Miscellaneous Tumors

33


Miscellaneous Tumors



image Section A



Hemangiosarcoma


Douglas H. Thamm



Incidence and Risk Factors


Hemangiosarcoma (HSA), also known as malignant hemangioendothelioma or angiosarcoma, is a malignant neoplasm of vascular endothelial origin. HSA occurs more frequently in dogs than in any other species.1,2 It represents about 5% of all noncutaneous primary malignant neoplasms and 12% to 21% of all mesenchymal neoplasms in the dog.35 HSA accounts for 2.3% to 3.6% of skin tumors in dogs1,6 and 45% to 51% of splenic malignancies.2,7,8 It is less common in the cat, occurring in approximately 0.5% of cats examined at necropsy in one study and accounting for 2% of all neoplasms in another.9,10


HSA is seen mostly in middle-aged to older animals, although there are reports in dogs less than 3 years of age.7,1014 German shepherds, golden retrievers, and Labrador retrievers are overrepresented in many case series.7,11,1416 There may be a slight male predisposition in dogs.11,12,14,15,17


Although the etiology is unknown, reports in humans have been related to exposure to thorium dioxide, arsenicals, vinyl chloride, and androgens.18 It is reported as a rare late sequela to breast-conserving irradiation in humans with breast cancer.19 The human vascular neoplasm Kaposi’s sarcoma is causally associated with human herpesvirus 8, and although some studies have demonstrated herpesviral elements in human angiosarcoma as well, the majority have not.2023 There is a documented increase in HSA development in dogs exposed to ionizing radiation prenatally or postnatally.24 Cutaneous HSAs are found more frequently in dogs with minimal pigmentation and thin hair coats25 and have been associated with ultraviolet light exposure in laboratory dogs.26


There is increasing evidence that dysregulation of molecular pathways governing angiogenesis may be important in the pathogenesis of HSA. Studies in humans and dogs have demonstrated abundant expression of angiogenic growth factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and angiopoietins-1 and -2 (Ang-1 and -2) in HSA cells and tissues and concomitant expression of the cellular receptors for VEGF, bFGF, and Ang-1.2736 This suggests the potential for autocrine stimulation of one or more of these receptors leading to dysregulated proliferation and survival. Indeed, enforced overexpression of VEGF is sufficient to transform immortalized murine endothelial cells into HSA,37 and in vivo overexpression of VEGF has led to vascular tumor formation in mice.38


Mutations in tumor suppressor genes such as p53,39,40 Ras,4143 and Tsc244 have likewise been implicated in the pathogenesis of HSA, based on murine or human studies. Recent studies suggest that p53 and Ras mutations are infrequent in canine HSA4547; however, PTEN inactivation was demonstrated in greater than 50% of evaluated canine HSA samples in one study.48 Key growth- and apoptosis-regulating proteins such as pRB, cyclin D1, BCL2, and survivin appear overexpressed in HSA when compared with hemangiomas or normal tissues.46,49 Gene expression profiling studies indicate an enrichment for genes involved in inflammation and angiogenesis.47



Pathology and Natural Behavior


In the dog, the most common primary site for HSA is the spleen.1,11,12,14,15 Other frequent sites include the right atrium, skin and subcutis, and liver.11,14,25,5053 Occurrence has also been reported in the lung, kidney, oral cavity, muscle, bone, urinary bladder, left ventricle, uterus, tongue, digit, and retroperitoneum.12,14,5460 In the cat, cutaneous and visceral (e.g., spleen, liver, intestine) locations are evenly distributed.10,61 Other reported sites in the cat include the heart, thoracic cavity, eyelid, and nasal cavity.10,53,6164 HSA is the most common splenic neoplasm encountered but is by no means the only differential for splenomegaly or splenic masses in dogs. The “double two-thirds rule” has been applied to canine splenic masses: approximately two-thirds of dogs with splenic masses will have a malignant tumor, and approximately two-thirds of those malignancies will be HSA2,8,17,65; however, recent studies have found that 63% to 70% of dogs with splenic masses presenting with nontraumatic hemoabdomen were HSA.6668 Several splenic mass lesions (e.g., HSA, hematoma, hemangioma) can have a similar gross and ultrasonographic appearance, and large masses do not necessarily denote malignancy.69 Histopathology is necessary to establish a definitive diagnosis in these cases.


