JPC SYSTEMIC PATHOLOGY
ENDOCRINE SYSTEM
February 2022
E-N11

Signalment (JPC #1965139):  11-year-old castrated male German shorthair pointer

HISTORY:  None provided

SLIDE A: HISTOPATHOLOGIC DESCRIPTION:  Fibroadipose tissue: Extending to all borders and compressing adjacent adipose tissue is a partially encapsulated, multilobular, densely cellular, infiltrative neoplasm composed of polygonal cells arranged in nests and packets supported by a thin rim of sustentacular cells and fine fibrovascular stroma, with lobules separated by dense bands of fibrovascular connective tissue.  Neoplastic cells have indistinct borders, a moderate amount of pale eosinophilic, frequently vacuolated, granular cytoplasm, and round nuclei with coarsely stippled chromatin and 1-2 variably distinct nucleoli. There is moderate anisocytosis and anisokaryosis; occasional neoplastic cells have large, multilobed nuclei (tumor giant cells). The mitotic count is 1 per 2.37mm² (10 high power fields). There are scattered areas of lytic necrosis characterized by loss of tissue architecture and replacement by eosinophilic cellular and karyorrhectic debris, scattered foci of coagulative necrosis characterized by retention of architecture with loss of differential staining, and individual cell death characterized by hypereosinophilic cytoplasm and nuclear pyknosis, karyorrhexis, and karyolysis. There are variably sized foci of mineral and acicular (cholesterol) clefts. Neoplastic cells multifocally impinge on vessel walls. There are multifocal peripheral infiltrates of lymphocytes, plasma cells, and macrophages (often hemosiderin-laden), as well as scattered hemorrhage, fibrin, edema, congestion, and accumulations of hematoidin pigment.

SLIDE B: (Churukian-Schenk):  The cytoplasm of neoplastic cells contains many discrete, brown to black, argyrophilic granules.

MORPHOLOGIC DIAGNOSIS:  Fibroadipose tissue:  Chemodectoma, German shorthair pointer, canine.

SYNONYMS:  Aortic/carotid body tumor, paraganglioma, nonchromaffin paraganglionoma, extra-adrenal paraganglionoma, glomus cell tumor

GENERAL DISCUSSION:

• Chemodectoma/paraganglioma is a tumor of nonchromaffin, extra-adrenal paraganglia cells (chemoreceptor cells) and may occur throughout the body where there are sympathetic and parasympathetic ganglia (i.e. head, neck, thorax, abdomen)
  • Brachycephalic breeds (e.g. boxers and Boston terriers) appear predisposed
  • Most affected dogs are >8 years of age; higher incidence in males
• Chemoreceptors are composed of parenchymal (chemoreceptor and glomus) cells and sustentacular/stellate cells (i. support cells)
  • Chemoreceptor organs: responsible for detecting and responding to changes in CO2, pH, and oxygen tension; aid in regulation of respiration and circulation
  • Carotid and aortic bodies: subset of chemoreceptor organs; initiate an increase in the depth, minute volume, and rate of respiration via parasympathetic nerves, resulting in an increased heart rate and arterial blood pressure via the sympathetic nervous system
• Aortic body tumors are more common than carotid body tumors
• Carotid body tumors are more likely to be malignant than are aortic body tumors
• There is a distinction between tumors of chromaffin (ganglia of the sympathetic trunk) and non-chromaffin paraganglia; paragangliomas of chromaffin origin may be referred to as extra-adrenal pheochromocytomas
• Clear delineation between benign and malignant is not always possible; two most definitive criteria are documented metastases or invasion (grossly or microscopically)

PATHOGENESIS: 

• Unknown etiology; suggested genetic predisposition that is aggravated by chronic oxygen hypotension (brachycephalic dog breeds, humans and animals living at high altitude)
  • Genetic pathogenesis is similar to pheochromacytomas – HIF1 pathway, MAPK/mTOR pathway, and hypermethylation/mutation of SDHx genes
• Nonfunctional neoplasm acts as a space-occupying lesion; larger aortic body adenomas and carcinomas may cause cardiac decompensation due to pressure on atria, vena cava, or both

TYPICAL CLINICAL FINDINGS: 

• Signs result from pressure on atria and/or vena cava:
  • Hydropericardium, hydrothorax, edema
  • Dyspnea, cyanosis, coughing
• Carotid body tumors may present as a slow-growing, palpable mass near angle of mandible; larger masses may cause dysphagia due to esophageal compression
• Dyspnea and cough reported in dogs with multiple pulmonary metastases of malignant carotid body tumors

TYPICAL GROSS FINDINGS:

• Aortic body tumors most often single masses within pericardial sac near heart base; considerable size variation from 0.5 to >12cm:
  • Adenoma: Single or multiple nodules, smooth surface, white mottled with red-brown hemorrhage; attached to adventitia of pulmonary artery or ascending aorta or embedded within adipose connective tissue separating these vessels; larger adenomas may partially surround great vessels at the base of the heart; little evidence of vascular invasion
  • Carcinoma: Larger than adenoma, locally invades heart and great vessels at heart base; can form papillary projections into lumen of pulmonary artery, metastasis to lung and liver; variably attached large mural thrombus
• Carotid body tumors arise near bifurcation of common carotid artery in cranial cervical area; more often malignant with more frequent metastasis:
  • Adenoma: Approximately 1 to 4 cm in diameter, unilateral, single, smooth, firm, encapsulated, white mottled with red-brown hemorrhage; attached to the carotid artery adventitia and can entrap the glossopharyngeal nerve
  • Carcinoma: Larger than adenoma (up to 12 cm in diameter), multinodular, hemorrhagic, cystic; may incorporate external jugular vein and cranial nerves; may deviate trachea; metastasis to lung, bronchial and mediastinal lymph nodes, liver, pancreas, kidney
• Multicentric neoplastic transformation of chemoreceptor tissue is common in brachycephalic breeds; 65% of carotid body tumor cases also have aortic body tumors

