Soft Tissue Sarcomas

22

Soft Tissue Sarcomas JUL IUS M. LIPTAK AND NEIL I. CHRISTENSEN

Incidence and Risk Factors Soft tissue sarcomas (STSs) are a heterogeneous population of mesenchymal tumors that comprise 15% and 7% of all skin and subcutaneous tumors in the dog and cat, respectively.1 The annual incidence of STSs in companion animals is about 35 per 100,000 dogs at risk and 17 per 100,000 cats at risk.2 In dogs, sarcomas have been associated with radiation, trauma, foreign bodies, orthopedic implants, and the parasite Spirocerca lupi.3–9 Most STSs are solitary tumors in middle-aged to older dogs and cats, except for rhabdomyosarcomas which occur in young dogs.10,11 There is no specific breed or sex predilection for STSs. STSs tend to be overrepresented in large-breed dogs.10 

Pathology and Natural History STSs are typically regarded as a heterogeneous group of tumors whose classification is based on similar pathologic appearance and clinical behavior; however, this may be an overly simplistic interpretation. Sarcomas arise from mesenchymal tissues and have features similar to those of the cell type of origin. These tumors originate in connective tissues, including muscle, adipose, neurovascular, fascial, and fibrous tissue, and can give rise to benign and malignant entities. STSs can arise at any anatomic location, but they most commonly involve the skin and subcutaneous tissues. For simplicity and consistency, a number of sarcomas arising from soft tissue are excluded from the umbrella term of cutaneous and subcutaneous STSs because of differences in anatomic location, biologic behavior (such as a higher metastatic rate and/or a different distribution of metastasis), and histologic features.12 These include histiocytic sarcoma (HS), synovial cell sarcoma (SCS), hemangiosarcoma (HSA), lymphangiosarcoma, rhabdomyosarcoma, oral fibrosarcoma (FSA), and peripheral nerve sheath tumors (PNSTs) of the brachial and lumbar plexi.12 HS, SCS, HSA, and oral FSA are covered in other chapters, with this chapter concentrating primarily on malignant STSs. The majority of cutaneous and subcutaneous STSs have a similar biologic behavior. This is characterized by a locally expansile mass growing between fascial planes, but STSs can also be infiltrative. STSs are often surrounded by a pseudocapsule formed by the compression of peritumoral connective tissue, which may contain or be confluent with neoplastic tissue.12,13 Overall, cutaneous and subcutaneous STSs have a low to moderate local recurrence rate after surgical excision, with or without adjuvant radiation therapy (RT), and a low metastatic rate. The likelihood of local recurrence 404

is dependent on tumor size, degree of infiltration, completeness of histologic excision, and histologic grade; the likelihood of metastasis is dependent primarily on histologic grade. STS is a general term encompassing a heterogenous group of tumors, but STSs can be subclassified according to the tissue of origin or phenotype.12 These include FSA, perivascular wall tumor (PWT), PNST (nonbrachial plexus), liposarcoma, myxosarcoma, pleomorphic sarcoma (or malignant fibrous histiocytoma), malignant mesenchymoma, and undifferentiated sarcoma.12,14,15 These can be difficult to differentiate histologically because common components include an intercellular collagen matrix and spindle or fusiform mesenchymal cells forming bundles, streams, and whorls.12 STSs may be characterized histologically by areas of mature tissue or via immunohistochemistry (IHC) by the expression of certain cellular markers to determine phenotype (Table 22.1).12,16–21 However, STSs may display more than one histologic pattern, and histologic patterns and IHC features may not be exclusive to a single cell type of origin or phenotype.12 STSs are sometimes referred to by alternate names such as spindle cell tumors of soft tissue because of the complexity of phenotypic differentiation, the use of the term “sarcoma” for tumors that have a low metastatic potential, and the difficulty in differentiating benign from low-grade malignant variants of some mesenchymal tumors of soft tissue (Table 22.2).12,22–25 Histologic distinction of tumor type may not be clinically important because most STSs have a similar biologic behavior (i.e., locally aggressive with a low to moderate risk of distant metastasis); however, this may be an overly simplistic approach as there is increasing evidence that discernible differences in presentations and outcomes may exist between different types of STSs. 

Specific Tumor Types Tumors of Fibrous Tissue

Nodular Fasciitis (Fibromatosis, Pseudosarcomatous Fibromatosis) Nodular fasciitis is a benign nonneoplastic lesion arising from the subcutaneous fascia or superficial portions of the deep fascia in dogs. These lesions are usually nodular, poorly circumscribed, and very invasive.26 Histologically, nodular fasciitis is characterized by large plump or spindle-shaped fibroblasts in a stromal network of variable amounts of collagen and reticular fibers with scattered lymphocytes, plasma cells, and macrophages.26 The morphologic and pathologic characteristics of nodular fasciitis can result in these lesions being misdiagnosed as FSA. Infantile desmoid-type

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TABLE 22.1  Types of Cutaneous and Subcutaneous Soft Tissue Sarcomas with Distinctions Based on

Histogenesis, Phenotype, Histologic Features, and Immunohistochemistry

Type

Tissue of Origin

Phenotype

Histologic Features

Fibrosarcoma

Fibrous tissue

Fibroblast, fibrocyte

Interwoven bundles, herringbone pattern, pronounced collagenous stroma

Myxosarcoma

Fibrous tissue

Fibroblast, fibrocyte

Stellate- or spindle-shaped cells in mucinous stroma

Pleomorphic sarcoma (malignant fibrous histiocytoma)

Fibrous tissue

Primitive mesenchymal cells (fibroblast or myofibroblast)

Mixture of fibroblastic cells and karyomegalic, cytomegalic, or multinucleate histiocytoid cells in storiform patterns with variable inflammatory infiltrate

Positive: lysozyme (29%–100%), MHC II (70%), desmin (86%), vimentin Negative: S-100, CD18

Perivascular wall tumor

Perivascular wall cells

Pericyte, myopericyte, smooth myocyte

Vascular growth patterns including staghorn, placentoid, perivascular whirling, and bundles from tunica media

Positive: calponin, pan actin, smooth muscle actin (50%) Negative: S-100, NSE, GFAP, myoglobin

Peripheral nerve sheath tumor

Peripheral nerve

Schwann cell, neurofibroblast

Interwoven bundles, whorls around collagen bundles, Antoni A and B patterns

Positive: NSE (45%–82%), S-100 (50%–100%), neurofilament (82%), NGFR (47%), myoglobin (64%), GFAP (0%–35%)

Liposarcoma

Adipose tissue

Lipoblast, lipocyte

Polygonal cells with distinctly vacuolated cytoplasm

Positive: MDM2 (67% of welldifferentiated and 75% of dedifferentiated), CDK4 (88% well-differentiated, 71% myxoid, 67% pleomorphic, and 100% dedifferentiated)84

Rhabdomyosarcoma

Skeletal muscle

Skeletal myoblast, skeletal mycoyte

Cytoplasmic striation, racket and strap cells

Positive: desmin, S-100 (75%), NSE (50%), GFAP (50%)

Lymphangiosarcoma

Lymph tissue

Irregular, anastomosing, and arborizing vascular channels and trabeculae lined by a single layer of flattened, elongate to plump spindle-shaped cells with scant cytoplasm supported on a collagenous stroma; with lumina characterized by a paucity of erythrocytes.91

Positive: PROX-1 (80%– 88%),90,91 Factor VIII-related antigen (100%), LYVE-1 (80%)91

Mesenchymoma

Any mesenchymal tissue

Multiple cell types

Immunohistochemistry

Multiple soft tissue mesenchymal cell types and matrix components including osteoid, chondroid, and collagen

GFAP, Glial fibrillary acidic protein; LYVE-1, lymphatic vessel endothelial receptor-1; MDM2, mouse double minute 2 homolog; MHC, major histocompatibility complex; NGFR, nerve growth factor receptor; NSE, neuron specific enolase; PROX-1, prospero-related homeobox gene 1. Modified from Dennis et al, Vet Pathol, 2011.12,84,90,91

  

TABLE 22.2  Soft Tissue Sarcoma Grading System

Score

Differentiation

Mitosisa

Necrosis

1

Resembles normal adult mesenchymal tissue

0–9

None

2

Specific histologic subtype

10–19

<50% necrosis

3

Undifferentiated

>20

>50% necrosis

Grade I: Cumulative score of ≤4 for the 3 categories. Grade II: Cumulative score of 5–6. Grade III: Cumulative score of ≥7. aMitosis

  

is calculated as the number of mitotic figures/10 HPF.

fibromatosis is a variant of nodular fasciitis and is characterized by fibroblast proliferation with a dense reticular fiber network and mucoid material.27 Wide excision of both nodular fasciitis and infantile desmoid-type fibromatosis lesions is usually curative.28 Local recurrence is possible with incomplete resection. These tumors do not metastasize.26 

Fibrosarcoma FSAs arise from malignant fibroblasts in any location, but most commonly in the skin, subcutaneous tissue, and oral cavity. Similar to other STSs, FSAs can range from well differentiated to anaplastic.29 FSAs tend to occur in older dogs and cats with no breed or sex predilection; however, a there was higher predilection in golden retrievers and Doberman pinschers in one study30 and

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dogs with FSAs were significantly younger than dogs with other histologic subtypes of STSs in another study.31 FSAs are more likely to recur after incomplete histologic excision and have higher mitotic rates than other histologic subtypes of STSs32–35 but, conversely, are more likely to be low grade.31 

Pleomorphic Sarcoma (or Malignant Fibrous Histiocytoma) Malignant fibrous histiocytoma (MFH) is a tumor with histologic characteristics resembling histiocytes and fibroblasts.36 According to the World Health Organization classification of soft tissue tumors, the preferred term for MFH is undifferentiated pleomorphic sarcoma because electron microscopic and IHC analyses of these tumors have shown that the term “fibrohistiocytic” is a misnomer.37 Pleomorphic sarcomas are typically diagnosed in middle-aged to older dogs. There is no sex predilection, although in one report 70% of dogs with the giant cell variant of pleomorphic sarcoma were female.38 Flat-coated retrievers, Rottweilers, and golden retrievers are overrepresented.38,39 Pleomorphic sarcomas is most commonly diagnosed in the subcutaneous tissues of the trunk and pelvic limbs and the spleen in dogs. Computed tomography (CT) and magnetic resonance imaging (MRI) characteristics of pleomorphic sarcomas have been described in humans but not in dogs.40 In people, pleomorphic sarcomas are typically characterized as a large lobulated inhomogeneous hypoto isodense mass with inhomogeneous enhancement on CT and hypo- to isointense on T1-weighted images, with inhomogeneous enhancement, hyperintensity, and hypointense areas on T2-weighted images on MRI.40 Four histologic subtypes of pleomorphic sarcoma are described: storiform–pleomorphic, myxoid, giant cell, and inflammatory.40 Definitive IHC staining patterns have not been established, but pleomorphic sarcomas will typically be vimentin positive and CD18 negative.39 Histologic subtype has prognostic significance in people, with the giant cell subtype having a higher local recurrence rate than storiform–pleomorphic subtype and a higher metastatic rate than the inflammatory subtype.41 Giant cell pleomorphic sarcomas have been described in 10 dogs: they were highly metastatic to subcutaneous tissue, lymph nodes (LNs), liver, and lungs; and the median survival time (MST) in these dogs was only 61 days.38 Canine pleomorphic sarcomas are significantly more likely to be high grade and have metastases at the time of diagnosis compared with other histologic subtypes of STSs.31  Myxosarcoma Myxosarcomas are neoplasms of fibroblast origin with an abundant myxoid matrix composed of mucopolysaccharides. These rare tumors occur in middle-aged or older dogs and cats. The majority are subcutaneous tumors of the trunk or limbs,29 but there are reports of myxosarcomas arising from the heart, eye, and brain.42–44 These tumors tend to be infiltrative growths with illdefined margins.29 

Tumors of the Vascular Wall Perivascular Wall Tumor PWTs are derived from the different cellular components of the vascular wall, excluding the endothelial lining.45 The components of the vascular wall depend on the type of vessel. Capillaries are composed of endothelium, pericytes, and basement membrane; large veins and arteries are composed of endothelium, subendothelial lining cells, basement membrane, a medial layer of smooth muscle cells, and an adventitial layer of myofibroblasts and

fibroblasts.45 PWTs are characterized by the amounts and types of cytoplasmic contractile proteins, which progressively increase from pericytes in capillaries to myopericytes and smooth muscle myocytes in the vascular subendothelial lining of larger vessels.45 PWTs have a characteristic cytologic appearance with moderate to high cellularity, cohesion of spindle cells, presence of capillaries, and multinucleate cells.45 They are diagnosed histologically based on vascular growth patterns (e.g., staghorn, placentoid, perivascular whirling, bundles of media) and are further characterized by IHC staining patterns.45 Pericytes express vimentin and variable amounts of pan and α-smooth muscle actin; myopericytes are characterized by the additional expression of desmin and calponin; and smooth muscle cells express smoothelin and heavy caldesmon.45 Based on IHC staining, canine PWTs have been classified similarly to human PWTs, with the following being recognized: myopericytoma, angioleiomyoma, angioleiomyosarcoma, hemangiopericytoma, angiofibroma, and adventitial tumor.45,46 PWTs are differentiated from PNSTs by both histology and IHC.45,47 PWTs are characterized by a less aggressive biologic behavior, with significantly lower rates of local recurrence than other histologic subtypes.34 