HSA may be solitary, multifocal within an organ, or widely disseminated at presentation. Grossly, they are of variable size, pale gray to dark red or purple, and soft or gelatinous, often containing blood-filled or necrotic areas on cut surface (Figure 33-1). They are poorly circumscribed, nonencapsulated, and often adhered to adjacent organs. They are extremely friable, and complications associated with rupture and hemorrhage are frequent presenting complaints. Histologically, HSA consists of immature, pleomorphic endothelial cells forming vascular spaces containing variable amounts of blood and/or thrombi.70,71 When such features are minimal but HSA is suspected, immunohistochemistry for von Willebrand’s factor (factor VIII–related antigen) or CD31/platelet endothelial cell-adhesion molecule (PECAM) can be used to demonstrate endothelial derivation and support the diagnosis of HSA.7174 Recently, claudin-5 and CD117 (KIT) have also been identified as potentially useful immunohistochemical markers for distinguishing canine tumors of vascular endothelial origin.75,76



Perhaps owing to its intimate association with the vasculature, facilitating extravasation and angiogenesis of metastatic clones, canine HSA is typified by very aggressive biologic behavior, with rapid and wide metastasis occurring frequently. An exception to this rule is pure cutaneous or dermal HSA, without any clinical or histologic evidence of subdermal infiltration.51 Metastasis is typically hematogenous or through transabdominal implantation following rupture. The most frequent metastatic sites are the liver, omentum, mesentery, and lungs.14,77 One study suggested that approximately, 25% of dogs with splenic HSA will also have right atrial involvement.77 However, the experience of the author suggests that this percentage at initial presentation is significantly lower (5% or less). Other reported sites of metastasis are the kidney, muscle, peritoneum, lymph nodes, adrenal gland, brain, and diaphragm. In dogs, HSA is considered the most common metastatic tumor to the brain.78,79


HSA in cats is considered to be a less aggressive disease. Cutaneous or subcutaneous HSA often behaves in a fashion similar to other soft tissue sarcomas, and local recurrence is the major concern.72,80,81 Reports do exist of more aggressive biologic behavior in a subset of cats with cutaneous HSA, however.8082 Visceral HSAs have a higher metastatic rate, similar to that in dogs, and the common sites include the liver, omentum, diaphragm, pancreas, and lung.10,61,81,83,84



History and Clinical Signs


Presenting complaints vary, depending on the location of the primary tumor, and can range from vague, nonspecific signs of illness, to asymptomatic abdominal swelling, to acute collapse and death secondary to hemorrhagic/hypotensive shock. Common presenting complaints for visceral HSA are acute weakness or collapse. This may have been preceded by similar transient episodes occurring over a period of weeks or days, which resolved spontaneously in 12 to 36 hours. In such cases, it is theorized that HSA rupture leads to hemoperitoneum, followed by subsequent reabsorption (i.e., autotransfusion) of red blood cells. For those dogs that present asymptomatically or with vague signs (lethargy, inappetence, weight loss, abdominal distension), an abdominal mass may be palpated during examination. Dogs with cardiac HSA typically present with signs related to pericardial tamponade and associated right-sided heart failure, such as exercise intolerance, dyspnea, and ascites.


Common physical examination findings for visceral HSA include pale mucous membranes with delayed capillary refill, tachycardia with poor pulse quality, and a palpable fluid wave in the abdomen, with or without a palpable abdominal mass. Dogs with cardiac HSA may display ascites, muffled heart sounds, and/or pulsus paradoxus (variation in pulse quality associated with respiration).


In the cat, signs will depend on location and extent of tumor. Cats with visceral tumors usually have a history of lethargy, anorexia, vomiting, sudden collapse, dyspnea, or a distended abdomen.61,81,83 On physical examination, pallor, pleural or peritoneal fluid, and a palpable abdominal mass may be detected.



Diagnostic Techniques and Work-Up


Complete staging for an HSA suspect typically includes hematology and serum biochemistry, coagulation testing, thoracoabdominal imaging, ±abdominocentesis, and/or echocardiography.


In both dogs and cats, anemia is often seen, usually characterized by the presence of schistocytes (associated with microangiopathic hemolysis) and acanthocytes in the peripheral blood.* Anemia may be regenerative or nonregenerative, depending on duration. Blood typing and/or crossmatching may be indicated if surgery is planned in a severely anemic patient. In addition, a neutrophilic leukocytosis may be seen.61,66 Thrombocytopenia is observed in 75% to 97% of cases, ranging from mild to severe.66,67,86,87 Serum biochemistry changes are typically nonspecific and can include hypoalbuminemia, hypoglobulinemia, and mild elevations in liver enzymes.66,83


A coagulogram is very useful in animals with suspected HSA. Perturbations in some aspect of the coagulation cascade (prothrombin time [PT], activated partial thromboplastin time [APTT], platelet count, activated clotting time, fibrinogen concentration, fibrin degradation products) are seen in the majority of patients (Table 33-1)66,8691 and approximately 50% have coagulation abnormalities that meet the criteria for disseminated intravascular coagulation (DIC).86,88 Tumor vasculature, especially in the case of HSA, differs significantly from normal vasculature, commonly containing blind-ended or irregular tortuous vessels, incomplete endothelial lining, arteriovenous shunts, exposed subendothelial collagen, and platelet-tumor aggregates.92 HSA-derived endothelial cells may also have an “activated” phenotype, further promoting initiation of the coagulation cascade.



