Splenic Hemangiosarcoma: A Case Review

Splenic hemangiosarcoma is a malignant neoplasm of vascular endothelial origin which occurs more frequently in dogs than in any other species1. It is diagnosed in middle aged to older dogs with the following breeds over-represented in published studies: German Shepherds, Golden Retrievers, Labrador Retrievers1.

Increasing evidence suggests that dysregulation of molecular pathways leading to overexpression of angiogenic growth factors and their receptors, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor, and angiopoietins, is important in the pathogenesis of this malignancy1.

The most common primary tumor site in the dog is the spleen. Other commonly reported primary tumor sites include: right atriums, skin/subcutis, liver. Hemangiosarcoma is the most common splenic neoplasm but it is by no means the only differential for splenomegaly or splenic masses in dogs. Generally in veterinary oncology we follow the double two-thirds rule for canine splenic masses in which approximately two-thirds of dogs with splenic masses will have malignant tumor, and approximately two-thirds of these malignant tumors will be hemangiosarcoma1. Other benign splenic masses can have similar gross and ultrasonographic appearance including hematoma and hemangioma1. One study reported that large masses may be more likely benign than malignant1. Due to its close association with endothelial cells, extravasation and angiogenesis of metastatic clones prevails, lending to very aggressive biologic behavior. The most common metastatic sites include: lungs, omentum, liver1.

When a splenic mass is suspected, diagnostic work-up recommended includes: comprehensive physical exam, CBC/Chemistry/PT/PTT, abdominal ultrasound, cardiac ultrasound to evaluate for right atrial masses, three view thoracic radiographs. If effusion is noted then diagnostic abdominocentesis is recommended which will often yield non-clotting blood with PCV similar or higher than the peripheral blood PCV.

A definitive diagnosis of splenic hemangiosarcoma requires surgical biopsy and histopathology. Needle aspiration cytology of suspicious masses, although simple and cost effective, may be of low diagnostic utility due to the hemodilution that usually accompanies sampling1. Needle core biopsies, as well as needle aspirates in some instances, may increase the risk of hemorrhage and subsequent seeding of tumor cells throughout the abdomen. In many cases, if there is high suspicion for malignancy, or in the case of hemoabdomen, splenectomy is recommended. Submission of large samples of the mass for histopathology is preferred to help maximize the likelihood of definitive diagnosis. In some instances, when only a small sample of the lesion is submitted, histopathology may reveal blood clots or other non-specific findings due to tumor heterogeneity (i.e. the mass lesion is not uniform, rather there are pockets of tumor cells, pockets of necrotic tissue, and blood clots throughout the mass).

Treatment of choice for splenic hemangiosarcoma is splenectomy to remove primary tumor and source for potential bleeding then chemotherapy to help slow metastatic progression. The chemotherapeutic regimen prescribed may depend on patient factors and clinician preference. Multiple protocols have been described, the majority of which utilize doxorubicin, in combination with other chemotherapeutic drugs or as single agent.1 In general dogs experience good quality of life while undergoing chemotherapy treatment. Adverse events including gastrointestinal deviations 2-5 days after treatment occur in 20-30% of dogs and myelosuppression 7-10 days after treatment occur in 15-25% of dogs1. These adverse events are typically transient and mild. Approximately 20% of dogs receiving doxorubicin chemotherapy may develop irreversible cardiomyopathy due to cumulative free radical damage to the cardiac muscle. Previous reports suggested that dogs receiving lifetime cumulative doses ranging from 180-240mg/m2 or more are at risk1. The protocols published and used by the majority of clinical oncologists are well below this cumulative dose, further reducing the risk of this adverse event.

In general splenic hemangiosarcoma is a highly malignant tumor with rapid clinical course. Median survival time of dogs receiving surgery alone is 19-86 days, while surgery with doxorubicin-based chemotherapy yields a median survival time of 141-179 days1.

Given the bleak outlook with current treatment protocols, novel adjunctive therapies are being explored. Therapy directed against angiogenesis is a hot area of research, given the endothelial derivation of this disease. Metronomic (low dose, continuous) chemotherapy is based on the fact that blood vessel endothelial cells are highly sensitive to continuous exposure to low doses of chemotherapeutic drugs2-7. There are several proposed mechanisms for the anti-angiogenic effects of metronomic chemotherapy including: (1) targeting the drug-sensitive endothelial cells of tumors, (2) inhibiting the mobilization of endothelial precursors from the bone marrow, and (3) stimulating the production of thrombospondin-1, an endogenous anti-angiogenic protein5-7. Metronomic chemotherapy has also been shown to alert the immune system of the tumor and exert anti-tumor immunity through inhibition of regulatory T cells (Tregs)8. Tregs are a subset of CD4+ lymphocytes that normally function to keep the immune system in check and prevent autoimmunity. Several studies have documented a high level of circulating Tregs in both human and canine cancer patients9-10. In these cases, Tregs prevent the patient’s endogenous immune system from attacking and destroying the cancer cells. Studies have shown that the administration of metronomic cyclophosphamide in both human and canine cancer patients selectively decreases circulating Treg numbers, thereby promoting the host immune response to destroy tumor cells(8-10). Several studies have evaluated metronomic chemotherapy treatment in dogs with hemangiosarcoma3-4,6