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Adenoma:
  • Multiple lobules of discrete cuboidal to polygonal cells divided by connective tissue trabeculae originating from the capsule with further subdivision into nests and packets by fine fibrovascular septa
  • Uniform, round to oval, central nuclei with finely granular chromatin
  • Mitoses infrequent; little cellular pleomorphism
• Carcinomas:
  • Tumor invasion through the capsule into walls of large muscular arteries, atria, tracheal bifurcation, and/or pericardium
  • Arranged in broad sheets with less distinctive nests and packets
  • Pleomorphic, hyperchromatic cells with frequent mitoses
• Mononuclear tumor giant cells with bizarre, multilobed nuclei are more common in carcinomas; not a criteria of malignancy as these may be also be found in adenomas
• Abundant eosinophilic, granular to vacuolated cytoplasm and indistinct cell borders
• Cells undergo rapid autolysis
• Well-vascularized; frequent hemorrhage, coagulative necrosis, cholesterol clefts, and mineralization

ULTRASTRUCTURAL FINDINGS:

• Clusters of polyhedral cells lacking normal orientation to sustentacular, neural, and vascular elements
• Variable cytoplasmic density due to variation in number of electron dense, membrane-bound secretory granules (granules more numerous in adenomas than in carcinomas); the granules in chemodetomas are endocrine secretory granules and NOT chromaffin granules (as seen in pheochromocytoma)
• Stellate (sustentacular cells) have long cytoplasmic processes that surround tumor cells and terminate near perivascular spaces

ADDITIONAL DIAGNOSTIC TESTS:

• Argyrophilic cytoplasmic granules (positive Churukian-Schenk or Grimelius)
• In contrast to pheochromocytomas, chemodectomas lack chromaffin granules
• IHC: inconsistently positive for synaptophysin, S-100, and neuron specific enolase; positive for chromogranin A

DIFFERENTIAL DIAGNOSIS: 

For gross finding of heart base tumor:

• Ectopic thyroid adenoma (white-tan, solid nodules) or carcinoma (multinodular, necrotic and hemorrhagic) - ectopic thyroid tumors with a compact cellular (solid) pattern are challenging to differentiate histologically; best ways to differentiate are to search for thyroid follicles and IHC(positive for TTF-1 and thyroglobulin); EM (lack secretory granules and have numerous microvilli on luminal surfaces); cells are smaller with more eosinophilic cytoplasm and hyperchromatic nuclei, follicles with colloid may be present and positive with thyroglobulin IHC; tumor giant cells are infrequent in ectopic thyroid tumors
• Ectopic parathyroid chief cell adenoma: Light brown to red, encapsulated; differentiate with IHC (positive for calcitonin)
• Malignant lymphoma: Most commonly involves right atrium, either nodular with a pale, flesh-like appearance or diffuse causing an irregular, thickened and gray myocardium
• Hemangiosarcoma: Most commonly involves right atrium; gray to red-black
• Thymoma: Cranial mediastinum

COMPARATIVE PATHOLOGY:

• Carotid body tumors have been reported in dogs, cats, cattle, and mink
• Aortic body tumors have been reported in dogs, cats, cattle, and birds
• Horses: Unique orbital paraganglioma where neoplastic cells locally invade retrobulbar tissue causing exophthalmos
• Humans: Carotid body tumors are more common than aortic body tumors

REFERENCES:

1. Holt DE, Henthorn P, Howell VM, Robinson BG, Benn DE. Succinate dehydrogenase subunit D and succinate dehydrogenase subunit B mutation analysis in canine pheochromacytoma and paraglanglioma. J Comp Pathol 2014; 151:25-34.
2. Miller LM, Gal A. Cardiovascular system and lymphatic vessels. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:592.
3. Miller MA. Endocrine system. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:692.
4. Romanucci M, Malatesta D. Cytological, histological and ultrastructural nuclear features of monster cells in canine carotid body carcinoma. J Comp Pathol. 2014; 151:57-62.
5. Rosol TJ, Grone A. Endocrine glands. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. St. Louis, MO: Elsevier; 2016:354-356.
6. Rosol TJ, Meuten DJ. Tumors of the endocrine glands. In: Meuten DJ, ed. Tumors in Domestic Animals. 5^th Ames, IA: John Wiley & Sons; 2017: 828-832.
7. Williams BH, Burek Huntington KA, Miller M. Mustelids. In: Terio K, McAloose D, Leger J, eds. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018: 294.
8. Yamamoto S, Fukushima R. Histopathological and Immunohistochemical evaluation of malignant potential in canine aortic body tumours. J Comp Pathol. 2013; 149:182-191.

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