.5-cm, round, focal, firm nodule was present in the right caudal lung lobe and appeared similar to the heart base tumor on cut section. The remainder of the heart, lungs, and thoracic cavity were grossly normal.
At the root of the mesentery and encompassing the location of the adrenal glands was a large, firm, lobulated, variegated (red, purple, and yellow) mass measuring 6 × 8 × 5 cm. The mass was closely adhered to, and extended into, the caudal vena cava. A 1.5 cm-diameter, firm, pink to light purple mass was found within the lumen of the caudal vena cava. On cross section, the large mass had an identical appearance to that of the heart base mass. The right adrenal gland was entrapped within the large mass and was mildly enlarged (measurement not recorded), but it was considered normal in color and shape. The left adrenal gland was not identified.
Histological examination of the heart base mass revealed that the mass was encapsulated and replaced myocardium. The neoplasm was divided into lobules by fibrous trabeculae and was further divided into packets by fine, fibrovascular stroma [Figure 1]. The neoplastic cells were cuboidal to polygonal with small to moderate amounts of granular, eosinophilic cytoplasm. The nuclei were round to oval, with finely stippled to coarsely clumped chromatin. Multiple, large (30 to 50 μ), polygonal cells were seen—each with a single, large, oval nucleus or, occasionally, multiple nuclei. Rare, focal areas of necrosis were present as well as occasional macrophages with intracytoplasmic, hemosiderin pigment. These findings were consistent with a paraganglioma.
Histological examination of the right adrenal gland revealed that the adrenal medulla and cortex were compressed by a well-delineated neoplasm that was surrounded by a finely fibrous capsule. The neoplasm was composed of nests of cells with moderate to abundant, eosinophilic, foamy cytoplasm. The nuclei were small and round, with hyperchromatic nucleoli, and a focal area of mineralization was present. This was consistent with adrenal cortical adenoma.
On histological examination, the mesenteric mass was encapsulated and focally protruded into the vena cava. The mass was composed of packets of neoplastic cells that were surrounded by a thin, fibrovascular stroma that was further divided into lobules by fibrous trabeculae [Figure 2]. The neoplastic cells were identical in histological appearance to those found in the heart base mass. Multiple areas of coagulative necrosis and hemorrhage were present. At the periphery of the neoplasm the lumens of a few mesenteric vessels were partially occluded by tumor cells [Figure 3]. These findings were consistent with a pheochromocytoma, since this mass was suspected to arise from the left adrenal gland.
The histological examination of the lung mass showed that it was a partially encapsulated neoplasm that compressed adjacent lung tissue and vasculature, infiltrating surrounding parenchyma. The neoplasm contained multiple fibrous bands that surrounded neoplastic cells. The cells had the same morphological features as the neoplastic cells described in the mesenteric and heart base neoplasms [Figure 4]. Multiple clusters of neoplastic cells were present in the vasculature and within adjacent alveoli. This mass was determined to be a metastatic paraganglioma.
Case No. 2
A 10-year-old, spayed female English bulldog (the only littermate of case no. 1 and owned by the same person) was presented to the primary care veterinarian for a nail trim on August 17, 2006. This dog was apparently healthy at the time of presentation; however, during the nail trim, the dog collapsed acutely and began coughing up pink, foamy fluid. She died 20 minutes later of respiratory and cardiac arrest. The body of this dog was submitted for necropsy.
On gross examination, a mass was identified at the heart base, located between the left atrium and the pulmonary artery. This mass was elongated and multinodular and measured approximately 4.5 × 3.5 × 7 cm. Due to the size of the mass, the aorta was deviated approximately 30° to the right. On cut section, the mass was mottled white to red, firm, and solid. No additional abnormalities were noted at necropsy.