HSA effusions are serosanguineous (or frank blood) and usually do not clot. Cytology of effusions is rarely diagnostic; although tumor cells are likely present, they are heavily diluted with peripheral blood.


Screening for metastasis is mandatory prior to definitive surgery for HSA. Dogs with gross evidence of metastasis have a grave prognosis, and surgery is purely palliative. Thoracic radiographs should be obtained in all cases. One study reported a 78% sensitivity and 74% negative predictive value for detecting pulmonary manifestations of HSA, and obtaining three views significantly decreased the false-negative rate.93 Dogs with hemopericardium secondary to cardiac HSA will typically have a globoid cardiac silhouette, with or without distension of the caudal vena cava.94 Abdominal radiographs may reveal a cranial abdominal mass in many cases; however, abdominal ultrasound is a superior modality for imaging the abdomen. Many animals with visceral HSA will have ascites, which diminishes abdominal detail with radiographs but not ultrasound. Ultrasound also allows for the more thorough evaluation of the rest of the abdomen for evidence of metastatic disease. HSA typically has a heteroechoic appearance, ranging from anechoic/cavitated to hyperechoic, or a targetoid appearance (Figure 33-2).95,96



Typical electrocardiographic signs consistent with pericardial effusion (decreased amplitude QRS complex, electrical alternans) can be seen in dogs with cardiac HSA and hemopericardium. Echocardiography can be useful in dogs with suspected pericardial effusion, and a right atrial mass may be visible in 65% to 90% of cases (Figure 33-3)97100; however, some dogs may develop blood clots within the pericardium that can have a mass effect. Thus the absence of a mass does not rule out HSA, and the presence of a mass is not pathognomonic. Despite this, detection of a mass on echocardiography is strongly associated with a worse prognosis in dogs with pericardial effusion.94,99 Other negative prognostic factors include history of collapse and presence of ascites.94 Routine evaluation of the heart for metastatic disease in a dog with subcutaneous or visceral HSA without evidence of other metastasis is rarely rewarding.



A clinical staging system for HSA is given in Table 33-2.



Ultimately, a definitive diagnosis of HSA usually requires a surgical biopsy. Needle aspiration cytology of suspicious masses, although simple and cost-effective, is of low diagnostic utility due to the hemodilution that usually accompanies sampling.101 Needle core biopsies can be obtained of cutaneous or subcutaneous lesions but should not be performed on suspect visceral lesions due to the risk of induction of hemorrhage and subsequent seeding of the peritoneum. If only small samples of suspected HSA are submitted, histopathology may only reveal blood clots or other nonspecific findings. Submission of large samples of suspected HSA is preferred to maximize the likelihood of capturing a true tumor if present. This includes submission of entire spleens whenever possible or, at the very least, numerous parts of the mass.


Several investigators are evaluating additional tests, which may allow more accurate presurgical diagnosis. Pericardial fluid pH was suggested to correlate with presence or absence of neoplasia in one study102; however, subsequent studies have shown pericardial fluid analysis to be of little diagnostic benefit.103,104 Recent studies have found a significant difference in concentrations of troponin I, an indicator of myocardial damage, between dogs with cardiac HSA and dogs with idiopathic pericardial effusions.105,106 Plasma concentrations of VEGF and urine concentrations of bFGF are elevated in dogs with HSA versus normal controls27,28; however, neither was found to correlate with remission status, disease stage, or outcome. Advanced imaging techniques such as contrast-enhanced ultrasound,107113 contrast-enhanced computed tomography (CT),114 and magnetic resonance imaging (MRI)115 have been useful in discriminating malignant versus benign lesions in preliminary studies. Additional blood-based biomarkers showing early promise include measurement of serum alpha-1 acid glycoprotein,116 lipocalin region of collagen XXVII alpha 1,117 and thymidine kinase activity,118,119 as well as multiparameter flow cytometry of peripheral blood utilizing a variety of endothelial and primitive hematopoietic cell markers.120



Treatment



Surgery


Surgery remains the primary method of treatment for almost all dogs and cats with HSA. Prior to surgery, appropriate treatment for shock (e.g., crystalloids, colloids) and correction of severe hematologic or coagulation abnormalities should be addressed with blood products as necessary. Surgery should be as aggressive as possible to remove all locally affected tissue.


