History
A 9-year-old 36.0-kg (79.2-lb) neutered male Bulldog was referred for evaluation of acute lethargy, vomiting, increased respiratory effort, and hemoabdomen. Results of a CBC and serum biochemical analysis from the referring veterinarian revealed moderate anemia (Hct, 22.47%; reference interval, 37% to 55%), mildly high glucose concentration (121 mg/dL; reference interval, 60 to 110 mg/dL), and mild thrombocytopenia (platelet count, 119 × 103 platelets/mL; reference interval, 200 × 103 to 500 × 103 platelets/μL). The dog's prothrombin and activated partial thromboplastin times were within reference limits.
Clinical and Clinicopathologic Findings
Physical examination findings for the dog included abdominal distention and increased respiratory effort. Two-view radiography revealed increased soft tissue opacity in the left cranial aspect of the thorax, cardiomegaly with border effacement of the cranial margin of the cardiac silhouette, and abdominal effusion. Abdominal ultrasonography revealed large amounts of fluid within the peritoneum. A 5.0 × 8.0-cm mediastinal mass located immediately cranial to the large vessels of the heart base was seen. Fine-needle aspirate specimens of the mediastinal mass were collected and evaluated.
The fine-needle aspirate specimens of the mediastinal mass were stained with modified Wright stain. Cytologic examination revealed primarily free (naked) nuclei (neuroendocrine-like appearance) and low to moderate numbers of intact nucleated cells (Figure 1). The intact nucleated cells were round to ovoid epithelial cells and were present singly or in small cohesive clusters. These cells each had an eccentrically placed, round nucleus with a finely stippled chromatin pattern, 1 to 3 indistinct nucleoli, and a moderate amount of basophilic cytoplasm often containing a moderate to large amount of fine, eosinophilic granular material. Mild anisocytosis and anisokaryosis were observed.
Photomicrograph of a slide preparation of a fine-needle aspirate specimen obtained from a mediastinal mass in a 9-year-old Bulldog that was referred for evaluation of acute lethargy, vomiting, increased respiratory effort, and hemoabdomen. Scattered free nuclei and clusters of epithelial cells with variably distinct cell borders and finely granular, eosinophilic, intracytoplasmic secretory material are present. There are a few neutrophils and a background of clumped RBCs among an amorphous, magenta material that is likely of a proteinaceous nature. Modified Wright stain; bar = 20 μm.
Citation: Journal of the American Veterinary Medical Association 256, 11; 10.2460/javma.256.11.1229
Formulate differential diagnoses from the history, clinical findings, and Figure 1—then turn the page→
Gross and Histopathologic Findings
Given the dog's poor prognosis, the owners elected euthanasia by IV injection of pentobarbital. Postmortem examination revealed approximately 3.35 L of frank blood in the dog's abdomen. In the mid-dorsal portion of the abdomen between the cranial poles of the kidneys and ventral to the vena cava, there was a large (6.0 × 5.0 × 4.0-cm) multilobulated, firm mass that was mottled red and white on cut sections. The mass had invaded the caudal vena cava as multiple, coalescing nodules (Figure 2). A separate mass (4.0 × 3.0 × 1.5 cm that tapered to 0.5 cm) with a 1.0-cm-long tear in the cranial pole was located dorsal and to the right of the abdominal mass; this was identified as the right adrenal gland on cut section. The liver was diffusely enlarged and the right and left medial lobes each had a single approximately 0.7-mm-diameter nodule that elevated the capsular surface. There was a firm, multilobulated mass (11.0 × 9.0 × 7.0 cm) in the cranial mediastinum; this mass was completely outside the pericardial sac and was firmly adhered to and had partially surrounded a segment of the thoracic aorta. The lumen of the right atrium had a 0.7-cm-diameter, red, pedunculated mass.
Photographs obtained during necropsy of the dog in Figure 1. A—Notice the large, firm, multilobulated mass (circle) cranial to the heart base and outside the pericardium. B—A cortical adenoma with a focal rupture (arrow) is present in the right adrenal gland. The left adrenal gland (asterisk) is grossly normal. C—A mid-dorsal abdominal mass (arrows) is seen ventral to and has invaded the caudal vena cava (asterisks) as multiple, coalescing nodules (arrowhead). The dog's head is to the right.
