Splenic Hemangiosarcoma

Splenic hemangiosarcoma (HSA) is a highly malignant, aggressive neoplasm of vascular endothelial origin that primarily affects the spleen in dogs. It is the most common primary splenic malignancy in dogs, accounting for up to 50% of all splenic tumors. The tumor is characterized by the proliferation of neoplastic endothelial cells that form irregular, blood-filled vascular channels, leading to a highly vascular, fragile mass that is prone to rupture and hemorrhage. Splenic HSA is a systemic disease with a high metastatic rate, often involving the liver, omentum, lungs, and right atrium. The disease is classified into three histological grades (I, II, III) based on differentiation, mitotic count, and necrosis, with grade III being the most undifferentiated and aggressive. Surgical resection (splenectomy) is the primary treatment, but due to the high metastatic potential, adjuvant chemotherapy is recommended to prolong survival. The prognosis is generally poor, with median survival times of 1-3 months with surgery alone and 4-6 months with surgery and chemotherapy.

The exact etiology of splenic hemangiosarcoma is unknown, but several factors are implicated. Genetic mutations, such as in the p53 tumor suppressor gene and activation of oncogenes like KIT and VEGFR, play a role in endothelial cell transformation. Chronic inflammation, oxidative stress, and exposure to environmental carcinogens (e.g., vinyl chloride, radiation) may contribute to DNA damage. In dogs, a hereditary predisposition is suspected in certain breeds, particularly Golden Retrievers, German Shepherds, and Labrador Retrievers, suggesting a genetic component. The spleen's role in hematopoiesis and immune surveillance may make it a site of neoplastic transformation. Trauma is not considered a cause but can precipitate rupture of an existing tumor. No infectious or viral etiology has been confirmed.

Splenic hemangiosarcoma is predominantly a disease of middle-aged to older dogs, with a median age of 10-12 years. It is rare in cats, but when it occurs, it is also malignant. Certain breeds are overrepresented, including Golden Retrievers, German Shepherds, Labrador Retrievers, Boxers, and Bernese Mountain Dogs. There is no strong sex predilection, though some studies suggest a slight male predominance. The incidence is higher in purebred dogs compared to mixed breeds. Working and sporting dogs may have a higher risk due to increased physical activity, which could predispose to splenic torsion or trauma, but this is not well established. The disease accounts for approximately 5-7% of all canine tumors and up to 50% of splenic masses.

Splenic hemangiosarcoma arises from the endothelial cells lining the splenic sinusoids. The neoplastic cells proliferate and form irregular, blood-filled vascular channels that disrupt the normal splenic architecture. The tumor grows rapidly and is highly vascular, leading to a fragile mass that is prone to spontaneous rupture, causing hemoperitoneum and acute anemia. The tumor can also cause splenic enlargement, leading to abdominal distension and discomfort. The malignant cells have a high propensity for hematogenous metastasis, with the liver, omentum, lungs, and right atrium being common sites. Metastasis occurs early, often before clinical signs are apparent. The tumor induces a systemic inflammatory response, with elevated levels of cytokines and growth factors that promote angiogenesis and tumor progression. Coagulopathies, such as disseminated intravascular coagulation (DIC), can occur due to the release of procoagulant factors and consumption of clotting factors.

Intrinsic factors include breed predisposition (Golden Retrievers, German Shepherds, etc.), age (older dogs), and genetic mutations (p53, KIT). Extrinsic factors include exposure to environmental carcinogens, such as tobacco smoke, pesticides, and radiation. Chronic inflammation or immune-mediated conditions may increase the risk. Obesity and high body weight have been suggested as risk factors in some studies. Prior splenic surgery or trauma may predispose to splenic torsion, but not directly to HSA. The role of sex hormones is unclear, but neutering at an early age has been associated with an increased risk in some breeds, possibly due to hormonal influences on immune function.

Clinical signs are often vague and may include lethargy, weakness, anorexia, weight loss, and intermittent vomiting. Acute collapse, pale mucous membranes, tachycardia, and abdominal distension are signs of hemoperitoneum due to tumor rupture. On physical examination, a palpable abdominal mass may be detected in the left cranial quadrant. Splenomegaly may be present. In cases of metastasis, signs related to the affected organ may appear, such as respiratory distress (lung metastasis), cardiac arrhythmias (right atrial mass), or hepatic dysfunction. Neurological signs may occur if there is cerebral metastasis or coagulopathy. The disease can be staged based on the WHO classification: Stage I (confined to spleen), Stage II (ruptured tumor or regional lymph node involvement), Stage III (distant metastasis).