Yunnan Baiyao (YB), a Chinese herbal developed in the Yunnan Province of China in 1902, may also have anti-tumor properties against hemangiosarcoma. It gained popularity among Chinese soldiers during World War II for use as a haemostatic agent on the battlefield. It is composed of a variety of herbal components with one of its major components as ginseng root. Studies (human) have shown it improves clotting and enhances platelet function. There is a vast body of literature demonstrating in vitro anti-tumor activity of various cell lines (human melanoma, human colorectal, human cervical) through tumor cell inhibition and apoptosis for various components of YB. There have been no studies (human or vet) to date evaluating YB in whole form. A recent veterinary study evaluated the in vitro effects of YB on canine hemangiosarcoma cell lines. These cell lines were exposed to increasing concentration of YB in vitro. Results showed dose dependent and time dependent exposure caused significant decrease in hemangiosarcoma cell proliferation by induction of cell apoptosis11.

Medicinal mushrooms may also play a role in hemangiosarcoma treatment. Polysaccharopeptide (PSP), the bioactive agent in the medicinal mushroom Coriolus versicolor, has been shown to have anti-tumor effect in both in vitro and human clinical trials. A recent study demonstrated benefit in 15 dogs with splenic hemangiosarcoma12.

Case Study
A 7 year old, castrated male, Rottweiler mix, presented to the Emergency Services at Hope Vet Specialists for acute onset of weakness and lethargy. He was reportedly normal up until the day of presentation. He had no other prior medical concerns other than mild osteoarthritis for which he received glucosamine-chondroitin. He was adopted as a puppy and had no history of travel outside NJ/PA.

Upon triage it was noted that he was tachycardic, tachypneic, had pale mucous membranes and abdominal distension with palpable fluid wave. A cursory ultrasound confirmed abdominal effusion and suspected splenic mass. A diagnostic abdominocentesis confirmed non-clotting blood with PCV of 40%. Peripheral blood PCV was 32%.

The clients elected for further stabilization and diagnostics. The patient was stabilized with IV fluids and blood transfusion. Vital signs, EKG and blood pressure were continuously monitored. CBC revealed anemia with Hct of 29%, no other significant changes. Chemistry panel revealed no abnormalities. PT/PTT were normal. Three view thoracic radiographs were negative for overt pulmonary metastasis, cardiac silhouette appeared normal size and shape. Full abdominal ultrasound revealed 8cm splenic mass, abdominal effusion, no other abnormalities. Cardiac ultrasound was negative for masses associated with the heart.

Based on diagnostic work-up, a list of differential diagnoses was established and these possibilities discussed with the client. Differentials discussed included: splenic hemangiosarcoma with secondary hemoabdomen, other splenic malignancy (other forms of sarcoma like fibrosarcoma, extraskeletal osteosarcoma, etc), or benign splenic lesion (hematoma, extramedullary hematopoiesis). Our top concern was for hemangiosarcoma, given patient age, breed, and no prior history of trauma. As such an oncology consultation was recommended prior to surgery. Treatment options with associated prognosis were discussed including: abdominal exploratory surgery with chemotherapy (if malignancy confirmed on histopathology) with average survival time of 6-9 months vs surgery alone with average survival time of 1-3 months if malignant tumor vs palliative supportive care with IV fluids and blood transfusion which will provide merely a ‘band-aid’ of relief of symptoms for a period of hours to days vs humane euthanasia.

Clients elected for abdominal exploratory surgery. Once the patient was fully stabilized he was taken to surgery where a bleeding splenic mass was confirmed. Routine splenectomy was performed. The remainder of the abdomen was evaluated and negative for other lesions. Continuous EKG and blood pressure were monitored throughout the surgery and in the post op period for up to 36 hours. The patient recovered uneventfully with no signs of hypotension nor cardiac arrhythmia. Norton returned home with his family 48-hours after splenectomy surgery.