Citation: Journal of the American Veterinary Medical Association 256, 11; 10.2460/javma.256.11.1229
Histologic examination of tissue specimens from the abdominal mass revealed an encapsulated, highly cellular, infiltrative neoplasm (Figure 3). The mass was subdivided into lobules by dense fibrous connective tissue trabeculae that were continuous with the capsule. The neoplastic cells were polygonal and arranged in packets and cords supported by a fine fibrovascular stroma with occasional pseudorosettes (neuroendocrine appearance). Most cells had a round to oval nucleus with either a dense and heterochromatic or open and vesiculate chromatin pattern. Occasional cells had a large, bizarre, round to elongated nucleus that had a dark to finely stippled chromatin pattern. Occasional binucleated and multinucleated cells (≤ 5 nuclei) were present. There was < 1 mitotic figure/10 hpf (40X). Adjacent to the mass was a large ganglion associated with a mid-sized artery, consistent with the celiaco-mesenteric ganglion and celiac artery, respectively. The mediastinal mass and the liver and heart nodules were composed of similar neoplastic cells.
Photomicrograph of a section of tissue from the mediastinal mass. Neoplastic cells are arranged in packets and cords and supported by a fine fibrovascular stroma with occasional pseudorosettes. Cells are polygonal and largely uniform in appearance with distinct cell borders, a moderate amount of granular, amphophilic cytoplasm, and a round to oval nucleus with a dense and heterochromic or open and vesiculate chromatin pattern. Mild to moderate anisocytosis and anisokaryosis are present. H&E stain; bar = 20 μm.
Citation: Journal of the American Veterinary Medical Association 256, 11; 10.2460/javma.256.11.1229
The mediastinal mass was partially encapsulated, and the outer tunica media of the aorta was infiltrated by fibrous connective tissue that was continuous with the capsule. Histopathologic findings for the right adrenal gland were most consistent with an adrenal cortical adenoma with a focal rupture (the only source of bleeding found that could have caused the hemoabdomen). The left adrenal grand was grossly and histologically normal.
Immunohistochemical staining of sections of the abdominal and mediastinal masses revealed diffuse and strong staining for synaptophysin and chromogranin A. The neoplastic tissues were multifocally positive for neuron-specific enolase, although most of the tissue of both masses was not stained. The mediastinal mass was negative for thyroglobulin.
Morphologic Diagnosis and Case Summary
Morphologic diagnosis and case summary: malignant extra-adrenal abdominal paraganglioma with metastasis to the cranial mediastinum, liver, and heart; right adrenal cortical adenoma with focal rupture; and hemoabdomen in a dog.
Comments
Paragangliomas are a diverse group of rare neuroendocrine tumors derived from paraganglia. Paraganglia are neural crest-derived cells found along the embryologic routes of the neural crest tissue (along the paravertebral axis) from the base of the skull to the distal pelvic region. Thus, paragangliomas may develop anywhere along these tracts and in multiple sites in the body.1–3 Paraganglionic neoplasms can be further classified into 3 groups on the basis of location: pheochromocytomas, extra-adrenal pheochromocytomas, and chemodectomas.2,4
Tumors that originate from the chromaffin cells of the adrenal medulla are termed pheochromocytomas (or intra-adrenal paragangliomas).3,5 Chromaffin cells secrete high amounts of catecholamines (mainly epinephrine and norepinephrine) in response to acetylcholine release from the sympathetic nervous system. In humans and dogs, antemortem diagnosis of these neoplasms can be difficult because they are infrequently functional and the associated clinical signs are often vague. Functional pheochromocytomas should be suspected when there is systemic hypertension as a result of catecholamine excesses. In dogs, these tumors are considered malignant, and local invasion into surrounding structures can occur.3,6
Closely related tumors arising from chromaffin cells of extra-adrenal sympathetic and parasympathetic paraganglia are classified as extra-adrenal paragangliomas. These tumors can develop along the paravertebral and para-aortic axes but most commonly develop caudal to the diaphragm.5 The largest group of paraganglionic cells in the retroperitoneum of dogs is in the mid-retroperitoneal region ventral and lateral to the abdominal aorta with smaller aggregates distributed around the origin of the caudal mesenteric artery and the adrenal glands.1 Extra-adrenal paragangliomas tend to be locally invasive with a high incidence of metastasis and are often difficult to diagnose and treat. In the dog of the present report, the location of the abdominal mass and histologic findings were suggestive of its origin from the paraganglion associated with the celiaco-mesenteric ganglion. There have been few reported cases of extra-adrenal paragangliomas in dogs.1,7 Extra-adrenal paragangliomas in the mediastinum (primary and metastatic) have also been reported,2,4,8 many of which were associated with spinal cord invasion.