Differential diagnoses for splenic masses include: 1) Splenic hematoma (benign, often associated with trauma, but can be indistinguishable from HSA on imaging); 2) Nodular hyperplasia (benign proliferation of splenic tissue); 3) Splenic abscess (infectious, often with fever and leukocytosis); 4) Splenic torsion (acute, painful, with splenomegaly and shock); 5) Lymphoma (diffuse splenic infiltration, often with generalized lymphadenopathy); 6) Myelolipoma (benign, often incidental); 7) Metastatic neoplasia (e.g., melanoma, mammary carcinoma); 8) Histiocytic sarcoma (malignant, often with systemic signs). Definitive diagnosis requires histopathology, but imaging and cytology can help narrow down the differentials.

The diagnostic workup begins with a thorough history and physical examination, including abdominal palpation. Baseline bloodwork (CBC, biochemistry, urinalysis) and coagulation profile (PT, aPTT, platelet count) are essential. Abdominal radiographs may reveal a splenic mass or loss of serosal detail due to effusion. Abdominal ultrasound is the preferred imaging modality to characterize the splenic mass, assess for other abdominal organ involvement, and guide fine-needle aspiration (FNA) for cytology. Thoracic radiographs (three views) are performed to screen for pulmonary metastasis. If the patient is stable, a CT scan of the abdomen and thorax may provide more detailed staging. If hemoperitoneum is present, abdominocentesis can confirm the presence of blood. Definitive diagnosis is made via histopathology after splenectomy. In cases where surgery is not immediately feasible, a percutaneous ultrasound-guided biopsy may be attempted, but it carries a risk of hemorrhage.

Hematology may show anemia (regenerative or non-regenerative), leukocytosis, and thrombocytopenia. Biochemistry may reveal elevated liver enzymes (ALT, AST) if hepatic metastasis or hypoxia is present. Hypoalbuminemia and hypoglycemia can occur in advanced disease. Coagulation abnormalities, such as prolonged PT and aPTT, elevated FDPs and D-dimers, and decreased antithrombin III, indicate DIC. Blood gas analysis may show metabolic acidosis due to hypoperfusion. Inflammatory biomarkers like C-reactive protein (CRP) and serum amyloid A (SAA) may be elevated. Cytology of abdominal effusion may show neoplastic cells, but it is not always diagnostic. Histopathology of the splenic mass is the gold standard, with grading based on mitotic count, nuclear pleomorphism, and necrosis.

Radiography: Abdominal radiographs may show a soft tissue mass in the splenic region, splenomegaly, or loss of serosal detail due to effusion. Thoracic radiographs may reveal pulmonary nodules (metastasis) or an enlarged cardiac silhouette (right atrial mass). Ultrasonography: Splenic HSA typically appears as a complex, mixed echogenic mass with cavitations and anechoic areas representing hemorrhage or necrosis. Color Doppler may show increased vascularity. Abdominal ultrasound can also detect hepatic lesions, peritoneal effusion, and lymphadenopathy. CT: Contrast-enhanced CT provides detailed assessment of the splenic mass, vascular invasion, and metastasis. It is superior for staging and surgical planning. MRI: Not commonly used for splenic masses but may be helpful in characterizing cardiac involvement. Angiography: Rarely used, but can identify tumor vascularity. Fluoroscopy: Not typically used.

Cytology: Fine-needle aspiration of the splenic mass may yield blood and clusters of spindle-shaped or polygonal cells with high nuclear-to-cytoplasmic ratio, anisocytosis, and anisokaryosis. However, cytology is often nondiagnostic due to hemodilution and necrosis. Histopathology: The tumor is composed of pleomorphic endothelial cells forming irregular vascular channels. Mitotic figures are frequent, and areas of necrosis and hemorrhage are common. Immunohistochemistry (IHC) can be used to confirm endothelial origin with markers such as factor VIII-related antigen, CD31, and vimentin. Grading is based on the degree of differentiation, mitotic count (per 10 high-power fields), and extent of necrosis. Grade I tumors are well-differentiated with low mitotic count; Grade III tumors are poorly differentiated with high mitotic count and extensive necrosis.