Tumors of Peripheral Nerves Peripheral Nerve Sheath Tumor PNSTs are tumors of nerve sheath origin, arising from Schwann cells, perineural cells, or perineural or endoneural fibroblasts.47 Benign and malignant variants have been described.48 The most common benign PNSTs are schwannomas and neurofibromas, and these tend to be well circumscribed, located in the skin and subcutaneous tissue, with an equal distribution of Antoni A and B histologic patterns.48 Malignant PNSTs are often subcutaneous, poorly circumscribed, and invasive into deeper tissues, and associated with high local tumor recurrence rates and relatively poor survival times.47,48 Malignant PNSTs can be differentiated from PWTs based on IHC staining; malignant PNSTs stain positive with S-100, vimentin, glial fibrillary acidic protein (GFAP), nerve growth factor receptor, and neuron-specific enolase.47–49 In additional, PNSTs have significantly higher Ki67 index than PWTs.49 Regardless of nomenclature, these tumors can occur anywhere in the body. Despite appearing encapsulated at surgery, they are similar to FSAs and are usually poorly defined without histologic encapsulation.48 Most are adherent to deeper tissues and may infiltrate underlying fascia, muscle, and skin.48 Although PNSTs are considered malignant, they have a modest metastatic rate. Local recurrence is common after conservative surgery.48 PNSTs tend to grow slowly and can range in size from 0.5 cm to greater than 12 cm in diameter. In some cases, they can easily be confused with lipomas on initial clinical examination.29 PNSTs of macroscopic nerves, which are not considered part of the conventional classification of STSs in dogs, are classified as peripheral, root, or plexus.50 Peripheral PNSTs involve macroscopic nerves distant to either the brain or spinal cord, and this form is much more amenable to treatment than either the root or plexus PNSTs. Plexus PNSTs can involve either the brachial or lumbrosacral plexus.50 The vast majority of cases will show signs of unilateral lameness, muscle atrophy, paralysis, and pain.50 They can invade the spinal cord, especially high-grade root and plexus PNSTs.50 Treatment options include surgery, surgery with adjuvant RT, or RT alone. Surgical excision typically involves forequarter amputation,50 although limb-sparing nerve-specific compartmental resection is occasionally possible.51

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In one study of 16 dogs with brachial plexus PNSTs treated with limb-sparing compartmental resection, the overall MST was 1303 days and was significantly better for dogs with complete histologic excision (MST 2227 days) compared with dogs with incomplete excision (MST 487 days).51 For peripheral nerve tumors extending through the foramen, hemilaminectomy may be required in addition to forequarter amputation for adequate tumor excision.50 Stereotactic RT has been described in 10 dogs with brachial plexus tumors with partial or complete resolution of neurologic signs in all dogs.52 The mean progression-free survival (PFS) and overall survival times (OSTs) were 240 days and 371 days, respectively, with progression reported in 90% of dogs.52 Regardless of histologic grade, local disease usually limits survival before metastasis occurs.50,52 

Tumors of Adipose Tissue Lipoma Lipomas are benign tumors of adipose tissue, and can be differentiated from liposarcomas based on morphologic, CT, and histologic appearance.53 There are three morphologic types of lipomas: regular, infiltrative, and intermuscular.53–59 Histologically, lipomas have indistinct nuclei and cytoplasm resembling normal fat, whereas liposarcomas are characterized by increased cellularity, distinct nuclei, and abundant cytoplasm with one or more droplets of fat.60 Histologic variants of lipomas have been reported and include angiolipoma and angiofibrolipoma.61 Regular lipomas are relatively common in older dogs, especially in subcutaneous locations, and are rarely symptomatic. They have been reported in the thoracic cavity, abdominal cavity, spinal canal, and vulva and vagina of dogs, and can cause clinical abnormalities secondary to either compression or strangulation.60,62–69 Marginal excision is recommended for lipomas that interfere with normal function; however, the majority are asymptomatic and do not require surgical intervention. Liposuction and intralesional triamcinolone have also been reported with variable results.70,71 Surgical resection is usually curative, but local recurrence has been reported.68  Intermuscular Lipoma Intermuscular lipomas are a variant of the subcutaneous lipoma and are located between muscle bellies. The most common location is the caudal thigh of dogs, particularly between the semitendinosus and semimembranosus muscles (Fig. 22.1), but they have also been reported in the axilla.72,73 Clinically, intermuscular lipomas appear as a slow-growing, firm, and fixed mass in either the axillary or caudal thigh region and may occasionally cause lameness.72,73 Cytologic analysis of fine-needle aspirates is usually diagnostic. The recommended treatment is surgical resection, involving blunt dissection and digital extrusion, and placement of a negative-suction drain. Seromas are a common complication in dogs in which a drain is not used.72 The prognosis is excellent with no recurrence reported after surgical excision in two published papers totaling 27 dogs.72,73  Infiltrative Lipoma Infiltrative lipomas are uncommon tumors composed of welldifferentiated adipose cells without evidence of anaplasia. These tumors cannot be readily distinguished from the more common simple lipoma by cytology or small biopsy specimens. They are considered “benign” and do not metastasize; however, infiltrative lipomas are locally aggressive and commonly invade adjacent muscle,

• Fig. 22.1  An

intermuscular lipoma arising from between the semitendinosus and semimembranosus muscles. Surgical dissection and removal was curative.

• Fig. 22.2  A CT scan of an infiltrative lipoma of the chest wall in a dog. Dif-

ferentiating an infiltrative lipoma from normal fat can be difficult on CT, but extension of the lipoma through the chest and body wall into the thoracic and abdominal (pictured) cavities is characteristic of an infiltrative lipoma.

fascia, nerve, myocardium, joint capsule, and even bone.55,74,75 CT is used to better delineate these tumors and they can be differentiated from regular lipomas based on differences in shape, margins, and type of attenuation53; however, they do not contrast enhance and differentiating infiltrative lipomas from normal fat can be problematic (Fig. 22.2).72 One retrospective analysis of 16

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subtype was not prognostic, but metastatic disease was more common in dogs with pleomorphic liposarcomas.76 A revised classification scheme has been proposed on the basis of IHC expression of MDM2 and CDK4. In one study, MDM2 and CDK4 were expressed in 67% and 88% of well-differentiated liposarcomas, 14% and 71% of myxoid liposarcomas, 0% and 67% of pleomorphic liposarcomas, and 75% and 100% of dedifferentiated liposarcomas.84 Furthermore, Ki67 index also correlated with histotype and was lowest in well-differentiated liposarcomas and highest in dedifferentiated liposarcomas.84 These results parallel the human data to some degree and suggest that not only are well-differentiated and dedifferentiated liposarcomas distinct entities, but that this classification scheme may have prognostic significance.84 

Surgery type Marginal excision Incisional biopsy Wide excision

Proportion surviving

1.0 0.8 0.6 0.4 0.2 0.0

0

1

2

Days

3

4

5

•

Fig. 22.3 Kaplan–Meier survival curve of 56 dogs with liposarcoma treated with either incisional biopsy, marginal resection, or wide excision. The median survival time is significantly longer, at 1188 days, after wide surgical resection than less aggressive techniques. (Reprinted with permission from Baez JL, Hendrick MJ, Shofer FS, et  al: Liposarcomas in dogs: 56 cases (1989–2000), J Am Vet Med Assoc 224:887, 2004.)

cases reported a 4:1 female-to-male ratio.57 Aggressive treatment, including amputation, may be necessary for local control. RT can be considered either alone or in combination with surgical excision. Complete and partial responses have been reported in the gross disease setting after external beam RT.59 

Liposarcoma Liposarcomas are uncommon malignant tumors originating from lipoblasts and lipocytes in older dogs.76 Liposarcomas are usually firm and poorly circumscribed. They are locally invasive with a low metastatic potential. Metastatic sites include the lungs, liver, spleen, and bone.29,76 Liposarcomas do not arise from malignant transformation of lipomas. Specific causes are not known, but foreign body–associated liposarcoma has been reported in one dog.5 There is no breed or sex predilection.76 They are commonly reported in subcutaneous locations, especially along the ventrum and extremities, but can also occur in other primary sites such as bone, spleen, and the abdominal cavity.76–78 Liposarcomas are differentiated from lipomas based on morphologic appearance, cytologic findings, and CT characteristics. Staining cytologic samples with Oil Red O can be useful to differentiate liposarcomas from other soft tissue saromas by staining lipid.79 Liposarcomas appear as mixed-attenuating, heterogeneous, multinodular, contrastenhancing masses on precontrast CT images, and these features can be used to differentiate liposarcomas from regular and infiltrative lipomas.53,80 The prognosis for liposarcoma is good with appropriate surgical management. The MST after wide surgical excision is 1188 days; this is significantly better than either marginal excision or incisional biopsy, which have MSTs of 649 days and 183 days, respectively (Fig. 22.3).76 Liposarcoma is histologically classified as well-differentiated, myxoid, round cell (or poorly differentiated), pleomorphic, or dedifferentiated. This classification scheme has clinical and prognostic importance in humans because pleomorphic liposarcomas have a high metastatic rate, myxoid liposarcomas are more likely to metastasize to extrapulmonary soft tissue structures, and well-differentiated liposarcomas are unlikely to metastasize.81–83 In a retrospective study in dogs, histologic

Tumors of Skeletal Muscle Rhabdomyosarcoma Rhabdomyosarcomas are rare malignant tumors originating from myoblasts or primitive mesenchymal cells capable of differentiating into striated muscle cells.85 In dogs, rhabdomyosarcomas are most frequently reported to arise from skeletal muscle of the urinary bladder, retrobulbar musculature (Fig. 22.4), larynx, tongue, and myocardium.86,87 They are locally invasive with a low to moderate metastatic potential. Metastatic sites include the lungs, liver, spleen, kidneys, and adrenal glands.85 Rhabdomyosarcomas are histologically classified as embryonal, botryoid, alveolar, and pleomorphic.86 The histologic diagnosis of rhabdomyosarcoma is difficult (see Fig. 22.4C), and IHC staining for vimentin, skeletal muscle actin, myoglobin, myogenin, and myogenic differentiation (MyoD) may be required for definitive diagnosis.88 Embryonal rhabdomyosarcomas have a predilection for the head and neck region, such as the tongue, oral cavity, larynx, and retrobulbar musculature.86,87 In contrast, botryoid rhabdomyosarcoma commonly arises in the urinary bladder of young, female large-breed dogs, with Saint Bernard dogs possibly being overrepresented in one data set.85 Botryoid tumors are characterized by their grapelike appearance. The histologic classification scheme for rhabdomyosarcoma has prognostic significance in humans.85,89 In humans, botryoid rhabdomyosarcoma has a good prognosis, embryonal rhabdomyosarcoma has an intermediate prognosis, and alveolar rhabdomyosarcoma has a poor prognosis.85,89 In dogs, botryoid rhabdomyosarcomas have a 27% metastatic rate whereas embryonal and alveolar rhabdomyosarcomas have a 50% metastatic rate.86 Metastatic disease is more common in younger dogs, with the majority of dogs with metastatic disease being less than 2 years of age in one study86 and, in another study, all dogs less than 4 years of age died of metastatic disease or local tumor recurrence (with an MST of 2.5 months), whereas no dog older than 4 years of age died of tumor-related reasons.87 

Tumors of Lymphatic Tissue Lymphangiosarcoma Lymphangiosarcoma is a rare tumor arising from lymphatic endothelial cells.29,90 They are usually soft, cystic-like, and edematous, usually occurring in the subcutis (Fig. 22.5).29 In most cases, clinical signs are associated with extensive edema and drainage of lymph through the skin or a cystic mass, or nonhealing, discharging wounds.90 Lymphangiosarcoma and HSA can be difficult to differentiate using histopathology and immunohistochemical markers for vascular endothelium, such

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B

A

C • Fig. 22.4  (A) Postcontrast axial CT image at the level of the cribriform plate from a 12-month-old Belgian Turvuren.

A hypoattenuating mass with a contrast enhancing rim (arrow) is causing significant dorsal displacement of the right eye. The dog developed local recurrence and pulmonary metastatic disease despite surgery and postoperative radiation therapy within 2 months after diagnosis. (B) A postoperative specimen image of a retrobulbar rhabdomyosarcoma resected from a 6-year-old Labrador retriever (arrows). An en bloc enucleation was performed because of adhesion of the rhabdomyosarcoma into the caudal aspect of the globe (stars). (C) Histopathology of the rhabdomyosarcoma in Fig. 4A reveals rafts of highly pleomorphic and haphazardly arranged polygonal to spindle cells with multiple mitotic figures. H&E, bar = 20 μm. Inset: Photomicrographs showing a basophilic mass expanding and partially effacing orbital and subconjunctival tissues, H&E. (Image courtesy Dr. L. Teixeira.)

as factor VIII–related antigen and CD31.29,91 IHC staining with the lymphatic endothelial cell-specific markers lymphatic vessel endothelial receptor-1 (LYVE-1) and propsero-related homeobox gene-1 (PROX-1) successfully differentiated lymphangiosarcoma from HSA in the majority of dogs.91 In one series of 12 dogs with lymphangiosarcoma, the MST was 168 days (range, 60–876 days) for three dogs with no treatment and 487 days (range, 240–941 days) for five dogs treated with surgery alone; one dog treated with surgery, RT, and chemotherapy had an ST of 574 days.90 All dogs treated surgically had incomplete histologic excision and all dogs were euthanized because of recurrent or progressive local disease.90 

Tumors of Uncertain Histogenesis •

Fig. 22.5 Lymphangiosarcoma of the ventral abdomen in a male cat. These tumors are often subcutaneous, soft, and edematous, and with poorly defined margins.

Malignant Mesenchymoma Malignant mesenchymomas are rare STSs comprising a fibrous component with two or more different varieties of other types of sarcoma.26 Malignant mesenchymomas have been reported in the heart, lungs, thoracic wall, liver, spleen, kidney, digits, and soft

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PA RT I V     Specific Malignancies in the Small Animal Patient

• Fig. 22.6  The typical gross appearance of a canine soft tissue sarcoma with a firm, well-circumscribed, expansile subcutaneous mass.

tissue.92–101 They have a slow rate of growth and can grow very large. Metastasis has been reported.96–100 The outcome for dogs with splenic mesenchymomas is better than for those with other types of splenic sarcomas, with a MST of 12 months and a 1-year survival rate of 50%.96 

History and Clinical Signs STSs generally present as slow-growing expansile masses. Rapid tumor growth, intratumoral hemorrhage, or necrosis can be seen in some cases. Symptoms are directly related to site of involvement and tumor invasiveness, with the vast majority of subcutaneous and cutaneous STSs causing no clinical signs. There is marked variability in the physical features of STS, but they are generally firm and well circumscribed (Fig. 22.6). They can be either mobile or adherent (fixed) to skin, muscle, or bone. STSs can also be soft and lobulated, mimicking lipomas. 

