Splenic hematoma (or splenomegaly) and splenic hemangiosarcoma (HSA) are more common in older (mean 10 years old) medium and large breed dogs. German shepherd dogs, golden retrievers, Labrador retrievers and standard poodles may be overrepresented. Splenic hemangiosarcoma (HSA) is the most common malignant disease of the spleen.¹ It is a highly malignant tumor of vascular endothelial origin that rapidly metastasizes, most commonly to the liver, omentum and lungs via the hematogenous route or transabdominal transplantation (following rupture of the tumor). Clinical signs are usually associated with anemia due to bleeding, with cases most commonly presenting with weakness, abdominal distension, pale mucous membranes and possibly weight loss. Some will have a weakness and recover in 1 to 2 days, while others may die due to exsanguination or due to metastases, disseminated intravascular coagulation or cardiac arrhythmias.²

Removal of a splenic mass/hematoma due to benign disease is associated with a good prognosis, while the long-term prognosis for splenic HSA is poor. The median survival time reported for splenic HSA treated with surgery alone is 86 days with one-year survival rates of 6.25 to 7%.^3,4 Splenic hematoma and splenic HSA are grossly indistinguishable from each other in most cases. (1) When a hematoma is diagnosed, there is concern that a HSA may be undetected because the hematoma arising in the HSA could obscure the sarcoma grossly and histologically. The usual response is to examine more histological sections.⁵

The difficulty in differentiating splenic hematoma from HSA and the marked disparity in outcome of the 2 conditions has given direction to a number of studies examining how to differentiate splenic hematoma from HSA.

Incidence of Benign Versus Malignant Disease

In one study in which 100 spleens were evaluated, 66% were neoplastic and 34% nonneoplastic. Of the dogs with neoplasia, 65.1% had HSA, leading to the "two-thirds" rule; i.e., two-thirds of splenic lesions are neoplastic and two thirds of those are HSA. In a pathology-driven study of all canine spleens submitted, 48.2% were neoplastic, 48.2% were nonneoplastic and 0.4% were unclassified. Of the neoplastic cases, HSA was present in 50.6%, leading to the "fifty-fifty rule"; i.e., 50% of splenic lesions are neoplastic, with 50% of those being HSA.²

In a study examining the prevalence of HSA in anemic dogs with a splenic mass and hemoperitoneum requiring a transfusion, malignant splenic neoplasms were found in 76.1% of cases and 23.9% had benign disease. Of the cases with malignant neoplasms, HSA was found in 92.6%.² In another study examining nontraumatic acute hemoperitoneum in 60 dogs, 63.3% had splenic HSA and 26.6% splenic hematoma.⁶

In a study of splenectomy for incidentally detected nonruptured splenic nodules of masses, 70.5% had benign splenic lesions and 29.5% had malignant disease. Of the malignant cases, 58% had HSA.

Since splenic HSA is usually found in older medium to large-breed dogs, a more recent study examined the relationship between body weight and splenic neoplasia. This study found that there was no difference in occurrence of malignant vs. benign disease in small- vs. large-breed dogs. Small-breed dogs were, however, less likely to be diagnosed with HSA (46% of malignant cases were HSA, compared with 65% in large-breed dogs).⁷ They also found that dogs with HSA were more likely to have preoperative anemia, hemoabdomen, thrombocytopenia and/or receive a blood transfusion.⁷ These are not definitive findings and one study found that 56% of dogs with benign splenic lesions presented with a hemoperitoneum.⁸

Methods for Differentiating Benign from Malignant Disease

The gold standard for differentiation of splenic hematoma from HSA is by histopathological examination. When one initially suspects a HSA and histology is consistent with a hematoma, the usual response it to examine more histopathological sections. Presence of lymphoid hyperplasia on histology lends support to a diagnosis of hematoma since it was associated with 0 HSA cases and 27% of hematoma cases in one study.⁵

There is much interest, however, in differentiating the 2 conditions since many clients may elect not to go ahead with surgery if HSA is present, due to the poor long-term prognosis. Staging should routinely be performed. The thorax may be imaged using 3-view radiographs or a computed tomography (CT) scan. The abdomen may be imaged using abdominal ultrasound or a CT scan.

Evidence of distant metastases is likely to be associated with malignant disease. If nodules are seen in the liver, they are not necessarily associated with spread of disease. In a study examining 79 dogs with splenic HSA, only 50% of grossly abnormal livers had metastases. No dogs with grossly normal livers had metastases on diagnosis. Dark-colored liver nodules and bleeding nodules were more likely to be metastases.⁹ Dogs with dark-colored liver nodules were 86% likely to have metastases. All 4 dogs with bleeding nodules had metastases (100%).⁹ It should be remembered, however, that all of cases in this study had HSA and dogs with other malignant splenic neoplasms with metastases to the liver could present differently.