On histological examination, the heart base mass was moderately cellular, expansile, and encapsulated. The neoplasm was divided into lobules by prominent fibrous tissue septa and further subdivided by fine collagenous septa into smaller packets of closely packed cells. Individual cells were cuboidal, round, or polyhedral with moderately distinct cell borders and lightly eosinophilic, finely granular cytoplasm, which occasionally contained clear vacuoles. Nuclei were round to oval and centrally placed with finely granular chromatin and one to three basophilic nucleoli. Marked anisocytosis and anisokaryosis were present, and multinucleated cells were common. One mitotic figure was counted per 10 high-powered fields. Scattered areas of hemorrhage and necrosis were present throughout the neoplasm, and thick bands of fibrous tissue were abundant. These findings were consistent with a paraganglioma.
The aortic body tumors from both dogs and the pheochromocytoma from case no. 1 were subsequently subjected to immunohistochemical staining for chromogranin A. In case no. 1, staining for chromogranin A was diffuse in both the aortic body tumor and pheochromocytoma [Figure 5]. In case no. 2, the results were inconsistent, with a large majority of the tumor not staining positive and a few areas showing light staining. This staining was much lighter than what was seen in the normal adrenal gland from case no. 2. Immunohistochemical staining for enolase, synaptophysin, and Ki-67 was not performed.
Discussion
To our knowledge, this is the first report describing aortic body tumors, or any paraganglioma, in sibling dogs. We are unaware of any study that has evaluated a familial tendency toward the development of paraganglioma in dogs, although a breed predisposition for dogs of English bulldog ancestry (e.g., English bulldog, Boston terrier, boxer) has been shown.3,4,9 Of the breeds reported in four retrospective studies on aortic body tumors, the boxer, Boston terrier, and English bulldog accounted for 39% of all cases.3–6 Within those three breeds, the boxer accounted for 55% of the cases, and the Boston terrier and English bulldog accounted for 34% and 11%, respectively. To our knowledge, no pedigree analysis has been performed to evaluate for a potential familial tendency.
In humans, eight major hereditary forms of pheochromocytoma and paraganglioma exist, and the genetic defect responsible has been identified in all but one (PGL2).2 Four of these syndromes (classified as PGL1, PGL2, PGL3, and PGL4) exhibit isolated head and neck paragangliomas. Syndromes PGL1 and PGL4 also may develop pheochromocytomas. Mutation of the succinate dehydrogenase subunit D, C, or B gene is responsible for PGL1, PGL3, and PGL4, respectively; however, the gene mutation for PGL2 has not been identified. In the face of chronic hypoxia, the succinate dehydrogenase gene mutation results in increased production of angiogenic and tumor-promoting substances, such as transforming growth factor-β, platelet-derived growth factor receptor-β, and a ligand for the epidermal growth factor receptor. This mutation has not been described in the dog.
In this report, pulmonary metastasis was identified in case no. 1 along with a pheochromocytoma, and it is uncertain whether the aortic body tumor or the pheochromocytoma was responsible for the metastasis. Although aortic body tumors are usually locally invasive, they can metastasize, most frequently to the liver and lungs. In one retrospective study, 12% of the dogs with aortic body tumors had metastases.3 Osseous metastases have also been reported in aortic and carotid body tumors, but the reports are isolated.10,11 For case no. 1, the invasive nature of the pheochromocytoma makes it the more likely candidate for the pulmonary metastasis. The presence of chromogranin A staining in the aortic body tumor of case no. 1 also supports the idea that the pulmonary metastasis originated from the pheochromocytoma, as aortic body tumors that are malignant or have metastasized do not typically stain positive for chromogranin A.5 The lack of convincing staining for chromogranin A in case no. 2 may have been caused by a prolonged postmortem examination, as rapid autolysis is a feature of the parenchymal cells forming paragangliomas.1
Concurrent neoplasia was reported in 48% of dogs with aortic body tumors in one study, and most (62%) of these dogs had only one additional neoplasm.3 The most common additional tumor type reported in this study was thyroid carcinoma, followed by interstitial cell tumors and seminomas. Pheochromocytoma was not reported as a concurrent neoplasm in any of the dogs from that retrospective study;3 however, in a separate retrospective study on pheochromocytomas in dogs, 5% had either a concurrent aortic or carotid body tumor.12
Retrospective studies of pheochromocytomas in dogs have suggested that middle-aged to older dogs are affected, and no gender or breed predilection is apparent.12,13 Physical examination findings and presenting complaints for pheochromocytomas are nonspecific, but they can include episodic weakness, restlessness, tachycardia, hypertension, and collapse associated with excessive epinephrine and norepinephrine secretion. Approximately half of all pheochromocytomas are apparently inactive and, therefore, remain clinically undiagnosed and are identified only as incidental findings at necropsy. No association is known between pheochromocytomas and aortic or carotid body tumors in dogs, although their similar embryological origin could be a predisposing factor to concurrent development in the presence of a genetic mutation.
