Canine Hemangiosarcoma

Rebecca Fankhauser, DVM; Bruce E. LeRoy, DVM, PhD; Heather L. Tarpley, DVM; Perry J. Bain, DVM, PhD; Melanie A. Johnson, DVM; Kenneth S. Latimer, DVM, PhD

Class of 2004 (Fankhauser) and the Department of Pathology (LeRoy, Tarpley, Bain, Johnson, Latimer), College of Veterinary Medicine, University of Georgia, Athens, GA 30602-7388

Introduction

Splenic masses and splenomegaly are commonly diagnosed on physical examination and abdominal survey radiographs in dogs. Hemangiosarcoma (HSA) is the most common splenic tumor of dogs, accounting for 51 to 66% of all splenic neoplasms.^4,16,17 Most studies have shown that one-half to two-thirds of splenic masses are neoplastic and are likely to be HSA (Fig. 1).¹⁹ These proportions were reported in one study, but more recent studies have shown that this estimate may be somewhat elevated. Three studies reported that 44 to 48 % of canine splenic masses were diagnosed histologically as neoplastic, and that 44 to 51% of these neoplasms were diagnosed as HSA.^4,8,16,17 Regardless of the true prevalence of HSA in dogs, these neoplasms are very aggressive and generally have a poor prognosis.^15,19

Figure 1. Spleen of a dog with hemangiosarcoma. Multiple raised masses are present. Image courtesy of Noah's Arkive, University of Georgia.

HSA occurs most frequently in older dogs with a mean age between 8 and 13 years.¹⁹ It occurs most commonly in large breed dogs.¹⁹ German Shepherd Dogs are the most commonly affected breed, followed by Golden Retrievers and Labrador

Retrievers.^{1,2,6,8,13,14,16} Other commonly affected breeds of dogs include Pointers, Boxers, English Setters, Great Danes, Poodles and Siberian Huskies.¹⁵ There is no clear sex predilection. Cutaneous hemangiosarcomas are more common in poorly pigmented breeds and dogs with light hair, including Beagles, Bloodhounds, white English Bulldogs, English Pointers, Salukis, Dalmatians, and Whippets.¹⁵

HSA is a malignant neoplasm of vascular endothelial origin that is characterized by early and aggressive metastasis.^15,19 This neoplasm can arise in any tissue with blood vessels but the spleen is the most common site of tumor development in the dog, accounting for 50 to 65% of all canine HSAs.¹⁵ HSA is the most common canine primary cardiac tumor (Fig. 2). Tumors of the right atrium account for 3 to 25% of all HSAs in the dog.¹⁵ Other common sites include subcutaneous tissues (13 to 17%) and the liver (5 to 6%).¹⁵

Figure 2. Heart of a dog with hemangiosarcoma. Multiple raised masses are present. Image courtesy of Noah's Arkive, University of Georgia.

Other primary sites of tumor origin that have been reported in the dog include the skin, lung, aorta, kidney, oral cavity, muscle, bone, urinary bladder, intestine, tongue, prostate, vulva/vagina, conjunctiva and peritoneum.¹⁵ Noncutaneous HSAs are aggressively metastatic, with greater than 80% of cases having metastasis at the time of clinical diagnosis.¹⁹ HSA tends to metastasize through hematogenous or transabdominal implantation and the most frequent metastatic sites are the liver, omentum, mesentery and lungs (Fig 3 A and B).¹⁹ Splenic HSAs metastasize to omentum, mesentery, and other abdominal organs, whereas right atrial HSA is more likely to metastasize to the lungs.⁶ Other reported sites of metastasis include kidney, muscle, peritoneum, lymph nodes, bone, adrenal glands, eye, prostate, brain and diaphragm.^15,19

Figures 3A & 3B. Reddish to blue-black metastases of hemangiosarcoma to the liver (A) and lungs (B) of a dog. Image courtesy of Noah's Arkive, University of Georgia.