For cutaneous or subcutaneous HSA, surgical considerations are similar to those for other soft-tissue sarcomas (see Chapter 21). Dermal HSA is usually discrete, and surgical margins of 1 to 2 cm are often adequate. Intramuscular HSA will often present with a large blood clot admixed with actual tumor. Wide margins can be difficult to achieve, short of limb amputation when possible. Debulking may provide short-term relief.


For splenic HSA, splenectomy is required and can be performed with sutures, staples, or electrothermal vessel sealant devices (e.g., LigaSure Force Triad, Covidien, Mansfield, MA).121 The spleen should be carefully delivered from the abdomen to avoid iatrogenic rupture. Attached omentum should be removed en bloc. Intraoperative autotransfusion of blood has been described but requires specialized equipment and personnel and still remains controversial.122 At the time of splenectomy, the abdomen should be thoroughly explored and any suspicious lesions in the liver or omentum, especially if actively bleeding, should be excised and submitted for histopathology. Biopsy of grossly normal livers is probably not useful. The abdomen should be thoroughly lavaged and instruments changed prior to closure to minimize the risk of abdominal/wound bed or suture line seeding. Dogs undergoing splenectomy are prone to develop ventricular arrhythmias following surgery. In one study of 59 dogs, 24% developed arrhythmias.123 Poor myocardial perfusion secondary to hypoxia, hypovolemia, or anemia or a neurohormonal response associated with manipulation of the spleen are all potential causes. An electrocardiogram should be monitored intraoperatively and in the postoperative period, and arrhythmias treated as they arise. Arrhythmias usually resolve within 24 to 48 hours.


Surgery can be performed for primary cardiac HSA. An open or thoracoscopic pericardiectomy can be used as a palliative procedure, allowing effusion to escape into the thorax rather than accumulating in the pericardium, where a small volume can readily restrict function. Right atrial appendage masses can be resected with a stapling device or hand stitching,124,125 and reconstructive procedures have been described in cases where extensive resection is required.126,127 A recent retrospective study suggests that dogs surviving the perioperative period have a prognosis similar to dogs with HSA of other visceral sites.125



Chemotherapy


Given the very high metastatic rate of most canine HSA and the poor outcome associated with surgery alone (see later), adjuvant chemotherapy is indicated in all cases, with the exception of pure cutaneous tumors. Single-agent and combination doxorubicin (DOX)-based chemotherapy protocols are most frequently used (Box 33-1).128134 Other combinations such as vincristine, cyclophosphamide, and methotrexate (VCM) have yielded only modest improvements in survival time.14 Recently, ifosfamide was shown to also have some modest antitumor activity in canine HSA.134,135 Both epirubicin and liposome-encapsulated DOX appear to have roughly equivalent activity to conventional DOX.136,137 In cats, similar DOX-based protocols are employed, although reports of systematic evaluations are lacking. For cases in which surgery is declined or impossible due to size/location or presence of metastasis, DOX-based chemotherapy induces meaningful tumor regression in a large minority of animals138140; however, remissions are typically incomplete and brief in duration. Isolated reports of antitumor activity have been reported with carboplatin as well.141




Immunotherapy


Very few studies have been conducted to evaluate biologic therapy for HSA (see Chapter 13). One study used a mixed killed bacterial vaccine following surgery and showed some improvement in survival time in dogs with splenic HSA.14 More recently, a surgical adjuvant study was conducted in dogs with splenic HSA to compare chemotherapy (DOX and cyclophosphamide) to the same chemotherapy combined with immunotherapy using liposome-encapsulated muramyl tripeptide-phosphatidylethanolamine (L-MTP-PE). The median survival time (MST) for those dogs treated with chemotherapy alone was 5.7 months versus 9.1 months (p = 0.03) for those treated with L-MTP-PE and chemotherapy, with 40% of dogs in the L-MTP-PE group experiencing long-term survival.133 L-MTP-PE is currently unavailable in the United States but has been granted orphan drug status for the treatment of pediatric osteosarcoma in the European Union. Investigations of allogeneic tumor cell vaccine approaches in combination with chemotherapy have shown initial promise in small numbers of dogs.142



Radiation Therapy


Radiation therapy (RT) is rarely utilized for HSA due to the anatomic sites involved and high metastatic rate. Coarsely fractionated (palliative) RT for peripheral masses (e.g., cutaneous and subcutaneous lesions) may dramatically decrease local disease but may not significantly impact overall survival.143145 It is conceivable that a combination of palliative RT and chemotherapy may provide better control, but this awaits further investigation. Full-course (definitive) RT may be reasonable for dogs with incompletely resected, solitary dermal HSA or feline nonvisceral HSA due to their reduced potential for metastasis.