Diagnostic Techniques and Workup Fine-needle aspiration (FNA) is recommended for a cytologic diagnosis; however, cytologic evaluation may not be sufficient for a definitive diagnosis because variable degrees of necrosis and poor exfoliation of cells may result in a nondiagnostic sample.26 The cytologic accuracy of correctly diagnosing an STS varies from 63% to 97%.32,102 Cytologic preparations should be assessed by a board-certified cytopathologist because a disproportionate number of false-negative cytologic results were associated with in-house cytologic assessments compared with evaluation by a board-certified cytopathologist in one study.33 Even in the absence of a definitive diagnosis, FNA cytology can exclude the diagnosis of readily exfoliating tumors such as epithelial and round cell tumors, and this may be sufficient for the suspected diagnosis of an STS by exclusion.102,103 Biopsy methods for definitive preoperative diagnosis of STSs include needle-core, punch, incisional, or excisional biopsies.

The biopsy should be planned and positioned so that the biopsy tract can be included in the curative-intent treatment without increasing the surgical dose or size of the radiation field. Although needle-core and incisional biopsies will typically provide sufficient tissue for a definitive diagnosis of STS, the determination of histologic grade from preoperative biopsies was incorrect in 41% of dogs compared with the definitive surgical sample, with histologic grade underestimated in 29% of dogs and overestimated in 12% of dogs.104 Excisional biopsies are not recommended because they may not be curative and the subsequent surgery required to achieve complete histologic margins is often more aggressive than surgery after core or incisional biopsies, resulting in additional morbidity and treatment costs. Furthermore, multiple attempts at resection, including excisional biopsy, before definitive therapy have a negative effect on ST in dogs with STSs.105 Diagnostic tests performed for workup and clinical staging include routine hematologic and serum biochemical blood tests, three-view thoracic radiographs, abdominal ultrasonography or advanced imaging, FNA or biopsy of the regional LNs, and regional imaging of the STS. Three-view thoracic radiographs should be performed before definitive treatment because the lungs are the most common metastatic site for typical STSs.35 Although LN metastasis is uncommon, FNA or biopsy of regional LNs should be performed in dogs with clinically abnormal LNs, grade III STSs, or suspected nonconventional STSs with a high rate of metastasis to regional LNs (e.g., HS).106 Abdominal imaging is recommended for the assessment of metastasis to intraabdominal organs in animals with highgrade pelvic limb STS. Imaging studies of the local tumor may be required for planning of the surgical approach or RT if the tumor is fixed to underlying structures or located in an area that may make definitive treatment difficult, such as the pelvic region. Three-dimensional (3D) imaging techniques such as CT and MRI are particularly useful for staging local disease.107 Other imaging modalities for staging of the local tumor include survey radiographs and ultrasonography.108 

Clinical Staging A modified staging system has been described for STSs in dogs.26 The American Joint Committee on Cancer (AJCC) staging system currently used in humans with STSs has been substantially modified from the original staging system, on which the modified animal staging system is based. The most important change to AJCC staging is categorization of local disease, with less emphasis on tumor size, which is an arbitrary assignment, and greater emphasis on depth of invasion.81,109 A superficial tumor is defined as an STS located above the superficial fascia and that does not invade the fascia, whereas a deep tumor is located deep to the superficial fascia, invades the fascia, or both.109 

Treatment The predominant challenge in the management of cutaneous and subcutaneous STSs is local tumor control. As such, surgical resection is the principal treatment for dogs with STSs. RT may also play a significant role in local tumor control, especially for incompletely resected and unresectable STSs. However, definitive treatment options depend on tumor location, clinical stage, histologic grade, and completeness of histologic margins.10,26,110 A suggested algorithm for managing dogs with STSs is presented in Fig. 22.7.

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Biopsy-confirmed soft tissue sarcoma

Wide surgical resection

Histologically incomplete margins

Histologically complete margins

Adjuvant radiation therapy

Grade I

Grade II

Routine follow-up (e.g., 1, 3, 6, 9, 12, 18 months etc.)

Wide surgical resection of scar

Grade III

Consider adjuvant chemotherapy with doxorubicin-based protocol

• Fig. 22.7  Suggested algorithm for the treatment of soft tissue sarcomas in dogs.

Surgery The surgical options for management of STSs include marginal resection, wide resection, or radical resection, and the preferred surgical approach can be tailored to each individual patient depending on location, size, degree of infiltration, histologic grade of the STS, and the outcome goals of the client. The majority of STSs are characterized by a locally expansile mass, but they can also be infiltrative.111 This was supported by a histologic study showing that grade I and II STSs were significantly less invasive than low-grade mast cell tumors in both circumferential and deep directions.112 STSs are often surrounded by a pseudocapsule formed by the compression of peritumoral connective tissue that may contain or be confluent with neoplastic tissue.12,26 The pseudocapsule can give the false impression of a well-encapsulated tumor; however, surgical removal of the encapsulated mass without adequate margins may result in incomplete histologic margins and a higher risk of local tumor recurrence.35 The minimum recommended margins for wide surgical resection of STSs are 2 to 3 cm lateral and one fascial layer deep to the tumor (Fig. 22.8),10,13,103,110,113,114 although this is an arbitrary recommendation and does not account for tumor size, patient size, tumor location, or local tumor characteristics.10,103,110,113,114 In one study of 22 dogs with 24 subcutaneous STSs, all STSs were completely excised with mean lateral and deep margins of 22.23 mm (range, 6–50 mm) and 7 mm (1–24 mm), respectively, with all deep margins including an uninvolved fascial plane (Fig. 22.9).113 A proportional margin system, where the lateral surgical margins are equal to the maximal diameter of the tumor as validated for the resection of low-grade mast cell tumors,115 may also be appropriate

for the resection of STSs in dogs because incomplete histologic excision is significantly more likely after surgical resection of larger tumors and tumors in smaller patients 46,116 Biopsy tracts and any areas of fixation, including bone and fascia, should be resected en bloc with the tumor using the recommended surgical margins. Radical surgery such as limb amputation or hemipelvectomy may be required to achieve adequate histologic margins and local tumor control, especially for fixed and invasive STSs. Wide excision of STSs is associated with a significantly increased likelihood of complete histologic excision,32 and dogs with complete histologic excision are 10.5 times less likely to have local tumor recurrence compared with dogs with incompletely excised STSs.35 Marginal excision may be an acceptable treatment option for well-circumscribed, noninfiltrative STSs less than 5 cm in diameter, and located on the limbs at or below the elbow or stifle. STSs in these locations tend to be less infiltrative and more well-circumscribed than STSs in other locations, such as the upper limbs and trunk (Fig. 22.10).46,117 In one study of 236 dogs with subcutaneous STSs treated with excisional biopsy, the local recurrence rate was 0% for completely excised tumors and dependent on histologic grade for incompletely excised tumors, with 7% of grade I and 34% of grade II incompletely excised STSs developing local tumor recurrence.118 Similar results have been reported in other studies after marginal excision of STSs from nonreferral practices and low-grade PWTs. In a study of 35 dogs with marginal excision of 37 low-grade STSs, the local recurrence rate was 11% and no prognostic factors for local recurrence were identified.117 In a study of 104 canine STSs managed with surgery alone in nonreferral practices, which did not include undifferentiated

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A

B

C • Fig. 22.8  Wide resection of a grade II soft tissue sarcoma from the craniolateral thigh of a dog. (A) Planned lateral surgical margins are indicated with a sterile marker pen 3 cm in all directions around the soft tissue sarcoma. (B) An incision is then performed along the marked margins, and continued deeply to include an uninvolved fascial layer. (C) Primary closure after wide resection of the soft tissue sarcoma.

STSs and liposarcomas, fewer than 10% were excised with 3 cm lateral margins, and local tumor recurrence was reported in 28% of dogs (29% of marginal excisions, 17% of narrow excisions, and 5% of wide excisions); local tumor recurrence was significantly more likely to occur with fixed and invasive

STSs.25 In two studies of dogs with PWTs, the local recurrence rate was 18% to 20.0% despite 60% to 63% of these tumors being incompletely excised.46,111 The only prognostic factor for local recurrence in both studies was tumor size, with local recurrence up to 7.0 times more likely for PWTs greater than 5 cm diameter with the risk of local tumor recurrence increasing by up to 1.3 times for every 1 cm increase in tumor size.46,111 In a study of 350 canine STSs treated surgically in nonreferral practices, the local recurrence rate was 21% despite only 5% of these STSs being excised with wide surgical margins.34 Histologic grade was the only prognostic factor for local tumor recurrence in this study, with grade III STSs having a 5.8-fold increased risk for local recurrence compared with grade I and II STSs.34 Taken in totality, these studies suggest that acceptable local tumor control rates are achievable with less aggressive surgical approaches; however, they also illustrate that the traditional consideration of STSs having a similar biologic behavior is overly simplistic. The ideal treatment for dogs with cutaneous and subcutaneous STSs should not necessarily be standardized but rather tailored to each individual case according to location, tumor size, degree of infiltration, histologic subtype, histologic grade, and completeness of excision. If insufficient information is available before surgery to individualize treatment options, then wide surgical resection (with 2–3 cm lateral margins and one fascial layer for deep margins) is the preferred surgical approach. The resected tumor should be pinned out to the original dimensions to prevent shrinkage during formalin fixation119; the lateral and deep margins should be inked to aid in histologic identification of surgical margins; and any areas of concern should be tagged with suture material, inked in a different color, or submitted separately for specific histologic assessment. Histologic margins and histologic grade are important in determining the need and type of further treatment. There are a number of limitations with our current ability to assess the adequacy of the completeness of the excision and risk of local tumor recurrence, and thus our ability to determine which patients require further therapy and which patients may benefit from monitoring. These include sample shrinkage after excision and during formalin fixation, the techniques used to assess margins histologically, the lack of information on the definition of a “narrow” histologic margin, and the significance of narrow margins on the risk of local tumor recurrence.13,120 Perhaps most important is that histopathology is an examination of excised tissue ex vivo and not residual tissue in vivo, and that this assessment is made days after surgery rather than in real time. A number of advancements are being made in both veterinary and human surgical oncology in the real-time assessment of the wound bed after excision of STSs for residual neoplastic disease.121–125 Hopefully, as these real-time in vivo assessment methods are validated and become available for clinical use, there will be an improvement in the rate of complete histologic excision and local tumor control. The treatment options for incompletely excised STSs include active surveillance (i.e., frequent observation for local tumor recurrence and appropriate treatment if the tumor recurs), staging surgery, wide excision (i.e., revision surgery), RT, metronomic chemotherapy, and electrochemotherapy. The first surgery provides the best opportunity for local tumor control, as the management of incompletely resected tumors increases patient morbidity and treatment costs, increases the risk of further local tumor recurrence, and potentially decreases ST.10,31,34,35,105,110,126–130 Active surveillance may be appropriate

CHAPTER 22  Soft Tissue Sarcomas

A

413

B

• Fig. 22.9  (A) Wide and marginal resection of soft tissue sarcomas should include an uninvolved fascial

layer for deep margins or, (B) if a defined anatomic fascia layer is not present, then either partial or full thickness muscle.

for dogs with grade I and possibly grade II STSs with favorable local characteristics, such as well-circumscribed tumors, less than 5 cm in diameter, and located on either the thoracic or pelvic limb at or below the elbow or stifle.25,34,46,110,111,117,118 Active surveillance may be appropriate in these cases because, as discussed earlier, local recurrence rates are relatively low (7% and 34% for incompletely excised grade I and II STSs, respectively)118 and further aggressive treatment may be unnecessary in up to 93% of dogs (with incompletely grade I STSs), with an associated increased risk in morbidity and costs. Staging surgery is a decision-making surgery. The surgical scar is excised with minimal margins (<1 cm), with the aim being to determine whether there is histologic evidence of residual tumor cells.33 In one study in which the surgical scar was excised with 0.5- to 3.5-cm lateral margins, histologic evidence of residual tumor was identified in only 22% of 39 dogs with incompletely excised STSs.33 If there is no evidence of tumor cells, then no further treatment is required and these dogs should be monitored regularly for local tumor recurrence. If there is evidence of residual tumor cells, then wide resection of the surgical scar should be performed with the same margins recommended for primary STSs (2–3 cm lateral to the tumor and one fascial layer deep to the tumor10,13,103,110,113,114) or the entire surgical scar should be irradiated.128,129 Surgery is preferred to RT for the management of incompletely resected STSs in humans because local tumor control is better with repeat surgical resection than adjunctive RT alone.128,129 Metronomic (or low-dose) chemotherapy is another option for the management of dogs with incompletely excised STSs. The administration of piroxicam and low-dose cyclophosphamide in 30 dogs with incompletely excised STSs resulted in a significantly prolonged disease-free interval (DFI) compared with a nonrandomized control group of 55 dogs with incompletely excised STSs and no metronomic chemotherapy.131 Of note, the control population used in this study experienced recurrence rates much greater than what is expected in the general population based on

the preponderance of current data, perhaps weakening the generalizability of this study. Metronomic chemotherapy has been much less thoroughly studied than wide excision or postoperative RT, and should not be considered an equivalent substitute for these other modalities at this time. Additional studies are needed to confirm the efficacy of metronomic chemotherapy in the management of dogs with incompletely excised STSs. Electrochemotherapy has also been investigated in the management of incompletely excised high-grade STSs in 22 dogs.132 Bleomycin was injected into the tumor bed followed by sequential application of trains of biphasic electrical pulses. The local recurrence rate was 36% with a mean time to recurrence of 730 days.132 Wound dehiscence was reported in 14% of dogs. 