For the full-sibling dogs described in this report, not enough family history is available to help establish a familial link to the development of paraganglioma. Some information is known about the bitch, as she was also under the care of the same owner until her death at the age of 13 years. Five months prior to her euthanasia, the bitch had been evaluated by the primary care veterinarian for a few weeks’ history of weight loss, hyporexia, disturbed sleeping patterns, increased water consumption, confusion or disorientation, difficulty climbing stairs, lethargy, and labored breathing. She was reported to have inspiratory dyspnea on physical examination at that time. One month later, a staphylectomy was performed; however, the labored breathing continued unabated. The dyspnea continued until she was euthanized 4 months later, at which time she was found to have ascites. Unfortunately, a necropsy was not performed, so determining if the dyspnea was caused by tracheal compression from an aortic body tumor (as in case no. 1) was not possible. The sire was not owned by the client, and its history remains unknown.
Conclusion
Although this is the first report of the concurrent temporal development of aortic body tumor in full-sibling dogs, this is not likely an isolated event. Of the brachycephalic breeds, only the English bulldog, boxer, and Boston terrier are reported to have an increased risk for the development of paragangliomas. Given the number of additional brachycephalic breeds in existence, a genetic mutation that is absent in normal dogs may play a role in the development of these tumors in at-risk breeds possibly influenced by chronic hypoxia. Nonetheless, we are unaware of any studies that document the presence of chronic hypoxia or that compare the degrees of airway obstruction in brachycephalic breeds of dogs with and without paragangliomas. Pedigree analysis and genetic studies are warranted to investigate this potential familial link.
Citation: Journal of the American Animal Hospital Association 46, 5; 10.5326/0460366
Citation: Journal of the American Animal Hospital Association 46, 5; 10.5326/0460366
Citation: Journal of the American Animal Hospital Association 46, 5; 10.5326/0460366
Citation: Journal of the American Animal Hospital Association 46, 5; 10.5326/0460366
Citation: Journal of the American Animal Hospital Association 46, 5; 10.5326/0460366
Photograph of the mass at the base of the heart of case no. 1, demonstrating sheets of cuboidal to polygonal cells subdivided into small packets by thin trabeculae. (Hematoxylin and eosin stain, bar=50 μm.)
Photograph of the mass in the mesentery of case no. 1, demonstrating sheets of cells morphologically similar to those making up the mass at the base of the heart. (Hematoxylin and eosin stain, bar=50 μm.)
Photograph of a medium-sized vessel in the mesentery at the periphery of the mesenteric mass in case no. 1. Most of the lumen is filled by tumor cells. (Hematoxylin and eosin stain, bar=100 μm.)
Photograph of the lung mass of case no. 1, demonstrating a sheet of cuboidal or round cells that are similar to those in the neoplasms at the base of the heart and in the mesentery. (Hematoxylin and eosin stain, bar=50 μm.)
Immunohistochemical stain for chromogranin A on the heart base tumor of case no. 1. The brown cytoplasmic staining represents a positive reaction for chromogranin A. (Hematoxylin counter stain, bar=50 μm.)
Contributor Notes