Novel Therapies


Given the endothelial derivation of HSA, therapy directed against angiogenesis is a logical avenue of exploration, and murine HSA has been used as a model for the evaluation of novel antiangiogenic strategies. Antitumor activity has been seen in a murine HSA model to a variety of antiangiogenic treatments, such as VEGF receptor kinase inhibitors,146 TNP-470,147 and several others,148150 and objective responses have been observed with several angiogenic receptor tyrosine kinase inhibitors in human reports.151,152 Interleukin-12 (IL-12) has been shown to retard tumor growth in a canine HSA xenograft as well.33


A small pilot study recently reported the outcome following treatment of dogs with splenic HSA with a combination of splenectomy, a nonsteroidal antiinflammatory drug (NSAID), and low-dose continuous (metronomic) chemotherapy with alternating courses of cyclophosphamide and etoposide. Outcome was similar to what has been reported following DOX-based injectable chemotherapy.153


Current studies are focusing on whether combinations of conventional DOX-based chemotherapy followed by “maintenance” therapy with low-dose continuous chemotherapy or VEGF receptor kinase inhibitors such as toceranib may improve postsurgical outcome in patients with HSA; the results of these studies are eagerly anticipated.


In humans with various vascular tumors, antitumor activity has been observed following the local administration of IL-2,154,155 and the local or systemic administration of interferon-α (IFNα) in combination with traditional cytotoxics.156159 Additionally, paclitaxel, docetaxel, and gemcitabine appear to have activity against human HSA.157,160162



Prognosis



Canine


A summary of the results of several reports on the treatment of splenic HSA is presented in Table 33-3. Overall, the prognosis for dogs with splenic HSA treated by surgery alone is extremely poor. MSTs for splenic HSA range from 19 to 86 days, and less than 10% survive to 12 months.2,8,14,163,164 Primary hepatic HSA is thought to carry an equally poor prognosis. In contrast, one study suggests that dogs with primary renal HSA may have a more favorable outcome than those with HSA of other visceral sites.60



Surgery plus anthracycline-based chemotherapy following surgery will increase median survival times to 141 to 179 days.* Even with the addition of chemotherapy, the 12-month survival percentage is 10% or less. In one report, the addition of immunotherapy (L-MTP-PE) to standard chemotherapy increased median survival time to 273 days.133 In splenic HSA, stage I (nonruptured) tumors may have a more favorable outcome than stage II (ruptured) tumors when postoperative chemotherapy is used.14,130,133 One study employed a histologic grading scheme, and demonstrated that dogs with low-grade tumors had a better prognosis than dogs with intermediate- or high-grade tumors.129


In a study of surgically treated cutaneous HSA, tumors involving the dermis (without subdermal invasion) had a MST of 780 days (n = 10).51 Tumors with invasion into the subcutaneous tissues or muscle generally have worse outcomes than those confined to the dermis.11,51,165,166 Therefore adjuvant medical therapy should be offered for subcutaneous or intramuscular HSA, although reports regarding efficacy are divergent.165,166


Overall, the prognosis is poor for cardiac HSA. In dogs undergoing surgery for right atrial HSA, the average survival time ranges from 1 to 4 months.99,124 A recent study reported an outcome following surgery and chemotherapy roughly equivalent to that reported for HSA of the spleen.125



Feline


In cats, the prognosis for visceral HSA is poor. Most cats die from recurrence of the primary tumor or metastasis, and MSTs are generally short, owing to metastasis.61,84 HSAs located in cutaneous and subcutaneous sites have recurrence rates of 60% to 80%,61,72 although one recent case series reported a favorable outcome following aggressive surgery, and complete excision is associated with improvement in outcome.80,81 Metastasis can develop following surgical resection in some cases, although the frequency is unknown.82


In summary, surgery still offers the best approach to diagnose and treat HSA even though it is generally only palliative. Novel avenues for adjuvant chemotherapy need evaluation. New approaches to treatment such as immunotherapy or antiangiogenic therapy may provide alternatives, and additional investigation into the biology of canine HSA, hopefully leading to clinical trials, is desperately needed.




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