JPC SYSTEMIC PATHOLOGY
 CARDIOVASCULAR SYSTEM

February 2025

C-N02 (NP)

 

Signalment (JPC #2630322): Old military working dog

 

HISTORY: This dog had a mass on the right atrium of the heart.

 

HISTOPATHOLOGIC DESCRIPTION: Heart, right atrium: Expanding the myocardium and replacing 80% of cardiac myocytes is an unencapsulated, poorly circumscribed, poorly demarcated, moderately cellular, infiltrative neoplasm composed of spindle cells that form irregular, variably sized, blood-filled vascular channels, often wrap collagen, and rarely form streams, bundles, or more solidly cellular areas. Neoplastic cells have often indistinct cell borders, a moderate amount of eosinophilic, fibrillar cytoplasm, and an irregularly oval to elongate nucleus that occasionally bulges into vascular channels with coarsely clumped chromatin and up to 2 distinct nucleoli. Mitoses average 3-7 per 2.37 mm². Anisokaryosis and anisocytosis are marked. Adjacent cardiac myocytes are swollen and pale (degenerate) or shrunken and hypereosinophilic with pyknotic nuclei (necrotic).There are few fibrin thrombi, scattered single cell necrosis, and scattered aggregates of lymphocytes, plasma cells, hemosiderin-laden macrophages, and intact and necrotic neutrophils. Surrounding the neoplastic cells is abundant hemorrhage, large coalescing areas of bright eosinophilic polymerized fibrin admixed with small amounts of necrotic debris, “canary-yellow” hematoidin crystals, and low numbers of hemosiderin laden macrophages. 

 

MORPHOLOGIC DIAGNOSIS: Heart, right atrium: Hemangiosarcoma, breed not specified, canine.

 

GENERAL DISCUSSION:

• Malignant neoplasm arising from vascular endothelium; overt metastasis is present in greater than 80% of dogs at clinical presentation
• Mean age of occurrence ranges from 6 to17 years in dogs
• Anatomic presentations of hemangiosarcoma:
  • Multicentric disease (i.e. visceral hemangiosarcoma): hemangiosarcoma often presents as multicentric disease involving spleen, liver, right atrium/auricle, and lungs of dogs; highly aggressive, poor prognosis
    • German shepherds are most commonly affected with multicentric disease, although any large breed dog appears to be at increased risk
    • Most common primary neoplasm of the heart in dogs
  • Skeletal hemangiosarcoma: Hemangiosarcoma occasionally presents as a primary, aggressive bone tumor with bone destruction and pathologic fracture
  • Must differentiate from the telangiectatic osteosarcoma and aneurysm (must demonstrate features of malignancy in endothelial cells)
  • Cutaneous or subcutaneous tumors not uncommon in dogs; these may be solitary or part of the multicentric disease; canine dermal hemangiosarcomas may be solar induced; lightly pigmented, sparsely haired breeds are at increased risk; must differentiate from hemangioma; less aggressive, longer survival times than visceral counterpart
  • Skeletal muscle: Hemangiosarcoma also may arise in skeletal muscle

 

PATHOGENESIS:

• Controversy over whether multicentric hemangiosarcoma is of true multicentric origin or one primary tumor with metastasis
• Mutations of the C-terminal domain of PTEN (phosphatase and tensin homolog gene on chromosome 10) have been identified in naturally-occurring canine hemangiosarcomas
• Increasing numbers of growth factors are found to be over expressed, and may be a target for future therapy:
  • CD 117 (C-Kit) and VEGF 3 are overexpressed in hemangiosarcoma
• Recent study of 11 canine hemangiosarcomas found that neoplastic cells expressed CD34, CD31, VEGF-R2, FVIII-related antigen, CD14, and p53, with variable expression of CD117 and CD133; this suggests neoplastic cells in canine hemangiosarcoma may arise from endothelial progenitor cells with hematopoietic origin rather than differentiated endothelial cells (Kakiuchi-Kiyota S et al, Toxicol Pathol, 2020)
• Nuclear factor kappa B (NF-kB) transcription factor overactivation is common in several human cancers, and there is evidence that similar signaling aberrations also occur in canine cancers including lymphoma, leukemia, hemangiosarcoma, mammary cancer, melanoma, glioma, and prostate cancer (Schlein LJ et al, Vet Pathol, 2022)