Histopathology confirmed splenic hemangiosarcoma. He returned to Hope Vet Specialists 10-days post op for suture removal and to start chemotherapy. Clients reported that the patient had returned to his normal routine and was fully recovered from surgery. Chemotherapy plan discussed with clients included multi-agent treatment utilizing doxorubicin chemotherapy given every 2 weeks for 5 treatments, metronomic (low dose) oral chemotherapy (cyclophosphamide or chlorambucil) starting at the time of second doxorubicin treatment and continuing for six months, I’m Yunity (Colorius vericus mushroom supplement) starting at the time of third doxorubicin treatment, and Yunnan Bia Yao starting at the time of first doxorubicin treatment. The metronomic chemotherapy and supplements were staged in an effort to reduce risk of potential side effects from adding multiple therapeutics all at one time.

Routine CBC and PCV were monitored prior to each IV chemotherapy treatment. Recheck exams including CBC and Chemistry, three view thoracic radiographs, abdominal and cardiac ultrasound, to re-evaluate for metastasis and progression of the disease, were performed every 3 months. The patient tolerated the treatments well and he enjoyed an excellent quality of life with his family both during and after the treatments.

Twelve months (yes, 12-months) post diagnosis with hemangiosarcoma, routine restaging exam confirmed a new cavitated liver mass that had not been present on the ultrasound exam 3-months prior. The remainder of the staging tests (CBC and chemistry, three view thoracic radiographs and cardiac ultrasound) were normal. Due to concern for hemangiosarcoma metastasis, a needle aspirate of the liver mass was not performed in an effort to mitigate risk for mass rupture with subsequent bleeding and tumor cell seeding in the abdominal cavity. It is not common for a patient with hemangiosarcoma to present with just one metastatic lesion. It was discussed with the client that the new liver mass may be a separate issue unrelated to the hemangiosarcoma or there may be metastatic lesions present that are too small to be detected on routine radiography and ultrasound or the patient is lucky enough to have just one metastatic nodule. We discussed the following options including: more sensitive diagnostic imaging such as CT of the abdomen and thorax to potentially rule out smaller metastatic lesions or recheck focal ultrasound of the liver in 4 weeks. Clients elected to pursue CT scan which confirmed only 1 liver mass, the remainder of the abdomen and thorax were negative for lesions. Immediately after CT scan the patient was taken to abdominal exploratory surgery. The liver mass and associated liver lobe were removed, the remainder of the abdomen was negative for lesions. He recovered uneventfully from surgery.

Histopathology of liver mass confirmed metastatic hemangiosarcoma. It was discussed with client that while the patient’s disease had progressed, and metastatic lesions are often more aggressive than the primary lesion, the disease is not behaving as the typical hemangiosarcoma given that he had outlived the median survival time by 3-6 months and only one known metastatic nodule was apparent. Since he tolerated the first round of chemotherapy well and his disease seemed to be sensitive to therapy with a better than anticipated outcome, additional chemotherapy was encouraged. Due to potential dose accumulating cardiotoxic effect of doxorubicin, further treatment with this agent was limited. As such we discussed alternative chemotherapy protocols including carboplatin, given every 3 weeks for 4 treatments. This was combined with metronomic oral chemotherapy and Chinese herbal supplements (I’m Yunity and Yunnan Bia Yao). Routine CBC and PCV was performed prior to each treatment. He tolerated these treatments well with minimal adverse events. We continued to monitor for progression of disease with recheck three view thoracic radiographs as well as abdominal and cardiac ultrasound every 3 months.

Six months later (now 18-months post initial diagnosis with hemangiosarcoma), the presented to the Emergency Service for acute onset of lethargy and weakness. Cursory ultrasound and diagnostic abdominocentesis confirmed hemoabdomen. Full abdominal ultrasound confirmed one new liver mass, the remainder of the abdomen and thoracic radiographs were normal. Further treatment including CT scan with surgical exploratory surgery vs trial treatment with chemotherapy alone was discussed. Based on the course of his disease, the first metastatic lesion appeared 12 months after diagnosis and then second in about half that time 6 months later. From this information we estimated that further treatment with surgery and chemotherapy may provide an additional 3-4 months of remission. Clients however elected for no further treatment as the patient was also experiencing diminished mobility from arthritis and thus a decline in quality of life.
This case exemplifies the benefits of treatment for canine hemangiosarcoma. While this patient’s outcome was better than average, the majority of dogs undergoing treatment for this disease experience an excellent quality of life for an extended period of time beyond that which they would have without treatment.

Submitted by: Kate Vickery, VMD, MS, DACVIM (Oncology), CVA

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