Surgery and Radiation Therapy RT is often recommended in the management of dogs with STSs, particularly after incomplete histologic excision, and adjuvant RT has a documented role in improving local tumor control in people with STSs.103,114,128,129 The evidence is less robust in veterinary medicine because all published studies of adjuvant RT in the management of dogs with incompletely excised STSs are retrospective and, more importantly, lack a control group. Local recurrence rates are similar in studies of dogs treated with marginal resection alone, compared with recurrence rates occurring in dogs with either marginal resection or incomplete histologic excision treated with adjuvant RT (fractionated or hypofractionated) or intralesional chemotherapy (Table 22.3); however, it is important to recognize that study results cannot be compared because of differences in study populations and methodologies. Furthermore, because canine STSs have a biologic behavior similar to that of low-grade STSs in people and because RT significantly improves local tumor control in people with incompletely excised STSs, RT should still be considered in the management of dogs with STSs.114,128,129 RT can be used as an adjunct to surgery after either planned marginal resection or unplanned incomplete histologic excision. Marginal surgical

A

B

C

D

•

Fig. 22.10 (A) Marginal resection of a well-circumscribed, noninfiltrative, grade I soft tissue sarcoma below the level of the stifle in a dog. (B) Freely movable skin over the soft tissue sarcoma is carefully dissected away from the mass to avoid iatrogenic penetration of the tumor capsule and (C, D) permit primary closure of the subsequent wound defect. This soft tissue sarcoma was resected with complete histologic margins and the dog remains tumor-free 2 years postoperatively.

TABLE 22.3  Comparison of Local Tumor Control Outcomes for Dogs with Cutaneous and Subcutaneous Soft

Tissue Sarcomas Between Different Treatment Modalities Local Recurrence Rate

Median DiseaseFree Interval

1-Year DiseaseFree Rate

2-Year DiseaseFree Rate

3-Year DiseaseFree Rate

Surgery25,32,34,46,111,113,117,118

Wide: 0%–5% Marginal: 11%–29%

368 days to not reached

89%–93%

78%–82%

66%–76%

Surgerya and fractionated radiation therapy135–138

17%–39%

412 days to not reached

71%–84%

60%–81%

57%–81%

Surgerya and hypofractionated Radiation therapy140,141

18%–21%

698 days to not reached

81%

73%

73%

Marginal surgical resection and intralesional chemotherapy162–164

17%–31%

264 days to not reached

81%–100%

69%–89%

59%–84%

aIncomplete

  

histologic excision.

CHAPTER 22  Soft Tissue Sarcomas

• Fig. 22.11  Planned marginal resection of a soft tissue sarcoma in a dog. Marginal resection followed by full-course postoperative radiation therapy provides excellent local tumor control and preserves both the limb and limb function. Radiation therapy should not involve the limb circumferentially to preserve both lymphatic and venous drainage of the distal extremity. If close but clean margins were obtained for a grade I soft tissue sarcoma, observation alone may be an acceptable alternative.

resection combined with full-course postoperative RT is an attractive alternative to limb amputation for extremity STS (Fig. 22.11). This multimodality approach requires additional planning and costs, but preserves the limb and limb function. Surgery involves completely removing all grossly visible tumor and then marking the lateral, proximal, and distal extents of the surgical field with radiopaque clips to assist in planning of RT.133 Migration of the radiopaque clips has been reported but does not significantly influence the planned radiation field.133 RT should be started a minimum of 7 days postoperatively to minimize the risk of radiation-induced complications with the surgical wound, such as delayed healing and dehiscence.134 Fullcourse fractionated protocols are recommended, with reported schedules including 3.0- to 4.2-Gy fractions on a Monday-to-Friday or Monday–Wednesday–Friday schedule for a total dose of 42 to 63 Gy.135–138 The optimal fractionation and total dose schemes for canine STS have not been determined, but cumulative doses greater than 50 Gy are recommended because local tumor control is better with higher cumulative doses.135 Acute side effects of RT, such as moist desquamation, are relatively mild and transient.136 Local tumor control and ST are very good when incompletely resected STSs are treated with postoperative, definitively fractionated RT with local tumor recurrence reported in 16.7% to 36.8% of dogs,135–137 and 1-, 2-, 3-, and 4-year local control rates of 71% to 84%, 60% to 81%, 57% to 81%, and up to 81%, respectively.135,136,138 The local tumor recurrence rates may have been adversely affected by the inclusion of incompletely excised oral FSAs in one study.135 The median time to local recurrence is 412 days to more than 798 days.105,135–137 The median time to recurrence was significantly shorter in dogs with grade III STSs (78 days) compared with dogs with grade I and II STSs (>1416 days) in one study.135 The overall MST for incompletely resected nonoral STSs treated with postoperative RT is 2270 days, with survival rates ranging from 80% to 87% at 1 year, 72% to 87% at 2 years, 92% at 3 years, and 76% at 5 years.135–139 In one study, dogs with STSs with a mitotic index greater than 9 per 10 highpower fields (HPFs) were more likely to have local recurrence and shorter ST.139

415

Hypofractionated RT after either incomplete or close complete (<3 mm) histologic excision of STSs has also been reported with encouraging results.140,141 Protocols reported have utilized weekly fractions of 6 to 9 Gy to a total dose of 24 to 36 Gy.140 An 18% to 21% local recurrence rate was reported in these studies; however, the majority of STSs were initially small (median size 3.6 cm) and either grade I or II (83%).140,141 Acute toxicity was mild, but late toxicities, although uncommon, were noted in both studies.140.141 An increased risk of late toxicity generally occurs with larger radiation doses per fraction and this risk must be considered in a group of patients who are expected to survive for prolonged periods after RT. Progression-free intervals (PFIs) in these studies were 698 days to not reached, and the probability of being free of local tumor recurrence at 1, 2, and 3 years was 81%, 73%, and 73%, respectively.140,141 In one study, delaying hypofractionated RT for more than 4 weeks after surgery was associated with an improved outcome, with local recurrence nine times more likely in dogs in which RT was started less than 4 weeks after surgical excision.140 Histologic grade was prognostic for both median PFS and OST in one study.141 Median PFS times were 1904 days, 582 days, and 292 days for dogs with grade I, II, and III STSs, respectively; the median tumor-specific OST was not reached for dogs with grade I and II STSs, but was 940 days for dogs with grade III STSs.141 

Radiation Therapy for Gross Disease RT can also be used a single modality, usually for palliation of clinical signs. RT alone, using a cumulative dose of 50 Gy, resulted in 1- and 2-year tumor control rates of 50% and 33%, respectively.142 Measurable and palpable (i.e., macroscopic) STSs are resistant to long-term control with conventional doses of radiation alone (40–48 Gy).143,144 Although one study reported a 30% complete response rate with RT alone,145 these tumors do not rapidly regress after RT and, if there is significant tumor shrinkage, it is not usually a durable response. Hypofractionated RT has been reported for the treatment of macroscopic STSs using a number of different protocols, including 3 to 4 fractions of 8 Gy once weekly for a total dose of 24 to 32 Gy, 5 to 6 fractions of 6 Gy once to twice weekly for a total dose of 30 to 36 Gy, and 5 fractions of 4 Gy for a total dose of 20 Gy.146–150 The results of hypofractionated RT are similar to those of full-course RT in the gross disease setting. In two studies, the overall response rate was 46% to 50%,146,148 whereas stable disease was more common in two other studies.147,149 The median PFI ranged from 155 to 419 days.146–150 Prognostic factors for median PFI include tumor location and previous surgeries. The median PFI is significantly better for limb STSs (466 days) than STSs located on the head or trunk (110 days), and dogs treated with more than one surgery had a significantly decreased median PFI (105 days) compared with dogs treated with one or no surgery (420 days).148 The MST after hypofractionated RT for macroscopic STS is 206 to 513 days.146–150 STS location has a significant effect on MST, with STSs located on the limbs (579 days) having a better outcome than those on the head (195 days) or trunk (190 days).148 In this study, 40% of dogs were also treated with metronomic chemotherapy. Metronomic chemotherapy did not improve median PFIs, but this adjunctive treatment did significantly improve MSTs (757 days compared with 518 days for dogs not treated with metronomic chemotherapy).148 Preoperative RT is becoming commonplace in veterinary oncology. The rationale and advantage of administering RT before surgery are that (1) the radiation field is smaller because, after

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surgery, the entire surgical site must be included in the field plus a margin of normal tissue and this may contribute to local toxicity; (2) a large number of peripheral tumor cells are inactivated (with reduced contamination of the surgical site); and (3) tumor volume reduction may make surgical resection less difficult.15,151–153 In a randomized phase III human trial of preoperative compared with postoperative RT, wound complications were found to be higher in people treated with preoperative RT (35% vs 17%); however, OST was found to be marginally improved in patients treated with preoperative RT.154 Other studies, including a meta-analysis of 1098 patients, have confirmed these findings and further suggested that both local recurrence rates and ST may be improved in patients treated with preoperative RT.155 Lower doses of preoperative RT (<50 Gy) are generally used to reduce the risk of surgical complications. 

Chemotherapy The role of chemotherapy in the management of dogs with STS is controversial. The metastatic rates for dogs with grade I, II, and III cutaneous STSs are 0% to 13%, 7% to 27%, and 22% to 44%, respectively.31,35,156 Metastasis often occurs late in the course of disease, with a median time to metastasis of up to 365 days,35 and this may minimize the beneficial effects of postoperative chemotherapy on the development of metastatic disease. In one retrospective study of 39 dogs with grade III STSs arising from various locations, including noncutaneous and subcutaneous sites, treated with either surgery alone (n = 18) or surgery and doxorubicin (DOX) (n = 21), there was no significant difference in survival outcomes with the addition of DOX to the treatment protocol.156 An alternating protocol of DOX and ifosfamide was reported in 12 dogs with various STSs after surgical excision, but survival outcomes were not investigated because of low case numbers.157 DOX and ifosfamide are the most effective single agents in the management of STS in humans, but meta-analyses show that single- and multiple-agent chemotherapy protocols do not significantly increase OST compared with surgery alone in people.158,159 Although adjuvant chemotherapy has not shown the same effect on local tumor control in dogs with STSs as it does in people,158 metronomic and local chemotherapy protocols may be effective in decreasing the rate of local tumor recurrence and improving DFIs in dogs with STSs. Metronomic chemotherapy improves local tumor control in experimental and human studies by inhibiting tumor angiogenesis and suppressing regulatory T cells, and a similar effect was demonstrated in dogs with STSs treated with low-dose cyclophosphamide at a dose of 15.0 mg/ m2/day, but not 12.5 mg/m2/day.160 Clinically, metronomic chemotherapy improved ST in dogs with macroscopic STSs treated with hypofractionated RT.148 Although not investigated clinically, there may be a role for tyrosine kinase inhibitors in the management of STS because increased vascular endothelial growth factor (VEGF) and VEGF receptor expression has been demonstrated in the peri- and intratumoral regions of canine STSs.161–163 Furthermore, VEGF has been postulated to have a role in the angiogenesis of canine STSs because serum VEGF levels decrease after STS excision.164 The effect of the local release of chemotherapy on local tumor recurrence rates after marginal excision of STSs has been investigated in dogs. Intralesional chemotherapy agents include cisplatin, released locally from either a biodegradable polymer or calcium sulfate and dextran sulfate beads implanted into the surgical bed, and 5-fluorouracil, injected weekly for a minimum of

six treatments.165–168 Local recurrence was reported in 17% to 31%, and this was significantly more likely for dogs with grade III STSs.162–164 Wound complications are common after treatment with intralesional chemotherapy and are reported in 47% to 84% of dogs.163–167 

Prognosis Local Tumor Recurrence Local tumor control is often the most challenging aspect of managing STSs, but this is dependent on a number of factors including tumor size, local tumor characteristics such as well-circumscribed or infiltrative, tumor location, histologic grade, completeness of histologic excision, and treatment methods. The overall local recurrence rates are 0% to 5% after wide resection,25,113 11% to 29% after marginal resection,25,34,46,111,117,118 17% to 37% after incomplete histologic excision and fractionated RT,135–137 and 18% to 21% after incomplete histologic excision and hypofractionated RT (see Table 22.2).140,141 The DFIs and local tumor control rates are also similar between the different treatment options, with a median DFI of 368 to 637 days to not reached and disease-free rates of 89% to 93%, 78% to 82%, and 66% to 76% at 1, 2, and 3 years, respectively, after surgery alone32,34,35,46,113; a median DFI of 412 to more than 798 days and disease-free rates of 71% to 84%, 60% to 81%, 57% to 81%, and up to 81% at 1, 2, 3, and 4 years, respectively, for incomplete excision and fractionated RT135,136,138; and a median DFI of 698 days to not reached and disease-free rates of 81%, 73%, and 73% at 1, 2, and 3 years, respectively, after incomplete excision and hypofractionated RT.140,141 Poor prognostic factors for local tumor control include large tumor size (>5 cm), infiltrative tumors, tumors in locations other than the limbs at or below the elbow or stifle, histologic subtypes, grade III STSs, and incomplete surgical margins. In one study of 75 dogs, the local tumor recurrence rate after incomplete histologic excision was 28% and 11 times more likely compared with STSs resected with complete histologic margins (Fig. 22.12).35 Complete histologic excision is significantly more likely when STSs are treated with wide resection rather than more conservative approaches,31,32 and complete histologic excision is associated with long-term survival in up to 98% of dogs with STSs.31,32,35,113 Despite the importance of complete histologic excision in the management of dogs with STSs, incomplete excision has infrequently been identified as a prognostic factor for local tumor recurrence after marginal resection,25,118 with the majority of studies showing no significant association between incomplete histologic excision and local tumor recurrence.34,46,111,117 Histologic grade has an effect on local tumor recurrence both overall and after incomplete histologic excision. Grade III STSs have a six-fold greater risk for local recurrence compared with lowgrade tumors.34 In one study of 236 dogs with subcutaneous STSs treated with excisional biopsy, the local recurrence rate was 0% for STSs excised with complete histologic margins and 19% overall for incompletely excised STSs.118 The recurrence rate for incompletely excised grade I, II, and III STSs was 7%, 34%, and 75% (three of four) respectively.118 Histologic subtype may also be associated with local tumor recurrence; however, it is important to recognize that differentiating histologic subtypes of STSs can be problematic, even with IHC.12,114 PWTs are often associated with a low risk of local tumor recurrence,12,34 whereas FSAs have been associated with a higher local recurrence rate.32–34

CHAPTER 22  Soft Tissue Sarcomas

417

Proportion of dogs free of tumor recurrence

1

0.8

0.6

0.4

0.2

0 0

500

1500 2000 1000 Recurrence-free interval (days)

2500

3000

Lack of tumor cells at surgical margins Evidence of tumor cells at surgical margins

• Fig. 22.12  Kaplan–Meier curve for disease-free interval in 39 dogs with complete surgical removal of soft tissue sarcomas and 36 dogs with incomplete surgical margins. (Reprinted with permission from Kuntz CA, Dernell WS, Powers BE, et  al: Prognostic factors for surgical treatment of soft-tissue sarcomas in dogs: 75 cases (1986–1996), J Am Vet Med Assoc 211:1147, 1997.)