Another study found that dogs with benign splenic disease had a higher mean mass-to-splenic volume ratio and a higher mean splenic weight (as a percentage of body weight), although there was a reasonable amount of overlap.⁸ Other methods that have been used to try and differentiate malignant from benign splenic masses include ultrasonography, contrast harmonic ultrasound and contrast enhanced computed tomography, although results have been inconsistent.^6,8

Although cytology of a fine-needle aspirate of the splenic mass has been examined in the past, the cytological diagnosis only agreed with histopathology 61.3% of the time. It was found to be wrong 16.1% of the time and was not diagnostic in 22.6% of cases.⁸

Immunohistochemical techniques have been used to differentiate splenic hematoma from splenic HSA.

Markers used include vWF, CD 31 and claudin-5 protein. CD31 is a better endothelial marker than vWF for detection of malignant endothelia cells in canine HSA, and claudin-5 protein is a stronger vascular marker than CD31. They were able to "unequivocally differentiate splenic vascular tumors...from non-tumoral hematomas."¹⁰

Serum "big endothelin-1" levels in dogs with HSA are higher than in dogs with other splenic tumors or with benign splenic lesions. This test was 100% sensitive and 95% specific.¹¹

Treatment of Splenic HSA

If staging tests are negative for evidence of distant metastases, surgery to remove the spleen and associated mass is indicated. Method of surgery and associated perioperative and postoperative complications will not be covered in this talk. Surgery alone, however, is associated with short median survival times of 19 to 86 days.¹²

Definitive chemotherapy has been shown to increase survival times over surgery alone, although it is a modest increase at best. Most chemotherapy protocols are doxorubicin-based, including doxorubicin as a sole agent. The prognosis is usually better if all gross tumor can be successfully removed. Other protocols include vincristine + doxorubicin + cyclophosphamide, vincristine + doxorubicin, ifosfamide + doxorubicin, doxorubicin + cyclophosphamide + minocycline. Studies have not shown a survival advantage over doxorubicin alone. Median survival times reported are around 145 to 189 days. Doxorubicin is cardiotoxic and epirubicin was found to be less cardiotoxic and myelotoxic. While epirubicin was found to be as efficacious as doxorubicin, it was found to have a much higher incidence of gastrointestinal side effects with 40% of animals being hospitalized for vomiting and diarrhea.

Metronomic chemotherapy¹³ is the administration of chemotherapy with a shorter or no break period. It likely works via decreased angiogenesis and/or altered tumour immunology. By eliminating the break period, tumor cells are continually exposed to drug, permitting more efficient cell kill as cells continue to cycle and avoiding resistance due to redistribution of cells. Blood vessels must be recruited for tumors to grow beyond a few millimeters in size. There is a large amount of research in to targeted drug inhibitors to neutralize proangiogenic growth factors.

There are 3 aspects of angiogenesis that may be impacted by metronomic chemotherapy:

 Direct cytotoxic effects on endothelial cells of blood vessels

 Tipping of the relative balance of angiogenic growth factors and inhibitors towards the latter

 Expansion of tumor blood vessels may require recruitment of bone marrow-derived endothelial progenitor cells.

There is some evidence that cyclophosphamide- based metronomic chemotherapy can increase survival (25–12 mg/m₂ PO every other day). Prolonged use of cyclophosphamide may be associated with development of a hemorrhagic cystitis and it is usually used in conjunction with furosemide to minimize this occurrence. Cyclophosphamide has been used in combination with etoposide and piroxicam and may be as effective as high-dose chemotherapy.¹⁴ Minocycline (a tetracycline derivative) has antiangiogenic and matrix metalloproteinase inhibitory properties, although its use has not demonstrated an increase in survival time. Interferons and thalidomide also have antiangiogenic properties. COX2 plays a role in the formation, growth and metastasis of tumors. Therefore COX2 inhibitors could also play a part in treatment.

It has been shown that c-kit, VEGFR2 and PDGFR2 are higher in canine splenic HSA than in normal spleens. Toceranib is a multitargeted tyrosine kinase inhibitor that blocks signaling of kit, PDGFR and VEGFR family members. It has demonstrated activity against multiple tumor types, although initial studies have not shown increased survival for canine HSA.

There are ongoing studies in to the use of metronomic chemotherapy or tyrosine kinase inhibitors following definitive chemotherapy to elucidate if survival times may be increased further.