 

TYPICAL CLINICAL FINDINGS:

• Signs of right heart failure (abdominal distension, jugular pulses) caused by cardiac tamponade
• Severe arrhythmias may cause syncope, ataxia, and cyanosis
• Rupture of atrial hemangiosarcoma can lead to fatal hemopericardium

 

TYPICAL GROSS FINDINGS:

• Dark red mass; may be fluctuant or cystic
• Blood runs freely from cut surface
• In the heart, occurs subepicardially in the wall of right atrium at entrance to the auricle near coronary groove or in the atrial appendage (i.e. auricle)
• Most common sites (dogs): spleen, skin, right atrium, liver
  15. When the CNS is affected by metastasis, grossly there are many scattered pinpoint to larger and variably shaped dark red hemorrhages both on the surface of the brain and spinal cord and following sectioning (Marr, J et al, Vet Pathol, 2021)
• Splenic hemagiosarcoma: Often hemorrhagic, making it difficult for identification

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Spindle to polygonal to ovoid neoplastic cells that usually form vascular channels, spaces, or small clefts somewhere in the tumor
• Pleomorphic, hyperchromatic nuclei that often bulge into the lumina of vascular channels (“hob-nail”)
• Frequent mitotic figures; hemorrhage and necrosis; collagen wrapping
• Large solid areas may be difficult to distinguish from poorly differentiated sarcomas
• Unencapsulated, invasive neoplasms typically form variably sized, irregularly shaped blood vascular spaces that are separated by thin septa or more solid areas, are often traversed by slender trabeculae, and contain blood

 

ULTRASTRUCTURE:

 

ADDITIONAL DIAGNOSTIC TESTS:

• IHC: Recommend panel of endothelial and angiogenic factors, especially in poorly differentiated hemangiosarcomas 
  • Endothelial markers: ERG, Factor VIII-related antigen (von Willebrand factor), claudin-5, and CD31 (platelet-endothelial cell adhesion molecule/PECAM), 
  • Angiogenic factors: VEGF-A or Ang-2
• CD206-/CD204-positive cells significantly higher within tumor hot spots and in the tumor tissue outside of hot spots than in the surrounding normal tissues (in dogs with HSA, regardless of location) (Kerboeuf M, et al. Vet Pathol, 2024)

 

DIFFERENTIAL DIAGNOSIS:

Gross masses in or near the heart:

• Aortic or carotid body tumor (chemodectoma/paraganglioma/glomus tumor, E-N11): Arises in aortic body (more common in animals), carotid body (more common in humans), or ectopic thyroid or parathyroid tissue; white, firm mass at the base of the heart 
• Rhabdomyoma/rhabdomyosarcoma: Rare in all species; gray nodules that often project into cardiac chambers
• Malignant lymphoma: Most common metastatic tumor involving the heart; nodular or diffuse, white, fleshy mass that resembles deposits of fat
• Granular cell tumor/granular cell myoblastoma: Described in right atrium of a dog, but is usually seen in brain, meninges (rat especially), lung (horse), tongue
• Pericardial mesothelioma (P-N06)
• Myxoma/myxosarcoma Most common cardiac tumor in adult humans, rare in animals; multilobular, soft and gelatinous
• Chondrosarcoma: Arises from cartilaginous or like-tissue of cardiac skeleton
• Osteosarcoma
• Fibroma/fibrosarcoma
• Lipoma
• Neurofibroma/Schwannoma (C-N01): Seen in cattle as single or multiple white nodules