Local tumor characteristics also influence local tumor control. Tumor size has been reported to have a negative effect on local tumor control, especially for incompletely excised STSs.35,46,111 Local tumor recurrence is up to 7.0 times more likely after marginal resection of PWTs greater than 5 cm diameter and the risk of local tumor recurrence increases by up to 1.3 times for every 1 cm increase in tumor size.46,111 This may be because a large tumor size influences the ability to achieve complete histologic excision or because a larger tumor size may indicate a more aggressive biologic behavior.46,116 Tumor size has not been identified as a prognostic factor in other studies,32,33,139,169 and does not influence local tumor control in dogs treated with surgery and adjuvant RT or RT alone.142,169,170 Dogs with fixed or invasive STSs have significantly decreased DFIs and STs.34 Invasive or fixed tumors are associated with a two-fold increased risk for local recurrence compared with well-circumscribed STSs after marginal resection,25 and PWTs invasive into muscle were eight times more likely to recur after marginal resection.32,111 Local tumor recurrence has been associated with an increased risk of tumor-related death and decreased STs in some studies.31,34 In one study of 350 dogs with STSs managed in nonreferral practices, local tumor recurrence was associated with a 5-fold risk of death.34 Although many dogs can live with recurrent STSs, local recurrence is more difficult to manage and may result in owners electing euthanasia rather than pursuing further treatment. The median postrecurrence ST for dogs euthanized because of their local tumor recurrence is 256 days and this is significantly worse than the 945 days median postrecurrence ST for dogs with local recurrence that die of unrelated reasons.34 This underscores the importance of wide excision of STSs initially, as the management of recurrent STSs is usually more difficult with curativeintent treatment of recurrent STSs requiring a more aggressive approach, resulting in increased treatment-related morbidity with the potential for shorter DFIs, higher metastatic rates, and

poorer STs.32,113,126–130 Local tumor recurrence is still possible after either complete resection or incomplete resection combined with adjunctive RT.35,135–138 Consequently, examination of the treatment site is recommended at regular intervals, such as monthly for the first 3 months, then every 3 months for the first 12 months, and then every 6 months thereafter.10,110 The median time to local tumor recurrence varies from 368 to greater than 798 days, which emphasizes the need for long-term follow-up in these cases.32,34,35,46,113,135–137,140,141 

Metastasis The overall metastatic rate in dogs with STS varies from 0% to 31%, with a median time to metastasis of 230 to 365 days.31– 34,35,46,113,135–138,141 Factors that increase the risk of metastatic disease include histologic grade, number of mitotic figures, percentage of tumor necrosis, and local tumor recurrence. The metastatic rates for dogs with grade I, II, and III STSs are 0% to 13%, 7% to 27%, and 22% to 44%, respectively.31,35,156 Metastasis is significantly more likely in dogs with pleomorphic and undifferentiated sarcomas compared with FSAs, PNSTs, myxosarcomas, and liposarcomas.31 Metastasis is five times more likely when tumors have a mitotic rate of 20 or more mitotic figures/10 HPF compared with fewer than 20 mitotic figures/10 HPF.35 In one study, no dog with a STS at or below the level of the elbow or stifle developed metastatic disease.35 

Survival The MST for dogs with STS ranges from 1013 to 1796 days after surgery alone to 2270 days with surgery and adjunctive RT for nonoral STSs.25,34,35,135,136 However, the majority of studies report MSTs that cannot be calculated because only 9% to 33% of dogs eventually die of tumor-related causes after curative-intent

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PA RT I V     Specific Malignancies in the Small Animal Patient

treatment.25,31–35,113,117,118,136,140,141 The 1-, 2-, 3-, 4-, and 5-year survival probabilities are 80% to 94%, 72% to 87%, 61% to 81%, 81%, and 76% respectively.34,141 Clinical factors associated with decreased ST include tumor invasiveness, surgical approach, completeness of excision, and local tumor recurrence, all of which may be related to some degree. Dogs with grossly invasive and fixed STSs have a 5-fold increased risk of tumor-related deaths,25,34 presumably because of greater difficulty in achieving complete excision of their STSs. Dogs treated with wide surgical resection have a MST of greater than 1306 days compared with 264 days for dogs treated with non–curative-intent surgeries.31 The MST for dogs with incompletely excised STSs is 657 days, and this is significantly worse than the MST of greater than 1306 days for dogs with completely excised STSs.31 Dogs with local tumor recurrence have a 5-fold risk of tumor-related death.34 Histologic and IHC features associated with survival include tumor necrosis, mitotic rate, histologic grade, argyrophilic nucleolar organizer region (AgNOR) score, and Ki67 score.31,34,35 Tumor-related deaths are three times more likely with greater than 10% tumor necrosis and three times more likely with a mitotic rate of 20 or more mitotic figures/10 HPFs.35 The MSTs for dogs with 10 or fewer, 10 to 19, and 20 or more mitotic figures/10 HPFs are 1444 days, 532 days, and 236 days, respectively.35 Histologic grade was prognostic in two adjuvant RT studies with an MST not reached and greater than 1461 days for dogs with grade I and II STSs compared with 78 days for dogs with grade III STSs in one study of incompletely excised STSs treated with fractionated RT,135 and a 940-day MST for dogs with grade III STSs compared with an MST not reached for dogs with grade I and II MSTs in dogs treated with incomplete excision and hypofractionated RT.141 The MSTs and survival rates for dogs with STSs with AgNORs below and above the median AgNOR scores were greater than 1188 days and 76% versus greater than 1306 days and 53%, and dogs with an increased AgNOR score are 77 times more likely to die as a result of their disease.31 Similarly, MSTs and survival rates for dogs with STSs with Ki67 scores below and above the median AgNOR scores were MST greater than 1188 days with 94% survival versus 657 days, and dogs with an increased Ki67 score are 12 times more likely to die as a result of their disease.31 

Feline Sarcomas and Injection-Site Sarcomas Epidemiology and Risk Factors The following events are linked to the development of postvaccinal sarcomas in the cat. The prevalence of feline rabies led to the enactment of a law in Pennsylvania in 1987 requiring rabies vaccinations for cats.171 In addition, two changes in vaccines occurred in the mid-1980s: development of a killed rabies vaccine licensed for subcutaneous administration and a killed vaccine for feline leukemia virus (FeLV). Epidemiologic studies have shown a strong association between the administration of inactivated feline vaccines, such as rabies and FeLV, and subsequent development of STSs at vaccination sites.172–179 This is further supported by the significant decrease in interscapular injection-site sarcomas (ISSs) and significant increase in body wall and left and right pelvic limb ISSs since the recommendations of the Vaccine-Associated Feline Sarcoma Task Force (VAFSTF) were published in 2001.180,181 Some authors report the reaction to vaccines was additive and this increased the likelihood of sarcoma development with multiple vaccines given at the same site simultaneously.175 The prevalence

of sarcoma development of at sites of vaccine administration has been estimated between 1 to 4/10,000 cases,176,182,183 but as high as 13 to 16/10,000 cases.177,184,185 The ratio of ISSs to non-ISSs has increased from 0.5 in 1989 to 4.3 in 1994.186 The time to tumor development postvaccination has been reported to be 4 weeks to 10 years, and is associated with a robust inflammatory reaction around the tumor.176 Adjuvant-containing vaccines have been proposed to be more likely to cause a vaccine site reaction and/or develop into an ISS176; however, three large epidemiologic studies did not provide evidence that aluminum-containing vaccines pose a greater risk,175,178,187 and thus it remains unclear whether nonadjuvanted vaccines are safer.180,187,188 A multicenter study of cats in the United States and Canada found that no single vaccine manufacturer or vaccine type had a higher association with the development of ISSs.178 Cats with pelvic limb ISSs are significantly more likely to have been vaccinated with an inactivated rabies vaccine than a recombinant rabies vaccine, and cats with interscapular ISSs were more likely to have received long-acting corticosteroid injections.187 Vaccination practices such as needle gauge, syringe reuse, use and shaking of multidose vials, mixing vaccines in a single syringe, and syringe type had no role in the development of tumors.178 Although no vaccine type has been associated with a higher risk of ISS development, nonadjuvanted vaccines are associated with less tissue inflammation compared with adjuvanted vaccines.180 ISSs are hypothesized to develop from an inflammatory reaction induced by injectable medications that leads to uncontrolled fibroblast and myofibroblast proliferation and eventual tumor formation, either alone or in association with immunologic factors.189–193 The thought that inflammation precedes tumor development is supported by histologic identification of transition zones from inflammation to sarcoma and microscopic foci of sarcoma located in areas of granulomatous inflammation (Fig. 22.13). A similar phenomenon of intraocular sarcoma development exists in cats after trauma or chronic uveitis.194–197 ISSs have also been reported to arise at sites of injections other than vaccines such as lufenuron, longacting steroids, nonsteroidal antiinflammatory drugs, cisplatin, vascular access ports, deep nonabsorbable sutures, and microchips,187,198–204 and for this reason the term ISS is preferred to vaccine-associated sarcoma. Growth factors regulate the cellular events involved in granulation tissue formation and wound healing. When these factors are added to fibroblast cultures, the cells develop a neoplastic phenotype. IHC identification and localization of growth factors and their receptors are being investigated in ISSs. ISSs are immunoreactive for platelet-derived growth factor (PDGF), epidermal growth factor and its receptors, and transforming growth factor (TGF)-β. Conversely, non–injection-site FSAs are negative or faintly positive for these factors and their receptors.205,206 Lymphocytes in ISSs are positive for PDGF, but lymphocytes in non–injection-site FSAs and normal LNs are negative for PDGF.205 Regional macrophages also stain positively for PDGF receptor (PDGFR). Neoplastic cells that are closest to lymphocytes in these tumors have the strongest staining for PDGFR, which has led to a hypothesis that lymphocytes in ISSs may secrete PDGF, recruit macrophages, and lead to fibroblast proliferation.205,206 The expression of c-jun, a proto-oncogene coding for the transcriptional protein AP-1, has also been examined in ISSs. c-jun was found to be strongly positive in ISSs and not expressed in non–injection-site FSAs.205,206 FeLV and the feline sarcoma virus are not involved in the pathogenesis of feline ISSs.207

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A • Fig. 22.14  The typical gross appearance of a feline injection-site sarcoma with a firm, large, multilobulated subcutaneous or cutaneous mass arising at a location consistent with the administration of a vaccine or other injections, such as the interscapular region, body wall, or pelvic limbs (pictured).

B •

Fig. 22.13 Histologic image of a feline subcutaneous injection-site myxosarcoma. (A) A poorly delineated, highly cellular, neoplastic mass composed of streams and bundles of spindle cells supported by a myxomatous extracellular matrix expands the subcutaneous adipose tissue. Peripheral lymphoplasmacytic nodules are characteristic for this entity. H&E, 4×. (B) Lymphoplasmacytic infiltrates in perivascular regions in the absence of tumor necrosis. H&E, 20×. (Image courtesy Dr. J. Dreyfus.)

Studies have attempted to link growth factors with development of ISSs in cats. Continued immunohistochemical probing of feline ISSs documents expression of growth-regulating proteins: p53 protein, basic fibroblast growth factor, and TGF-α.208 Researchers recently concluded that PDGF and PDGFR play an important role in the in vitro growth of ISS cell lines, both alone and in the presence of chemotherapeutic agents. 