Cutaneous HSAs have been associated with ultraviolet light exposure in dogs and often arise on the ventral abdomen and prepuce, where the hair coat is sparse.^15,18 In contrast to visceral HSAs, cutaneous HSAs have a low incidence of metastasis.¹⁸

Clinical Signs

Clinical signs will vary depending on the location of the primary tumor and can range from sudden death to very vague symptoms. Sudden death via hemorrhage can occur from rupture of a cardiac or visceral neoplasm or from acute blood loss into a body cavity.¹⁹ More subtle clinical signs associated with visceral masses may include weakness, abdominal distention, tachycardia, tachypnea, mucous membrane pallor and weight loss.¹⁹ Often there will be a history of episodic weakness or acute collapse followed by gradual recovery.¹⁵ These clinical signs are associated with episodic acute hemorrhage from a visceral mass followed by clinical recovery as the blood is reabsorbed from the body cavity.¹⁵

If the primary mass is associated with the heart, pericardial effusion may develop and may lead to cardiac tamponade.¹⁹ This will present as right-sided heart failure and clinical signs may include abdominal distention, jugular pulses, muffled heart sounds, and dyspnea.^15,19 Arrhythmias also may occur (see below) and may cause syncope, ataxia and cyanosis in some cases.¹⁵

Other clinical presentations will vary greatly depending on the site of the primary tumor. Subcutaneous masses in critical areas may cause lameness. Osseous tumors can cause lameness secondary to pathological fractures or bone pain and vertebral HSA can cause pain or paresis.¹⁵ HSA in the urinary tract or nasal cavity may present as hematuria or epistaxis, respectively.¹⁵ Seizures may be the presenting complaint with metastasis to the brain.¹⁵ Hemorrhage or petechiae of mucous membranes may occur in dogs that develop disseminated intravascular coagulation (DIC).¹⁵

Diagnostic Testing

HSA is often suspected based on breed, age, clinical signs, history and physical examination. Other tests that may provide further support of this presumptive diagnosis include complete blood count (CBC), serum chemistry profile, abdominocentesis (although the presence of neoplastic cells is infrequent), coagulation profile, three-view thoracic radiographs, abdominal radiographs, abdominal ultrasound, echocardiogram and electrocardiography. These diagnostic tests can also be used to clinically stage the severity of disease.^15,19 This system uses the size, site and character of the primary tumor, and whether the cancer has spread to the regional lymph nodes or undergone metastasis to distant sites to categorize the disease into one of three clinical stages.¹⁹ However, there is no proven difference in median survival times between different stages of disease, so patients with HSA are not always fully staged.^2,8

Clinical Pathology Abnormalities

HSA may cause a regenerative anemia via intracavitary hemorrhage or microangiopathic hemolysis.¹⁹ The CBC may reveal evidence of a regenerative anemia, including anisocytosis, polychromasia, increased red blood cell distribution width and reticulocytosis.¹⁵ Acanthocytosis has also been associated with HSA.^6,13 Schistocytes may be present in cases of microangiopathic hemolysis.¹⁵ Large splenic masses are often associated with extramedullary hematopoiesis. Therefore, metarubricytosis (increased nucleated red blood cell in the circulating blood) may be observed in the peripheral blood smear. This is one of the more reliable predictors of neoplasia when a splenic mass is present.^8,15 A neutrophilic leukocytosis, caused by stress, tumor necrosis, or nonspecific bone marrow response also may be present.¹⁵ Thrombocytopenia is a common finding, occurring in 30 to 75% of dogs with HSA, and may be due to immune-mediated processes, platelet sequestration, severe hemorrhage or DIC.^5,15 HSA also may cause DIC via tissue necrosis secondary to rapid tumor growth and pooling of blood in the vascular channels of the tumor.⁷ These situations are associated with the release of tissue thromboplastin, activating the extrinsic clotting cascade.⁷ DIC may occur in up to 34% of dogs with HSA.^5,15 This condition is characterized by thrombocytopenia, prolonged activated partial thromboplastin time, prolonged one-stage prothrombin time, prolonged thrombin clotting time, hypofibrinogenemia, decreased anti-thrombin III concentration, and excessive production of fibrin(ogen) degradation products (FDPs) or D-dimers.¹⁵

The serum chemistry profile test results may be within reference intervals in dogs with HSA or may reflect specific organ system involvement. For example, serum alkaline phosphatase and alanine transferase activities may be elevated with either primary hepatic HSA or with metastasis to the liver. Hypoglycemia has also been reported as a paraneoplastic syndrome with HSA.¹²

Diagnostic Imaging

Abdominal radiography and ultrasonography may demonstrate peritoneal effusion secondary to hemorrhage or right heart failure associated with cardiac tamponade.¹⁵ Abdominal radiographs may also be helpful in demonstrating splenomegaly, hepatomegaly, or other intra-abdominal masses consistent with primary or metastatic HSA.¹⁵ Abdominal ultrasonography is valuable in evaluating the primary neoplasm and in detecting metastases.¹⁹ Splenic HSA typically has a mixed or nonhomogenous echo pattern, while hepatic HSA usually appears hypoechoic or anechoic on ultrasound examination.¹⁹ If cardiac involvement is suspected, echocardiography is the best method to detect cardiac masses.^1,19