The primary treatment is surgical splenectomy. Preoperative stabilization is crucial, especially in cases of hemoperitoneum. Intravenous fluid therapy, blood transfusion (packed red blood cells or whole blood) to correct anemia and hypovolemia, and oxygen supplementation may be necessary. Emergency splenectomy is performed to control hemorrhage. The surgical approach is a midline celiotomy. The spleen is exteriorized, and the splenic vessels are ligated individually or using an electrosurgical vessel-sealing device (e.g., Ligasure). The omentum is inspected for metastasis, and any suspicious lesions are biopsied. Liver biopsy is recommended even if grossly normal, as microscopic metastasis is common. Postoperative pain management includes opioids (e.g., hydromorphone 0.05-0.1 mg/kg IV q4-6h) and NSAIDs (e.g., carprofen 2.2 mg/kg PO q12h) once renal function is normal. Adjuvant chemotherapy is recommended to delay metastasis. Protocols include doxorubicin (30 mg/m² IV q3 weeks) alone or in combination with cyclophosphamide (50-75 mg/m² PO q3 weeks) or vincristine (0.5-0.7 mg/m² IV q3 weeks). Metronomic chemotherapy with cyclophosphamide (10 mg/m² PO q24h) and piroxicam (0.3 mg/kg PO q24h) may also be used. The prognosis remains poor despite treatment.

The prognosis for splenic hemangiosarcoma is poor. With surgery alone, median survival time (MST) is approximately 1-3 months. With surgery and adjuvant chemotherapy, MST is 4-6 months. The 1-year survival rate is less than 10%. Negative prognostic indicators include high histologic grade, presence of metastasis at diagnosis, tumor rupture, and presence of clinical signs. Stage I disease has a slightly better prognosis than Stage III. The mitotic index is a significant predictor of survival. Dogs that survive the perioperative period and complete chemotherapy may have longer survival, but long-term cure is rare. Quality of life is a major consideration, and owners should be counseled about the guarded prognosis.

Postoperative follow-up is essential. Suture removal is typically 10-14 days after surgery. Serial thoracic radiographs and abdominal ultrasound are recommended every 2-3 months to monitor for metastasis. Bloodwork, including CBC and biochemistry, should be performed before each chemotherapy session. Physical examination should be performed at each visit. Activity restriction is advised for 2-4 weeks postoperatively to allow healing. Long-term monitoring for recurrence or metastasis is recommended, but due to the aggressive nature, most dogs succumb to the disease within 6-12 months. Palliative care may be needed to manage pain and respiratory distress.

Pearls: 1) Always perform a thorough abdominal exploration during splenectomy, including liver biopsy, as metastasis is common. 2) Use a vessel-sealing device to reduce surgical time and hemorrhage. 3) Consider preoperative blood transfusion in anemic patients to stabilize them before surgery. 4) Administer prophylactic antibiotics (e.g., cefazolin 22 mg/kg IV) at induction and every 90 minutes during surgery. 5) Monitor for DIC postoperatively with coagulation panels. Pitfalls: 1) Delaying surgery in a hemodynamically unstable patient with hemoperitoneum can be fatal. 2) Incomplete ligation of splenic vessels can lead to fatal hemorrhage. 3) Failure to biopsy the liver may miss metastasis, leading to inaccurate staging. 4) Overlooking cardiac involvement (right atrial mass) can cause arrhythmias and sudden death. 5) Using NSAIDs in dehydrated or hypotensive patients can cause renal injury.

Perioperative antimicrobial prophylaxis: Cefazolin 22 mg/kg IV at induction, repeated every 90 minutes during surgery. Postoperative analgesia: Hydromorphone 0.05-0.1 mg/kg IV q4-6h, or fentanyl CRI at 2-5 mcg/kg/h. NSAIDs: Carprofen 2.2 mg/kg PO q12h, or meloxicam 0.1 mg/kg PO q24h, after renal function is confirmed. Chemotherapy: Doxorubicin 30 mg/m² IV q3 weeks, with cardiac monitoring (echocardiogram) before each dose. If doxorubicin is contraindicated, epirubicin 30 mg/m² IV q3 weeks may be used. Metronomic protocol: Cyclophosphamide 10 mg/m² PO q24h, piroxicam 0.3 mg/kg PO q24h. Antiemetics: Maropitant 1 mg/kg IV or PO q24h. Gastroprotectants: Omeprazole 1 mg/kg PO q12h. For DIC: Fresh frozen plasma 10-20 ml/kg IV, heparin 75 IU/kg SC q8h.

Multiple studies have evaluated the efficacy of surgery and chemotherapy for splenic hemangiosarcoma. A landmark study by Wood et al. (1998) reported a median survival of 86 days with surgery alone and 172 days with surgery plus doxorubicin. Another study by Hammer et al. (1991) found that dogs receiving doxorubicin-based protocols had a median survival of 172 days compared to 42 days for surgery alone. A more recent study by Thamm et al. (2006) evaluated metronomic chemotherapy and reported a median survival of 178 days. The use of immunotherapy (e.g., liposome-encapsulated muramyl tripeptide) has shown some benefit in prolonging survival in a study by Vail et al. (1995). The ACVS consensus statement recommends splenectomy and adjuvant chemotherapy for splenic HSA. The prognosis remains poor, and clinical trials are ongoing to improve outcomes.