Pathology There are many similarities between histologic subtypes and biologic behavior of STSs in cats and dogs. The three principal exceptions in cats are ISSs, virally induced multicentric FSA, and the relative rarity of PNST, SCS, and HS.192,209 There are significant differences between ISSs and non-ISSs. Clinically, ISSs are usually large with a rapid growth rate and typically arise from the subcutis at sites consistent with the administration of vaccines and other injections, such as the interscapular region, body wall, and pelvic limbs (Fig. 22.14), whereas non-ISSs are smaller, slower growing, and will often arise from the skin rather than

subcutaneous tissue.174,210,211 ISSs are typically mesenchymal in origin and include FSAs, rhabdomyosarcomas, MFHs, undifferentiated sarcomas, and extraskeletal osteosarcomas and chondrosarcomas.205,212,213 ISSs have histologic features consistent with a more aggressive biologic behavior than non–ISSs, such as marked nuclear and cellular pleomorphism, increased tumor necrosis, high mitotic activity, multinucleate giant cells, and the presence of a peripheral inflammatory cell infiltrate consisting of lymphocytes and macrophages.172,185,186,193,205 In a series of 91 cats with histologically confirmed and graded ISSs, the prevalence of high-grade lesions was substantially higher than reported in dogs,35 with 59% of cats diagnosed with grade III tumors and only 5% with grade I tumors.214 Microscopically, areas of transition between inflammation and tumor development are frequently observed in cats with ISS.205,215 The macrophages in these peripheral inflammatory cell infiltrates often contain a bluish-gray foreign material that has been identified as aluminum and oxygen by electron probe x-ray microanalysis.192 Aluminum hydroxide is one of several adjuvants used in currently available feline vaccines.192 Although nonadjuvanted vaccines are currently available for FeLV and rabies, it is unknown if these vaccines are less likely to result in sarcoma formation, especially as studies have shown that all vaccines have the potential to cause ISSs.180,187,188 ISSs are histologically similar to mesenchymal tumors arising in the traumatized eyes of cats, which suggests a common pathogenesis of inflammation and the development of STSs in these cats.196,197,206 The presence of inflammatory cells, fibroblasts, and myofibroblasts in and adjacent to ISSs supports this hypothesis.26,216,217 

Diagnosis and Workup The diagnostic techniques and clinical staging tests recommended for cats with suspected ISSs are similar to those described in dogs earlier in this chapter. Advanced imaging, such as contrast-enhanced CT or MRI, is recommended for local staging of the tumor because these 3D imaging modalities provide essential information for proper planning of surgery and/or RT (Fig. 22.15).192,218–223 The volume of tumor based on contrastenhanced CT is larger than the volume measured using calipers during physical examination.191,223 Furthermore, the presence

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Fig. 22.15 Contrast-enhanced magnetic resonance imaging of a cat with an injection-site sarcoma. Note the fingerlike projections of the tumor (arrows).

of skip metastases on CT scans was significantly associated with local tumor recurrence.222 Although CT and MRI are both very sensitive for the detection of the peritumoral extent of disease in cats with suspected ISSs, up to 59% of these peritumoral lesions are nonneoplastic when examined histologically.221 Moreover, the low-field MRI characteristics of ISSs can vary and this may be influenced by previous incisional or excisional biopsies.218 For interscapular ISSs, it is important to perform postcontrast CT scans with the thoracic limbs extended cranially and caudally along the body to permit better evaluation of the relationship between the ISS and the adjacent tissue.219 Accurate pretreatment knowledge of the extent of disease is important because ISSs are very invasive, are frequently located in areas in which regional anatomy can complicate an aggressive surgical approach (e.g., interscapular area, body wall, and proximal pelvic limb), and have a high rate of local tumor recurrence, especially if incompletely excised. Excisional biopsy of a suspected ISS is not recommended because the risk of local tumor recurrence is increased, and DFI and ST are significantly decreased.224,225 

Treatment Surgery ISSs are poorly encapsulated tumors with extension and infiltration along fascial planes.215,216 The VAFSTF has recommended surgical resection with a minimum of 2 cm margins both lateral and deep to the tumor192; however, this recommendation is now considered inadequate. The preferred approach is based on how the extent of the ISS is assessed, with 5-cm lateral margins and two fascial layers for deep margins recommended when the extent of disease is based on gross palpation, whereas 3-cm lateral margins and one fascial layer for deep margins are recommended when the extent of disease is based on contrastenhanced CT scans.214,226,227 Only 50% of ISSs are completely excised when resected with 2- to 3-cm lateral margins compared with 95% to 97% when excised with 4- to 5-cm lateral margins.214,224–226 Marginal resection or excisional biopsy should not be attempted. The median DFI and MST are significantly decreased with marginal resection, with more than one attempt at surgical resection, and if surgery is performed by nonreferral surgeons.214,224,225 The median time to first recurrence after marginal resection is 79 days compared with 325 to 419 days

for wide resection or radical surgery.224 In addition, the median time to first recurrence is only 66 days when the first surgery is performed at a nonreferral institution compared with 274 days at referral institutions.224 Inadequate biopsy planning, preoperative staging, and/or attempts at first surgery will result in an increase in tumor margins and may make further surgical treatment more difficult to impossible. The first attempt at surgical management of cats with ISSs should be performed by a referral surgeon with experience in aggressive resection, especially in the interscapular, body wall, or pelvic regions, to increase the chance of a successful outcome.214,224–228 Similar to dogs with STSs, biopsy tracts and any areas of fixation, including bone and fascia, should be resected en bloc with the tumor. In cats with ISSs, wide surgical resection of tumors located in the interscapular region will often involve excision of dorsal spinous processes (Fig. 22.16), whereas thoracic or body wall resection is often required for truncal tumors (Fig. 22.17).224,225 Limb amputation or hemipelvectomy is usually required to achieve adequate surgical margins and local tumor control for ISSs located on the extremity.214 Local tumor control is very good if the ISS is treated aggressively with 5-cm lateral margins and one to two fascial layers for deep margins, or compartmental resections. When the VAFSTF recommendations of 2- to 3-cm lateral margins and one fascial layer for deep margins are used, complete resection is achieved in fewer than 50% of cats and overall 1- and 2-year disease-free rates are only 35% and 9%, respectively.224,225 In comparison, the complete excision rate is 97% and the local recurrence rate is 14% at 3 years when ISSs are resected with 5-cm lateral margins and two fascial layers for deep margins, including ISSs located in the interscapular region, body wall, and extremities.214 These findings are supported by an earlier study of 57 cats treated with 4- to 5-cm lateral margins and one fascial layer for deep margins, in which complete histologic excision was achieved in 95% of cats.226 Chest wall and body resection, using a minimum of 3-cm margins, was well tolerated in six cats and local tumor recurrence was not reported in any of these cats at a minimum of 12 months postoperatively.228 Compartmental resections of interscapular ISSs, in combination with neoadjuvant epirubicin, resulted in a local recurrence rate of 14% in 21 cats after a median follow-up time of 1072 days.229 Despite these aggressive approaches, major wound healing complications are relatively uncommon, with wound dehiscence reported in 11% to 17% of cats.214,227 Wound dehiscence is more common after wide resection of interscapular ISSs compared with other locations214 and in overweight cats, cats with larger tumors, ISSs that required longer anesthetic and surgical times for surgical resection, and wound defects which were closed in an X-shape rather than linearly.227 Real-time in vivo assessment of residual tumor in the wound bed has been investigated with good initial results in 12 cats with ISSs,230 and local tumor control rates may be improved when this technology becomes commercially available. Neoadjuvant chemotherapy or RT may have benefits when combined with surgery. In people, both preoperative chemotherapy and RT have resulted in the conversion of the tumor pseudocapsule into a thick, collagenized capsule with no viable tumor cells.114 Clinically, this may result in a better defined tumor that is more amenable to complete histologic excision. In one study, there was no difference in local recurrence rates or STs in 49 cats treated with neoadjuvant DOX and surgery compared with 20 cats treated with surgery alone.231 However, in another study,

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E •

Fig. 22.16  Aggressive resection of injection-site sarcomas, with 5-cm lateral margins and one to two uninvolved fascial layers for deeps margins, is required for the best opportunity for complete histologic excision and local tumor control. (A) Planned lateral surgical margins are indicated with a sterile marker pen 5 cm in all directions around an interscapular injection-site sarcoma. (B) An incision is then performed along the marked margins, and continued deeply to include two uninvolved fascial layers. (C) In this cat, ostectomy of the dorsal spinous processes was performed with bone cutters to achieve deep surgical margins and compartmental resection of the injection-site sarcoma. (D) The wound defect after these aggressive wide resections can be large, but primary closure is almost always achievable (E).

neoadjuvant chemotherapy with three doses of epirubicin followed by compartmental resection of interscapular ISSs resulted in an overall local recurrence rate of 14% in 21 cats after a median follow-up time of 1072 days.229 

Surgery and Radiation Therapy Although aggressive surgical resection is recommended for the management of cats with ISSs, this may not always be feasible. In these cases, multimodality therapy with either preoperative or

postoperative RT results in better rates of local tumor control than more conservative surgical approaches alone.213,232–236 In two studies investigating preoperative RT, local tumor recurrence was reported in 40% to 45% of cats at a median of 398 to 584 days postoperatively.232,234 In both studies, complete resection significantly improved the time to local recurrence, with a 700- to 986-day median DFI for completely excised tumors and 112- to 292-day median DFI for tumors resected with incomplete margins.232,234 However, complete resection after preoperative RT does

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Fig. 22.17  Aggressive resection of injection-site sarcomas, with 5-cm lateral margins and one to two uninvolved fascial layers for deeps margins, is required for the best opportunity for complete histologic excision and local tumor control. (A) Planned lateral surgical margins are indicated with a sterile marker pen 5 cm in all directions around a body wall injection-site sarcoma. (B) An incision is then performed along the marked margins. (C) Deep margins of two uninvolved fascial layers included chest (seven ribs) and body wall. (D) After caudal lung lobectomy and diaphragmatic advancement, the body wall defect was reconstructed with an omental pedicle graft and prosthetic mesh. (E) The wound defect was closed primarily.

not appear to improve local control rates because local tumor recurrence was reported in 42% of 59 cats with complete histologic excision and 32% of 28 cats with incomplete histologic excision.234 The outcome after postoperative RT is similar to preoperative RT. In one study of 79 cats treated with surgery and curative-intent RT,

the MST was significantly longer in cats treated with postoperative rather than preoperative RT; however, the practice at this institution was to treat larger tumors with preoperative RT and hence this finding may be due to a selection bias.236 In one study, local tumor recurrence was reported in 41% of 76 cats at a median of 405 days

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postoperatively.232 In another study investigating the effects of chemotherapy in cats treated with surgery and postoperative RT, local tumor recurrence occurred in 28% of 25 cats with a median time to first recurrence not reached in cats treated with surgery and RT alone and 661 days in cats also treated with DOX.233 In a study of 46 cats treated with surgery and curative-intent postoperative RT, the median PFI was 37 months, with 1- and 2-year progression-free rates of 63% and 60%, respectively.235 In comparison, 27 cats treated with postoperative palliative hypofractioned protocols had a median PFI of 10 months and a MST of 24 months.235 Importantly, RT should start 10 to 14 days postoperatively as DFI and ST decreases as the interval between surgery and starting RT increases.213 Local tumor recurrence does not influence ST and, regardless of the timing of RT relative to surgery, survival data are encouraging with MSTs of 600 to 1307 days and 1-, 2-, and 3-year survival rates of 86%, 44% to 71%, and 28% to 68%, respectively.213,232–235 Local tumor control is still disappointing with 28% to 45% of tumors recurring after multimodality treatment with surgery using 2- to 3-cm lateral margins and RT.213,232–236 The radiation field used in these studies typically included a minimum of 3-cm margins around the tumor or surgical scar. The majority of tumors recur within the radiation field, although tumors have been reported to recur outside the radiation field.234 Similar to surgery alone, a more aggressive approach may be warranted to improve local tumor control, such as higher radiation doses, larger radiation fields, and more aggressive surgical resections. 

Radiation Therapy for Gross Disease Although RT alone is rarely effective for the management of cats and dogs with measurable STSs, RT may have a role in the palliative setting for cats with large and unresectable ISSs. In a pilot study of 10 cats with ISSs, 7 cats achieved partial responses and 2 cats had complete responses after treatment with liposomal DOX as a radiation sensitizer and irradiation with a median of 5 fractions of 4 Gy for a total dose of 20 Gy; however, PFIs were not durable (median of 117 days).237 Similar findings were reported in 17 cats with gross disease treated with 4 fractions of 8 Gy for a total dose of 32 Gy in which the median PFI was 4 months and MST was 7 months.235 Stereotactic RT (SRT) has also been reported in a series of 11 cats.238 These cats were treated with variable protocols (most commonly 3 fractions of 10 Gy) with three complete and five partial responses documented. The median PFI was 242 days and the MST was 301 days.238 A margin for subclinical microscopic disease was not utilized in these patients and thus the intent of SRT alone cannot be considered definitive; however, it may facilitate surgical resection or result in palliation of clinical signs.  Chemotherapy The role of chemotherapy in the management of cats with ISS remains undefined. Metastasis has been reported in 0% to 26% of cats with ISSs, despite the aggressive histologic appearance and prevalence of high-grade lesions in these tumors, with a median time to metastasis of 265 to 309 days.209,210,220–222,228,230 ISS cell lines have shown in vitro sensitivity at clinically relevant doses to DOX, mitoxantrone, vincristine, lomustine, and paclitaxel.239–241 Clinically, partial and complete responses to DOX, either alone or in combination with cyclophosphamide, or lomustine have been reported in 25% to 50% of cats with gross tumors, but these responses are often short-lived with a median duration of 83 to 125 days.242–244 However, MSTs are significantly prolonged in cats that respond to chemotherapy: 242 days for responders and 83 days for nonresponders.242 Furthermore, MSTs are significantly increased for cats with gross residual disease after surgical

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excision and treated with postoperative RT and chemotherapy with an MST of 29 months compared with 5 months for cats treated with surgery and postoperative RT.235 Postoperative chemotherapy has minimal effect on survival in cats treated with curative-intent surgery and RT.214,226,232,233,243 Chemotherapy may, however, have beneficial effects on local tumor control and time to local tumor recurrence. DOX and liposome-encapsulated DOX significantly prolonged DFI after surgery, with a median DFI of 393 days for cats receiving chemotherapy and 93 days for those in which chemotherapy was not administered.243 The completeness of surgical margins may be a confounding factor in this analysis because the median DFI was greater than 449 days in cats with complete surgical margins compared with 281 days after incomplete resection.243 Chemotherapy has also been reported to affect MST but not DFI in cats treated with hypofractionated RT for gross disease.235 Carboplatin was associated with an insignificant but numerically superior median DFI of greater than 986 days in cats treated with preoperative RT and surgery.234 Other studies have shown no effect of adjunctive chemotherapy on either local tumor control or ST.232,233 The tyrosine kinase inhibitors toceranib phosphate (Palladia), masitinib mesylate (Kinavet/Masivet), and imatinib mesylate (Gleevec) have also been investigated for the therapy of ISSs in cats based on dysregulation of PDGFR in feline ISS cell lines.245,246,247,248 Imatinib has been shown to result in inhibition of the PDGF/PDGFR pathway and results in chemosensitization of feline ISS cells.245 Masitinib also resulted in inhibition of PDGFR and cellular proliferation in feline ISS cell lines, but at doses that were higher than those readily achievable clinically.246 Masitinib was also investigated as a radiation sensitizer in feline ISS cell lines, but was not found to result in sensitization in vitro.247 Finally, toceranib was administered to 18 cats with unresectable ISSs and, although well tolerated at doses commonly administered in dogs, responses were not documented.248 Novel treatments such as electrochemotherapy and immunotherapy are also being investigated with some encouraging results. In one study, cats with high-grade STSs were treated either intraoperatively or postoperatively with intratumoral bleomycin followed by eight biphasic pulses of up to 1300 V/cm.249 The median time to local tumor recurrence in the control (surgery only) group was 4 months compared with 12 months for cats treated intraoperatively and 19 months for cats treated postoperatively. Of further interest, the metastatic rate was only 1.7%.249 In a second study, 64 cats with FSA were treated postoperatively with two rounds of electrochemotherapy utilizing cisplatin.250 The local recurrence rate was 29%. Minimal systemic toxicity, including pulmonary, renal, or cutaneous toxicity, was documented in these cats.250 It should be noted that cisplatin cannot be administered systemically in cats because cisplatin causes fatal pulmonary edema even at relatively low doses.251 Immunotherapy, using recombinant viruses expressing interleukin-2 (IL-2), has shown some promise in improving local tumor control rates in cats with ISSs. After surgical resection and iridium-based brachytherapy, the 1-year local tumor recurrence rate was 61% in cats receiving no adjunctive treatment, 39% in cats administered human IL-2 using a vaccinia virus vector, and 28% with feline IL-2 using a canary pox virus vector.252 In a randomized trial by the same group comparing surgery and brachytherapy with surgery and brachytherapy combined with high- and low-dose IL-2 vaccine, the frequency of relapse was significantly reduced in the groups receiving the IL-2 vaccine at both 12 (52% vs 28%) and 24 months (59% vs 28%).253 This product is now commercially available in the United States and European Union for the postoperative treatment of feline ISSs. In a phase I trial, two doses of intratumoral feline IL-2, interferon-gamma