Three-view thoracic radiographs should be taken to evaluate the lungs for the presence of metastatic disease.^15,19 HSA metastases may consist of either solitary nodules or a diffuse to coalescing military pattern.¹⁹ Thoracic radiographs also can be helpful in demonstrating pleural or pericardial effusion due to hemorrhage or right heart failure.¹⁵ Soft tissue masses at the heart base also may be evident on thoracic radiographs.¹⁵

Electrocardiography

Cardiac arrhythmias may occur with both splenic and cardiac neoplasms.¹⁵ These arrhythmias may occur before, during, or after surgery in cases of splenic or cardiac HSA.^1,11 Up to 39% of dogs with splenic HSA have arrhythmias; up to 25% of all dogs with splenic HSA may have preoperative arrhythmias.^11,15 These arrhythmias are ventricular in origin and include premature ventricular contractions, paroxysmal ventricular tachycardia and ventricular tachycardia.¹¹ Arrhythmias are more frequently associated with splenic disease than with cardiac involvement, but do occur with primary tumors from both sites.^1,11 Pericardial effusion associated with cardiac tumors may result in decreased complex amplitude or electric alternans.¹⁵ An electrocardiogram recording (ECG) is recommended for all dogs with splenic masses prior to anesthesia. Furthermore, ECG monitoring during, and after splenic surgery is recommended.¹¹

Cytology

Abdominocentesis or pericardiocentesis can be performed to provide clinical relief and to obtain a fluid sample for cytologic analysis.¹⁵ Most effusions due to HSA are hemorrhagic, have a high packed cell volume and do not clot.¹⁵ Cytologic examination typically will reveal evidence of fresh or previous hemorrhage.¹⁵ Hemorrhage alone is not an indicator of neoplasia, and idiopathic pericardial effusions also can be hemorrhagic.¹⁵ Neoplastic cells can be seen in the effusion fluid in about 25% of cases and this allows for a presumptive diagnosis of HSA, although false-positive results for malignancy have been reported in up to 13% of cases with this procedure.¹⁵ Neoplastic endothelial cells are large spindle to polyhedral cells. The nucleus is round to oval and contains one or more prominent nucleoli. The cytoplasm appears dark blue and usually contains many small, discrete, nonstaining vacuoles (Fig. 4). Mitoses also may be observed.

Figure 4. Cytologic aspirate of hemangiosarcoma containing pleomorphic neoplastic cells with an oval nucleus, prominent nucleoli, and abundant, blue, finely vacuolated cytoplasm. Wright stain; image courtesy of Noah's Arkive, University of Georgia.

Fine-needle aspiration cytology of masses often is not helpful in diagnosing HSA because the blood that is obtained is typical of hemorrhage and neoplastic endothelial cells are observed infrequently.¹⁵ However, cytologic examination may detect other causes of splenomegaly or masses such as extramedullary hematopoeisis, primary hematopoietic tumors (lymphoma, plasmacytoma), or metastatic disease (carcinoma, mast cell tumor).¹⁵

Histopathology

While all of the above diagnostics will help support a diagnosis of HSA, the definitive diagnosis of HSA often requires biopsy or splenectomy and histopathology.¹⁹ Excisional biopsy is preferred, as it will not only provide tissue specimens, but is also a therapeutic procedure.¹⁵ Splenectomy (surgical removal of the spleen) with submission of the entire organ for gross examination and histopathology is recommended.¹⁵ Alternatively, the spleen may be sectioned like a loaf of bread and multiple samples submitted from different areas of the organ as well.¹⁹ During surgery, biopsies should be taken of any suspicious lesions within the spleen, liver, or omentum and these should be submitted for histopathology as well.¹⁵