Prognostic and Risk Factors

Stage has been shown in some studies¹⁵ to be of prognostic value and not in others.²

In a recent study of 208 treated cases, the median survival time of stage I cases was 5.5 months, compared to a median survival time of 0.9 months for stage III.

Dogs not treated have a shorter survival time that dogs that are treated. Dogs that receive transfusions are more commonly affected by malignant than benign splenic lesions, and dogs that receive a transfusion had higher odds of death or euthanasia.

In a study examining large and small dogs treated with splenectomy for splenic masses⁷, large dogs with HSA were 8.4x more likely to have thrombocytopenia than large dogs with non-HSA malignancy, and small dogs with HSA were 4.2x more likely to have a thrombocytopenia thank with non-HSA malignancy.

Large dogs with HSA were 9.0x and 5.4x more likely to have hemoperitoneum compared with non-HSA malignancy and benign disease, respectively. Small dogs with HSA were 7.8x and 9.8x more likely to have hemoperitoneum compared with non-HSA malignancy and benign disease, respectively.

References

1.  Spangler WL, Culbertson MR. Prevalence, type, and importance of splenic diseases in dogs: 1,480 cases (1985–1989). J Am Vet Med Assoc. 1992;200(6):829–834.

2.  Hammond TN, Pesillo-Crosby SA. Prevalence of hemangiosarcoma in anemic dogs with a splenic mass and hemoperitoneum requiring a transfusion: 71 cases (2003–2005). J Am Vet Med Assoc. 2008;232(4):553–538.

3.  Wood CA, Moore AS, Gliatto JM, Ablin LA, Berg RJ, Rand WM. Prognosis for dogs with stage I or II splenic hemangiosarcoma treated by splenectomy alone: 32 cases (1991–1993). J Am Anim Hosp Assoc. 1998;34(5):417–421.

4.  Cleveland MJ, Casale S. Incidence of malignancy and outcomes for dogs undergoing splenectomy for incidentally detected nonruptured splenic nodules or masses: 105 cases (2009–2013). J Am Vet Med Assoc. 2016;248(11):1267–1273.

5.  Cole PA. Association of canine splenic hemangiosarcomas and hematomas with nodular lymphoid hyperplasia or siderotic nodules. J Vet Diagn Invest. 2012;24(4):759–762.

6.  Aronsohn MG, Dubiel B, Roberts B, Powers BE. Prognosis for acute nontraumatic hemoperitoneum in the dog: a retrospective analysis of 60 cases (2003–2006). J Am Anim Hosp Assoc. 2009;45(2):72–77.

7.  Sherwood JM, Haynes AM, Klocke E, et al. Occurrence and clinicopathologic features of splenic neoplasia based on body weight: 325 Dogs (2003–2013). J Am Anim Hosp Assoc. 2016.

8.  Mallinckrodt MJ, Gottfried SD. Mass-to-splenic volume ratio and splenic weight as a percentage of body weight in dogs with malignant and benign splenic masses: 65 cases (2007–2008). J Am Vet Med Assoc. 2011;239(10):1325–1327.

9.  Clendaniel DC, Sivacolundhu RK, Sorenmo KU, et al. Association between macroscopic appearance of liver lesions and liver histology in dogs with splenic hemangiosarcoma: 79 cases (2004–2009). J Am Anim Hosp Assoc. 2014;50(4):e6–10.

10. Jakab C, Halasz J, Kiss A, et al. Claudin-5 protein is a new differential marker for histopathological differential diagnosis of canine hemangiosarcoma. Histol Histopathol. 2009;24(7):801–813.

11. Fukumoto S, Miyasho T, Hanazono K, et al. Big endothelin-1 as a tumour marker for canine haemangiosarcoma. Vet J. 2015;204(3):269–274.

12. Teske E, Rutteman GR, Kirpenstein J, Hirschberger J. A randomized controlled study into the efficacy and toxicity of pegylated liposome encapsulated doxorubicin as an adjuvant therapy in dogs with splenic haemangiosarcoma. Vet Comp Oncol. 2011;9(4):283–289.

13. Mutsaers AJ. Metronomic chemotherapy. Top Companion Anim Med. 2009;24(3):137–143.

14. Lana S, U'Ren L, Plaza S, et al. Continuous low-dose oral chemotherapy for adjuvant therapy of splenic hemangiosarcoma in dogs. J Vet Intern Med. 2007;21(4):764–769.

15. Wendelburg KM, Price LL, Burgess KE, Lyons JA, Lew FH, Berg J. Survival time of dogs with splenic hemangiosarcoma treated by splenectomy with or without adjuvant chemotherapy: 208 cases (2001–2012). J Am Vet Med Assoc. 2015;247(4):393–403.