 

Histologic differential diagnosis for vascular proliferations: 

• Hemangioma: Well circumscribed neoplasm, vascular spaces are lined by a single layer of uniform endothelial cells and are filled with erythrocytes 
• Hematoma: Can arise within a hemangiosarcoma, and obscure the sarcoma both grossly and histologically, especially within the canine spleen; lymphoid hyperplasia has been shown to be associated with splenic hematoma but not in hemangiosarcoma
• Vascular hamartoma: An improper proliferation of normal blood vessels; endothelial cells are surrounded by tunica media and tunica adventitia 
• Kaposi-like vascular tumor: Well-circumscribed neoplasm with angular slit-like vascular spaces with few erythrocytes surrounded by large cavernous vascular spaces, lymphocytes, and a thick fibrous capsule (this tumor is named for its similar histologic appearance to the human Kaposi sarcoma and has NO association with human herpes virus 8 or immunosuppression) 
• Lymphangiosarcoma: Vascular channels containing few erythrocytes
• Granular cell tumor/granular cell myoblastoma: Spindle to polygonal with granular cytoplasm; S-100+, PAS+ and diastase resistant

 

COMPARATIVE PATHOLOGY:

Hemangiosarcoma in other species:

• Cats
  • Most common sites: spleen, intestine, subcutaneous tissues; other primary locations include liver, mesentery, omentum 
  • Incidence of cutaneous involvement appears to be on the rise; the head (especially eyelids), distal limbs, and paws are most often affected
• Sheep: Report of hepatic hemangiosarcoma
• Horse: Uncommon
• Cow: Rare reports
• Snake: Hemangiosarcomas of the heart and spleen have been reported in colubrids; neoplastic cells in a cardiac hemangiosarcoma of a giant hognose snake were immunopositive for factory VIII-related antigen

 

REFERENCES:

1. Cooper BJ, Valentine BA. Muscle and Tendon. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. St Louis, MO: Elsevier; 2016: 244-245.
2. Craig LE, Dittmer KE, Thompson KG. Bones and Joints. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. St Louis, MO: Elsevier; 2016:122.
3. Gal A, Castillo-Alcala F. In: Zachary JF, ed. Cardiovascular System, Pericardial Cavity, and Lymphatic Vessels. In: Pathologic Basis of Veterinary Disease, 7th ed. St. Louis, MO: Elsevier; 2022:667, 676, 680, 691, 693-4. 
4. Kakiuchi-Kiyota S, Obert LA, Crowell DM, et al. Expression of hematopoietic stem and endothelial cell markers in canine hemangiosarcoma. Toxicol Pathol. 2020;48(3):481-493.
5. Kerboeuf M, Haugeberg DA, Olsen T, et al. Tumor-associated macrophages in canine visceral hemangiosarcoma. Vet Pathol. 2024;61(1):32-45.
6. Marr J, Miranda IC, Miller AD, Summers BA. A Review of Proliferative Vascular Disorders of the Central Nervous System of Animals. Vet Pathol. 2021;58(5):864-880.
7. Ossiboff RJ. Serpentes. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. San Diego, CA:Elsevier. 2018:908.
8. Robinson WF, Robinson NA. Cardiovascular System. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. St Louis, MO: Elsevier; 2016:98-101.
9. Roccabianca P, Kiupel M, eds. Surgical Pathology of Tumors of Domestic Animals, Volume 3: Tumors of Soft Tissue. Gurnee, IL:Davis-Thompson Foundation. 2020:149-200.
10. Schlein LJ, Thamm DH. Review: NF-kB activation in canine cancer. Vet Pathol. 2022;59(5):724-732.
11. Valli VE, Bienzle D, Meuten DJ. Tumors of the Hemolymphatic System. In: Meuten J, ed. Tumors in Domestic Animals. 5th ed. Ames, Iowa: Iowa State Press; 2017:309-313.

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