Grossly, hemangiosarcomas are of variable size, pale gray to dark red in color, nodular, and soft.¹⁹ They usually contain areas of hemorrhage and necrosis.¹⁹ Histologically HSAs consist of vascular spaces lined by elongated, plump, anaplastic endothelial cells (Fig. 5).¹⁰ The nuclei are large and hyperchromatic, and mitotic figures are often seen.⁹ The neoplastic cells have little cytoplasm and may be arranged in sheets or form irregular vascular spaces that are filled with blood.⁹ The presence of these blood-filled vascular spaces is necessary to distinguish HSAs from fibrosarcomas.¹⁰ In addition, these neoplasms often have evidence of repeated hemorrhage and necrosis.⁹ Poorly differentiated HSA can be difficult to distinguish from fibrosarcoma, but may be differentiated with the use of immunohistochemical staining for Factor VIII- related antigen (von Willebrand's factor), a marker of endothelial cells (Fig. 6).¹⁰ Alternatively, CD31 or monoclonal antibody 3B5 can be used to confirm HSA as these markers are very specific for cells of vascular endothelial origin.¹⁵

Figure 5. Histologic section of an hemangiosarcoma from a dog. Notice the irregular blood filled spaces that are lined by plump, neoplastic, endothelial cells. Hematoxylin and eosin stain; image courtesy of Noah's Arkive, University of Georgia.	Figure 6. Immunohistochemical staining for factor VIII related antigen (brown color) identifies neoplastic endothelial cells of an hemangiosarcoma. Image courtesy of Noah's Arkive, University of Georgia

Treatment

Surgical intervention traditionally has been the treatment of choice for dogs with HSA.^3,19 Surgical removal of a bleeding mass provides relief from clinical signs for a period of time, although it does little to improve overall survival time.^3,15 Unfortunately, many cases of HSA already have metastasized by the time they are clinically evident. Splenectomy is performed for splenic HSA.¹⁹ For cardiac tumors, surgical resection of right auricular masses is possible in some cases to palliate a bleeding tumor while pericardectomy may help relieve the clinical signs of cardiac tamponade.¹⁵

Cutaneous and subcutaneous HSA can be removed surgically with wide margins of excision.¹⁵ Other primary or secondary HSA also may be surgically removed depending on the location of the neoplasm.¹⁵ Amputation can be performed for bone tumors of the extremities, nephrectomy for renal tumors, and partial cystectomy can be performed to remove a bladder tumor.¹⁵ However, all primary locations except superficial cutaneous tumors have a poor long-term prognosis and surgery is only for palliative purposes in most instances.¹⁵

Due to the poor prognosis of visceral HSA following attempted surgical resection, chemotherapy has become a principal component of treatment.³ Doxirubicin has the greatest chemotherapeutic efficacy against canine HSA and has been used as both a single agent and in combination with vincristine and cyclophosphamide.^3,15 Survival times seem to be similar when comparing doxorubicin alone versus combination chemotherapy.¹⁵ Alternate routes of administration of chemotherapy, including inhalation and intra-abdominal administration are being investigated in dogs and have shown some promise in increasing survival times with no increase in drug toxicity.³

Immunomodulator therapy has been investigated and seems to be useful in prolonging survival times, especially in combination with chemotherapy.¹⁵ Immunomodulator therapy involves the nonselective activation of cells of macrophage lineage into a tumorcidal state.³ Both a mixed bacterial vaccine and liposome-encapsulated muramyl tripeptide (L-MTP) have been used to treat HSA and have been associated with increased median survival times compared with those achieved with surgery alone.¹⁵ Survival times were increased even further when chemotherapy also was added to the treatment regimen.¹⁵

Radiation therapy is rarely used to treat HSA since the tumor is generally considered a systemic rather than localized disease.^15,19 However, palliative radiation has been used to control superficial bleeding masses that cannot be resected surgically and to relieve pain associated with osseous neoplasms.¹⁵ This treatment may help to control clinical signs but has not been shown to significantly improve survival time.^15,19

Prognosis

The prognosis for patients with splenic HSA is poor despite aggressive surgical, drug, or radiation therapy.^15,19 Median survival times for splenic HSA treated with surgery alone range from 19 days to 3 months; a one-year post-treatment survival rate for dogs is less than 10%.^{2,3,8,14,15,16,19} Chemotherapy either with a single agent doxorubicin protocol or with a combination drug protocol following splenectomy has been reported to increase the median survival time to 140 to 202 days.^3,19 Addition of immunotherapy (L-MTP) reportedly increased survival to a median of 273 days in one study¹⁹.