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(IFN-γ), and granulocyte-macrophage colony-stimulating factor (GM-CSF) followed by magnetofection before surgical resection resulted in a 1-year local recurrence rate of 24%.254 In another phase I trial by the same research group, two doses of intratumoral GMCSF followed by magnetofection before surgical resection resulted in a 1-year local recurrence rate of 50% and minimal treatment-related toxicities.255 Other immunotherapeutic agents such as IL-12 and acemannan have been investigated with less favorable results.256–258 

Prognosis Local Recurrence Local tumor control is the most challenging aspect of managing cats with ISS. The best results are achieved after complete histologic excision, and complete histologic excision is more likely after aggressive surgical resection. The rate of complete histologic excision is less than 50% when ISSs are excised with 2- to 3-cm lateral margins,224,225 compared with 95% to 97% when excised with 4- to 5-cm lateral margins.214,226 The local tumor recurrence rate is 14% to 22% after complete histologic excision compared with 58% to 69% after incomplete excision.214,229,243,259 Incomplete histologic excision of ISSs is associated with a 10-fold increased risk of local tumor recurrence.259 Overall, the 1- and 2-year disease-free rates are 35% and 9%, respectively, after wide resection with 2- to 3-cm lateral margins,224,225 compared with a 3-year disease-free rate of 86% after wide resection with 5-cm lateral margins or compartmental resections.214,229 When surgical resection is combined with either preoperative or postoperative RT, the local recurrence rates are 28% to 45% with median DFIs of 13 to 37 months.213,226,228,232–234,260 Similar to surgical management of ISSs, complete histologic excision results in a significant improvement in time to local recurrence for cats treated with surgery and RT, with a 700- to 986-day median DFI for completely excised tumors and 112- to 292-day median DFI for tumors resected with incomplete margins.232,234 However, complete excision after preoperative RT does not appear to improve local control rates because local tumor recurrence was reported in 42% of 59 cats with complete histologic excision and 32% of 28 cats with incomplete histologic excision.234 Prognostic factors for local recurrence include tumor size, surgical dose or aggressiveness, completeness of histologic excision, and histologic grade. In one study of 24 cats with ISSs, local recurrence was significantly more likely after wide resection of larger tumors; and for each unit increase in tumor size, cats were two times more likely to develop local recurrence and two times more likely to have a tumor-related death.261 A number of studies have shown the importance of an aggressive surgical approach in the management of cats with ISSs, but this most likely is related to the ability to achieve complete histologic excision rather than the surgical approach specifically. The median time to first recurrence after marginal resection is 79 days compared with 325 to 419 days for wide resection or radical surgery.225 In addition, the median time to first recurrence is only 66 days when the first surgery is performed at a nonreferral institution compared with 274 days at referral institutions.224,225 In another study of 57 cats with wide resection of ISSs, the local recurrence rate was 39% and significantly more likely with grade III ISSs compared with either grade I or II ISSs.226  Metastasis Metastasis is relatively uncommon in cats with ISSs. The metastatic rate varies from 0% to 24%.209,213–215,225,226,232,234,261,262 Metastasis is significantly more likely in cats with grade III ISSs226; and the metastatic rates for cats with grade I, II, and III ISSs are

0% to 17%, 15% to 19%, and 22% to 100%.214,226 The lungs are the most common site of metastasis, with other sites including regional lymph nodes, kidney, liver, spleen, intestines, and epidural and ocular infiltration.214,215,225,226,232 

Survival The overall prognosis for cats with ISSs is often very good despite their propensity for local tumor recurrence. The overall MST is 804 to 901 days to not reached for cats treated with wide surgical resection of 4-cm to 5-cm lateral margins and one to two fascial layers for deep margins.214,226,229 For cats treated with less aggressive surgery, the overall MST varies from greater than 395 days to 608 days.224,225,262 For cats treated with surgery and RT, regardless of the timing of RT, the overall MSTs range from 520 to 1307 days with 1-, 2-, and 3-year survival rates of 62% to 86%, 42% to 71%, and 28% to 68%, respectively.213,232–236,260 Prognostic factors associated with survival in cats with ISSs include anemia, tumor size, treatment type, histologic subtype, mitotic rate, local tumor recurrence, and metastatic disease. For cats treated with surgery and either preoperative or postoperative RT, anemia with a packed cell volume (PCV) less than 25% was associated with decreased ST.236 The MSTs for cats with a PCV less than and greater than or equal to 25% were 308 days and 760 days, respectively, with a 2-fold increased risk of tumor-related death for cats with a PCV less than 25%.236 The 1- and 2-year survival rates for cats treated with a PCV less than 25% were 40% and 24%, respectively, whereas the 1- and 2-year survival rates for cats with a PCV greater than or equal to 25% were 72% and 50%, respectively.236 Tumor size was associated with prognosis in two studies of cats treated with surgery alone. Cats with STSs smaller than 2 cm in diameter had an MST of 643 days, which was significantly longer than the MSTs of 558 days for cats with tumors 2 to 5 cm in diameter and 394 days for cats with STSs larger than 5 cm in diameter.262 In another study, cats with ISSs greater than 3.75 cm had a significantly decreased ST.261 Although most studies do not show differences in outcomes between cats treated with surgery and either preoperative or postoperative RT, the outcome was significantly worse for cats treated with preoperative RT (MST 310 days) than postoperative RT (MST 705 days) in one study, and cats treated with preoperative RT had a 2-fold increased risk of tumorrelated death.236 The 1- and 2-year survival rates for cats treated with preoperative and postoperative RT were 42% and 29%, and 70% and 47%, respectively.236 In another study of 52 cats treated with surgery alone, including eight cats with presumed ISSs, histologic subtype was prognostic with MSTs for cats with FSA (640 days) and PNST (645 days) significantly better than for cats with MFH (290 days).262 Survival was significantly associated with mitotic rate in one study of 24 cats with a 994-day MST for cats with mitotic count greater than 20 mitoses per 10 HPFs compared with an MST that was not reached in cats with a mitotic rate less than or equal to 20 mitoses per 10 HPFs.261 The MST for cats with local tumor recurrence was 327 to 499 days compared with 1098 to 1461 days to not reached for cats without local tumor recurrence.214,226,261 The estimated 2-year survival rates for cats without and with local recurrence are 75% and 37%, respectively.261 The MST for cats without distant metastasis was 929 to 1528 days compared with 165 to 388 days for the 20% to 21% of cats that developed distant metastasis.214,226 Distant metastasis increased the risk of tumor-related death by three times.226 

Prevention The recommendations on preventing ISSs in cats are controversial. These include changing the sites of vaccine administration, decreasing the use of polyvalent vaccines, using nonadjuvanted

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vaccines, avoiding the use of aluminum-based adjuvants, and increasing the interval between vaccinations.26,177,263,264 The VAFSTF has recommended that no vaccine be administered in the interscapular region, rabies vaccines be administered in the distal aspect of the right pelvic limb, FeLV vaccines be administered in the distal aspect of the left pelvic limb, and all other vaccines be administered in the right shoulder.26,192 The location of each injection, the type of vaccine, and the manufacturer and serial number of the vaccine should be documented in the patient records. These recommendations are intended to provide epidemiologic information rather than prevent ISSs. Vaccines should be administered into the distal, rather than mid to proximal, aspects of the limb to aid in earlier detection and increase the chance of achieving complete resection. Subcutaneous and intramuscular administration can both cause local inflammatory reactions and result in the development of ISSs.26 Subcutaneous administration is preferred to intramuscular injection because ISSs developing from subcutaneous sites are more readily palpable and diagnosed earlier in the course of disease. The VAFSTF has recommended that masses at vaccination sites be interrogated if the mass is evident 3 or more months after vaccination, is larger than 2 cm in diameter, or is increasing in size more than 1 month after vaccine administration (3–2–1 Rule).191,192 Unfortunately, feline ISSs are still occurring at sites not recommended by the VAFSTF.178,179,181,185 Vaccination in the tail has been recommended by some investigators because masses are more readily visible and palpable in the tail than other sites and the tail is relatively simple to amputate with good margins and minimal effect on the function and quality of life of cats, especially compared with other locations such as interscapular resections, body wall resections, and limb amputations or hemipelvectomies.265 In a pilot study, vaccination in the tip of the tail was well tolerated and did not require sedation or restraint.265 Traditionally, annual boosters have been recommended for most vaccines in cats. The U.S. Department of Agriculture–Animal Plant Health Inspection Service (USDA-APHIS) does not require duration of immunity studies for licensing of vaccines; however, if a duration of immunity study has not been performed, the USDA-APHIS requires that vaccine labels include a recommendation for annual revaccination.192 Vaccine practices have been questioned by the profession and this has been supported by duration of immunity studies. The duration of immunity for a single commercially available inactivated, adjuvanted combination of feline panleukopenia, herpesvirus, and calicivirus is greater than 7 years, with persistent antibodies against all three viruses for more than 3 years.266–268 Local and state requirements often mandate annual rabies boosters, despite a duration of immunity of at least 3 years, because of the significant public health concern of rabies infection.192 The VAFSTF has recommended that the administration of vaccines is a medicinal procedure and vaccination protocols should be customized for individual cats.192 A vaccine should not be administered until the medical importance and zoonotic potential of the infectious agent, risk of exposure, and legal requirements have been considered and balanced against the risk of ISSs and other adverse effects.192 

Comparative Aspects In general, STSs have a similar pathologic appearance, clinical presentation, and behavior in humans and animals. However, a higher incidence is seen in young people as opposed to young companion animals, with the exception of rhabdomyosarcoma,

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which is seen in young dogs. The distribution of STS in humans is similar to animals. In humans, 43% are in the extremities, with two-thirds occurring in the lower limb, and 34% are intraperitoneal, with 19% visceral in origin and 15% retroperitoneal. STSs of the trunk occur in 10% of human patients, and the remaining 13% occur at other sites. Metastasis is generally hematogenous and appears to be more common in human STS than in dogs, which may partially be explained by the higher numbers of nerve sheath tumors (with lower metastatic rate) seen in the dog. Most sarcomas recognized in humans are also diagnosed in animals, although the specific incidences may vary markedly. There are many more histologic subtypes recognized in humans, which are often site dependent. With the exception of benign smooth muscle tumors and subcutaneous lipomas, there is little evidence that these lesions arise from their mature (differentiated) tissue counterparts. One current theory is that switching on a set of genes that programs mesenchymal differentiation in any mesenchymal cell may give rise to any type of mesenchymal tumor. Common subtypes of STSs seen in the extremities of humans are liposarcomas, MFHs, SCS, and FSAs. In the retroperitoneal location, liposarcomas and leiomyosarcomas are the most common histotypes noted in humans. The most common subtype noted viscerally are gastrointestinal stromal tumors (GISTs). Overall, leiomyosarcoma is the most common genitourinary sarcoma. Up to 15% of all sarcomas occur in children, and the subtypes most commonly represented are rhabdomyosarcomas, Ewing’s sarcomas, and primitive neuroectodermal tumors. Prognostic variables in humans include clinical stage, histologic grade, necrosis, site, size, LN involvement, and aggressiveness of surgery or RT. The histopathologic grading system used and shown to be predictive for metastasis in dogs is a grading system adopted from human pathology that is also predictive for survival.26 In addition, it appears that histologic grade is the predominant predictor of early recurrence, whereas tumor size plays a more important role for late recurrence. It is unclear whether age plays a prognostic role in human STS. Surgical treatment is the mainstay of therapy for STS in the control of local disease. The definition of the surgical approach varies between different organizations, with 1- to 4-cm lateral margins considered a wide resection and those 5 cm or greater termed a curative resection; however, tissue barriers are also taken into account in determining surgical margins, with thin and thick tissue barriers being considered equivalent to 2 cm and 3 cm of margins, respectively.13 Surgery can be combined with neoadjuvant chemotherapy, neoadjuvant RT, and/or adjuvant RT to improve local tumor control.114 Amputation is reserved for patients with unresectable tumors, no evidence of metastasis, and the potential for good long-term rehabilitation. Local recurrence is greater in those patients undergoing limb-sparing therapies compared with amputation; however, there is no difference in disease-free survival between the two groups. Distant metastasis is more common in people with STS; however, chemotherapy is not routinely used because of either a lack of or small but significant improvements in tumor control and survival outcomes with adjuvant chemotherapy.114 Ifosfamide is currently the most active salvage agent for patients who have failed DOX-based protocols, but tyrosine kinase inhibitors are also used. Permanent local control with the first treatment is related to long-term survival. High-risk STS patients are treated with combined chemoradiation before surgical resection. The chemotherapy protocol often used is DOX, ifosfamide, mesna, and dacarbazine. In human patients with metastatic disease, combination chemotherapy produces response rates of 20%, and most of these patients are candidates for investigational agents.