Extra-adrenal paragangliomas involving chemoreceptor organs (aortic or carotid bodies) are termed chemodectomas (or nonchromaffin paragangliomas).1,3,9 These chemoreceptor organs are responsible for detecting changes in blood oxygen and carbon dioxide concentrations and blood pH.9,10 Chemodectomas are the most common paragangliomas that develop in the thoracic region of dogs and are frequently identified in brachycephalic breeds.2,10
Most canine pheochromocytomas and extra-adrenal paragangliomas express neuron-specific enolase, synaptophysin, and chromogranin A.1,2 There may be less expression of chromogranin A in higher-grade paragangliomas.1 Similar to other neuroendocrine tumors, chemodectomas are typically immunopositive for neuron-specific enolase and synaptophysin.2,9,11 Results of an immunohistochemical study of 25 chemodectomas in dogs indicated that 14 (56%) tumors expressed chromogranin A, whereas only 1 (4%) was positive for S100.10
In the case described in the present report, the concurrent cortical adenoma was considered an odd finding, and reports of extra-adrenal paragangliomas with concurrent cortical adenomas in dogs were not found on review of the veterinary medical literature. One consideration was that it could have been a component of multiple neuroendocrine neoplasia (typically associated with chemodectomas), although the location of the mediastinal mass (outside the pericardial sac and more cranial in the mediastinum), compared with locations of typical chemodectomas, made chemodectoma less likely. The mediastinal and abdominal masses could also have represented 2 primary tumors (multicentric paraganglioma). The retroperitoneal mass may also have represented metastasis from the primary mediastinal mass; however, this was considered unlikely given the histologic features of the contiguous ganglion.
References
1. Ilha MR, Styer EL. Extra-adrenal retroperitoneal paraganglioma in a dog. J Vet Diagn Invest 2013;25:803–806.
2. Rizzo SA, Newman SJ, Hecht S, et al. Malignant mediastinal extra-adrenal paraganglioma with spinal cord invasion in a dog. J Vet Diagn Invest 2008;20:372–375.
3. Reusch CE. Pheochromocytoma and multiple endocrine neoplasia. In: Feldman EC, Nelson RW, Reusch CE, et al, eds. Canine and feline endocrinology and reproduction. 4th ed. St Louis: Saunders, 2015;546–547
4. Mascort J, Pumarola M, Altman NH, et al. Posterior mediastinal paraganglioma spinal cord of a dog. J Small Anim Pract 1995;36:274–278.
5. Disick GI, Palese MA. Extra-adrenal pheochromocytoma: diagnosis and management. Curr Urol Group 2007; 8:83–88.
6. Locke-Bohannon LG, Mauldin GE. Canine pheochromocytoma: diagnosis and management. Compend Contin Educ Pract Vet 2001;23:807–815.
7. Couturier L, Guillaumot P, Duboy J, et al. Paraganglioma of a presumed celiac ganglion in a dog. Flem Vet Mag 2014;83:73–77.
8. Hines ME II, Newton JC, Altman NH, et al. Metastasizing extra-adrenal paraganglioma with neurological signs in four dogs. J Comp Pathol 1993;108:283–290.
9. Deim Z, Szalay F, Glávits R, et al. Carotid body tumor in dog: a case report. Can Vet J 2007;48:865–867.
10. Brown PJ, Rema A, Gartner F. Immunohistochemical characteristics of canine aortic and carotid body tumours. J Vet Med A Physiol Pathol Clin Med 2003;50:140–144.
11. Doss JC, Grone A, Capen CC, et al. Immunohistochemical localization of chromogranin a in endocrine tissues and endocrine tumors of dogs. Vet Pathol 1998;35:312–315.