The prognosis for cardiac HSA also is poor despite therapeutic attempts. The reported mean survival times of dogs with cardiac HSA that underwent surgical therapy alone ranged from 3 to 5 months.^1,3,19

Cutaneous HSAs have a better prognosis than all other primary sites of tumor origin. One study of surgically-treated cutaneous HSAs had a median survival time of 780 days.¹⁸ In this same study, HSA that had invaded the subcutaneous tissues and muscle had a median survival time of 172 and 307 days, respectively.¹⁸ Chemotherapy may be warranted with HSA that invades either the subcutaneous tissues or muscle.¹⁸

The Future

While the current prognosis for dogs with non-cutaneous HSA is poor despite the type of treatment even with treatment, many new treatment regimens such as angiogenesis inhibitors and dietary therapy are being investigated in the hope that they may help improve survival times of affected patients.³ New diagnostic aids also are being investigated for early detection of HSA so treatment may be instituted prior to development of overt clinical signs or grossly detectable disease.³ Eventually, these investigations may result in improved diagnosis and treatment of HSA, increased patient mean survival time and improved quality of life for patients with HSA.³

References

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2. Brown NO, Patnaik AK, MacEwen EG. Canine hemangiosarcoma: Retrospective analysis of 104 cases. J Am Vet Med Assoc 186:56-58, 1985.

3. Clifford CA, Mackin AJ, Henry CJ. Treatment of canine hemangiosarcoma: 2000 and beyond. J Vet Intern Med 14:479-485, 2000.

4. Day MJ, Lucke VM, Pearson H. A review of pathological diagnoses made from 87 canine splenic biopsies. J Small Anim Pract 36:426-433, 1995.

5. Hammer AS, Cuoto CG, Swardson C, Getzy D. Hemostatic abnormalities in dogs with hemangiosarcoma. J Vet Intern Med 5:11-14, 1991.

6. Hirsch VM, Jacobsen J, Mills JH. A retrospective study of canine hemangiosarcoma and its association with acanthocytosis. Can Vet J 22:152-155, 1981.

7. Hosgood G. Canine Hemangiosarcoma. Comp Cont Educ Small Anim Prac 13:1065-1076, 1991.

8. Johnson KA, Powers BE, Withrow SJ, Sheetz MJ, Curtis CR, Wrigley RH. Splenomegaly in dogs, predictors of neoplasia and survival after splenectomy. J Vet Intern Med 3:160-166, 1989.

9. Jones TC, Hunt RD, King NW (eds). Veterinary Pathology, 6^th ed. Williams and Wilkins, Baltimore, 1997, pp. 944, 1024-5, 1103.

10. Jubb KVF, Kennedy PC, and Palmar N (eds): Pathology of Domestic Animals, 4^th ed, vol 3. Acdemic Press Inc, San Diego, 1993, p. 99.

11. Knapp DW, Aronsohn MG, Harpster NK. Cardiac arrhythmias associated with mass lesions of the canine spleen. J Am Anim Hosp Assoc 29:122-128, 1993.

12. Leifer CE, Peterson ME, Matus RE, Patnaik AK. Hypoglycemia associated with nonislet cell tumor in 13 dogs. J Am Vet Med Assoc 186:53-55, 1985.

13. Ng CY, Mills JN. Clinical and haematological features of haemangiosarcoma in dogs. Aust Vet J 62:1-4, 1985.

14. Prymak C, McKee LJ, Goldschmidt MH, Glickman LT. Epidemiologic, clinical, pathologic, and prognostic characteristics of splenic hemangiosarcoma and splenic hematoma in dogs: 217 cases (1985). J Am Vet Med Assoc 193:706-712, 1988.

15. Smith Annette N. Hemangiosarcoma in dogs and cats. In: The Veterinary Clinics of North America, Small Animal Practice, Advances in Medical Oncology. W.B. Saunders Co, Philadelphia, 2003, pp. 533-552.

16. Sprangler WL, Culbertson MR. Prevalence, type, and importance of splenic diseases in dogs: 1,480 cases (1985-1989). J Am Vet Med Assoc 15:829-834, 1992.

17. Sprangler WL, Kass PH. Pathologic factors affecting post-splenectomy survival in dogs. J Vet Intern Med 11:166-171, 1997.

18. Ward H, Fox LE, Calderwood-Mays MB, Hammer AS, Cuoto CG. Cutaneous hemangiosarcoma in 25 dogs: A retrospective study. J Vet Intern Med 8:345-348, 1994.

19. Withrow SJ, MacEwen EG. Small Animal Clinical Oncology, 3^rd ed. W.B. Saunders Co, Philadelphia, PA, 2001, pp. 639–645.

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