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References 1. Theilen GH, Madewell BR: Tumors of the skin and subcutaneous tissues. In Theilen GH, Madewell BR, editors: Veterinary cancer medicine, Philadelphia, 1979, Lea & Febiger, pp 123–191. 2. Dorn ER: Epidemiology of canine and feline tumors, J Am Anim Hosp Assoc 12:307–312, 1976. 3. Hardy WD: The etiology of canine and feline tumors, J Am Anim Hosp Assoc 12:313–334, 1976. 4. Madewell BR, Theilen GH: Etiology of cancer in animals. In Theilen GH, Madewell BR, editors: Veterinary cancer medicine, Philadelphia, 1979, Lea & Febiger, pp 13–25. 5. McCarthy PE, Hedlund CS, Veazy RS, et  al.: Liposarcoma associated with a glass foreign body in a dog, J Am Vet Med Assoc 209:612–614, 1996. 6. Thrall DE, Goldschmidt MH, Biery DN: Malignant tumor formation at the site of previously irradiated acanthomatous epulides in four dogs, J Am Vet Med Assoc 178:127–132, 1981. 7. Johnstone PA, Laskin WB, DeLuca AM, et  al.: Tumors in dogs exposed to experimental intraoperative radiotherapy, Int J Radiat Oncol Biol Phys 34:853–857, 1996. 8. Barnes M, Duray P, DeLuca A, et  al.: Tumor induction following intraoperative radiotherapy: late results of the National Cancer Institute canine trials, Int J Radiat Oncol Biol Phys 19:651–660, 1990. 9. Sinibaldi K, Rosen H, Liu SK, et al.: Tumors associated with metallic implants in animals, Clin Orthop 118:257–266, 1976. 10. Ehrhart N: Soft‐tissue sarcomas in dogs: a review, J Am Anim Hosp Assoc 41:241–246, 2005. 11. Kim DY, Hodgin EC, Cho DY, et al.: Juvenile rhabdomyosarcomas in two dogs, Vet Pathol 33:447–450, 1996. 12. Dennis MM, McSporran KD, Bacon NJ, et al.: Prognostic factors for cutaneous and subcutaneous soft tissue sarcomas in dogs, Vet Pathol 48:73–84, 2011. 13. Bray JP: Soft tissue sarcoma in the dog – part 2: surgical margins, controversies, and a comparative review, J Small Anim Pract 58:63– 72, 2017. 14. Duda RB: Review: biology of mesenchymal tumors, Cancer J 7:52– 62, 1994. 15. Thrall DE, Gillette EL: Soft-tissue sarcomas, Semin Vet Med Surg Small Anim 10:173–179, 1995. 16. Ordonez NG: Immunocytochemistry in the diagnosis of soft-tissue sarcomas, Cancer Bull 45:13–23, 1993. 17. Madewell BR, Munn RJ: The soft tissue sarcomas: immunohistochemical and ultrastructural distinctions, ACVIM Proc 9:717–720, 1991. 18. Ciekot P, Powers B, Withrow S, et al.: Histologically low-grade, yet biologically high-grade, fibrosarcoma of the mandible and maxilla in dogs: 25 cases (1982–1991), J Am Vet Med Assoc 204:610–615, 1994. 19. Zhang P, Brooks JS: Modern pathological evaluation of soft tissue sarcoma specimens and its potential role in soft tissue sarcoma research, Curr Treat Options Oncol 5:441–450, 2004. 20. Hogendoorn PC, Collin F, Daugaard S, et al.: Pathology and Biology Subcommittee of the EORTC Soft Tissue and Bone Sarcoma Group. Changing concepts in the pathological basis of soft tissue and bone sarcoma treatment, Eur J Cancer 40:1644–1654, 2004. 21. Nilbert M, Engellau J: Experiences from tissue microarray in soft tissue sarcomas, Acta Orthop Scand Suppl 75:29–34, 2004. 22. Perez J, Bautista MJ, Rollon E, et al.: Immunohistochemical characterization of hemangiopericytomas and other spindle cell tumors in the dog, Vet Pathol 33:391–397, 1996. 23. Williamson MM, Middleton DJ: Cutaneous soft tissue tumours in dogs: classification, differentiation, and histogenesis, Vet Dermatol 9:43–48, 1998. 24. Gaitero L, Anor S, Fondevila D, et al.: Canine cutaneous spindle cell tumours with features of peripheral nerve sheath tumours: a histopathological and immunohistochemical study, J Comp Pathol 139:16–23, 2008.

25. Chase D, Bray J, Ide A, et  al.: Outcome following removal of canine spindle cell tumours in first opinion practice: 104 cases, J Small Anim Pract 50:568–574, 2009. 26. MacEwen EG, Powers BE, Macy D, et al.: Soft tissue sarcomas. In Withrow SJ, MacEwen EG, editors: Small animal clinical oncology, ed 3, Philadelphia, 2001, Saunders, pp 283–304. 27. Cook JL, Turk JR, Pope ER, et al.: Infantile desmoid-type fibromatosis in an Akita puppy, J Am Anim Hosp Assoc 34:291–294, 1998. 28. Gwin RM, Gelatt KN, Peiffer RL: Ophthalmic nodular fasciitis in the dog, J Am Vet Med Assoc 170:611–614, 1977. 29. Goldschmidt MH, Hendrick MJ: Tumors of the skin and soft tissue. In Meuten DJ, editor: Tumors in domestic animals, ed 4, Ames, IA, 2002, Iowa State Press, pp 45–117. 30. Goldschmidt MH, Shofer FS: Skin tumors of the dog and cat, Oxford, 1998, Butterworth Heinemann. 31. Ettinger SN, Scase TJ, Oberthaler KT, et al.: Association of argyrophilic nucleolar organizing regions, Ki-67, and proliferating cell nuclear antigen scores with histologic grade and survival in dogs with soft tissue sarcomas: 60 cases (1996–2002), J Am Vet Med Assoc 228:1053–1062, 2006. 32. Baker-Gabb M, Hunt GB, France MP: Soft tissue sarcomas and mast cell tumours in dogs: clinical behaviour and response to surgery, Aust Vet J 81:732–738, 2003. 33. Bacon NJ, Dernell WS, Ehrhart N, et al.: Evaluation of primary reexcision after inadequate resection of soft tissue sarcomas in dogs: 41 cases (1999-2004), J Am Vet Med Assoc 230:548–554, 2007. 34. Bray JP, Polton GA, McSporran KD, et al.: Canine soft tissue sarcoma managed in first opinion practice: outcome in 350 cases, Vet Surg 43:774–782, 2014. 35. Kuntz CA, Dernell WS, Powers BE, et al.: Prognostic factors for surgical treatment of soft-tissue sarcomas in dogs: 75 cases (19861996), J Am Vet Med Assoc 21:1147–1151, 1997. 36. Fulmer AK, Mauldin GE: Canine histiocytic neoplasia: an overview, Can Vet J 48:1041–1050, 2007. 37. Fletcher CDM, Unni KK, Mertens F: World Health Organization classification of tumors: pathology and genetics of tumors of soft tissue and bone, Lyon, 2002, IARC Press. 38. Waters CB, Morrison WB, DeNicola DB, et al.: Giant cell variant of malignant fibrous histiocytoma in dogs: 10 cases (1986-1993), J Am Vet Med Assoc 205:1420, 1994. 39. Morris JS, McInnes EF, Bostock DE, et al.: Immunohistochemical and histopathologic features of 14 malignant fibrous histiocytomas from flat-coated retrievers, Vet Pathol 39:473–479, 2002. 40. Choi H, Kwon Y, Chang J, et  al.: Undifferentiated pleomorphic sarcoma (malignant fibrous histiocytoma) of the head in a dog, J Vet Med Sci 73:235–239, 2011. 41. Weiss SW, Enzinger FM: Malignant fibrous histiocytoma: an analysis of 200 cases, Cancer 41:2250–2266, 1978. 42. Foale RD, White RA, Harley R, et al.: Left ventricular myxosarcoma in a dog, J Small Anim Pract 44:503–507, 2003. 43. Briggs OM, Kirberger RM, Goldberg NB: Right atrial myxosarcoma in a dog, J S Afr Vet Assoc 68:144–146, 1997. 44. Richter M, Stankeova S, Hauser B, et al.: Myxosarcoma in the eye and brain in a dog, Vet Ophthalmol 6:183–189, 2003. 45. Avallone G, Helmbold P, Caniatti M, et al.: Spectrum of canine perivascular wall tumors: morphologic, phenotypic and clinical characterization, Vet Pathol 44:607–620, 2007. 46. Stefanello D, Avallone G, Ferrari R, et al.: Canine cutaneous perivascular wall tumors at first presentation: clinical behavior and prognostic factors in 55 cases, J Vet Intern Med 25:1398–1405, 2011. 47. Chijiwa K, Uchida K, Tateyama S: Immunohistochemical evaluation of canine peripheral nerve sheath tumors and other soft tissue sarcomas, Vet Pathol 41:307–318, 2004. 48. Boos GS, Bassuino DM, Wurster F, et  al.: Retrospective canine skin peripheral nerve sheath tumors data with emphasis on histologic, immunohistochemical and prognostic factors, Pesq Vet Bras 35:965–974, 2015.

CHAPTER 22  Soft Tissue Sarcomas

49. Teixeira S, Amorim I, Rema A, et al.: Molecular heterogeneity of canine cutaneous peripheral nerve sheath tumors: a drawback in the diagnosis refinement, Vivo 30:819–827, 2016. 50. Brehm D, Steinberg H, Haviland J, et al.: A retrospective evaluation of 51 cases of peripheral nerve sheath tumors in the dog, J Am Anim Hosp Assoc 31:349–359, 1995. 51. Van Stee L, Boston S, Teske E, et al.: Compartmental resection of peripheral nerve tumors with limb preservation in 16 dogs (19952011), Vet Surg 26:40–45, 2017. 52. Dolera M, Malfassi L, Bianch C, et al.: Frameless stereotactic volumetric modulated arc radiotherapy of brachial plexus tumours in dogs: 10 cases, Br J Radiol 90:20160617, 2017. 53. Spoldi E, Schwarz T, Sabattini S, et al.: Comparisons among computed tomographic features of adipose masses in dogs and cats, Vet Radiol Ultrasound 58:29–37, 2017. 54. Gleiser CA, Jardine JH, Raulston GL, et al.: Infiltrating lipomas in the dog, Vet Pathol 16:623–624, 1979. 55. McChesney AE, Stephens LC, Lebel J, et al.: Infiltrative lipoma in dogs, Vet Pathol 17:316–322, 1980. 56. Doige CE, Farrow CS, Presnell KR: Parosteal lipoma in a dog, J Am Anim Hosp Assoc 16(87), 1980. 57. Bergman PJ, Withrow SJ, Straw RC, et al.: Infiltrative lipoma in dogs: 16 cases (1981-1992), J Am Vet Med Assoc 205:322–324, 1994. 58. McEntee MC, Page RL, Mauldin GN, et al.: Results of irradiation of infiltrative lipoma in 13 dogs, Vet Radiol Ultrasound 41:554– 556, 2000. 59. McEntee MC, Thrall DE: Computed tomographic imaging of infiltrative lipoma in 22 dogs, Vet Radiol Ultrasound 42:221–225, 2001. 60. Head KW, Else RW, Dubielzig RR: Tumors of the alimentary tract. In Meuten DJ, editor: Tumors in domestic animals, Ames, IA, 2002, Iowa State Press, pp 401–481. 61. Liggett AD, Frazier KS, Styler EL: Angiolipomatous tumors in dogs and a cat, Vet Pathol 39:286–289, 2002. 62. Brodey RS, Rozel JF: Neoplasms of the canine uterus, vagina, vulva: a clinicopathologic survey of 90 cases, J Am Vet Med Assoc 151:1294–1307, 1967. 63. Woolfson JM, Dulisch ML, Tams TR: Intrathoracic lipoma in a dog, J Am Vet Med Assoc 185:1007–1009, 1984. 64. Anderson SM, Lippincott CL: Intrathoracic lipoma in a dog, Calif Vet 43(9), 1989. 65. Umphlet RC, Vicini DS, Godshalk CP: Intradural-extramedullary lipoma in a dog, Compend Contin Educ Pract Vet 11:1192, 1989. 66. McLaughlin R, Kuzma AB: Intestinal strangulation caused by intra-abdominal lipomas in a dog, J Am Vet Med Assoc 199:1610– 1611, 1991. 67. Plummer SB, Bunch SE, Khoo LH, et al.: Tethered spinal cord and an intradural lipoma associated with a meningocele in a Manx-type cat, J Am Vet Med Assoc 203:1159–1161, 1993. 68. Mayhew PD, Brockman DJ: Body cavity lipomas in six dogs, J Small Anim Pract 43:177–181, 2002. 69. Gibbons SE, Straw RC: Intra-abdominal lipoma in a dog, Aust Vet Pract 33:86, 2003. 70. Hunt GB, Wong J, Kuan S: Liposuction for removal of lipomas in 20 dogs, J Small Anim Pract 52:419–425, 2011. 71. Lamagna B, Greco A, Guardascione A, et  al.: Canine lipomas treated with steroid injections: clinical findings, PLoS One 7:e50234, 2012. 72. Thomson MJ, Withrow SJ, Dernell WS, et al.: Intermuscular lipomas of the thigh region in dogs: 11 cases, J Am Anim Hosp Assoc 35:165–167, 1999. 73. Case JB, MacPhail CM, Withrow SJ: Anatomic distribution and clinical findings of intermuscular lipomas in 17 dogs (2005-2010), J Am Anim Hosp Assoc 48:245–249, 2012. 74. Kramek BA, Spackman CJA, Hayden DW: Infiltrative lipoma in three dogs, J Am Vet Med Assoc 186:81–82, 1985.

427

75. Frazier KS, Herron AJ, Dee JF, et al.: Infiltrative lipoma in a stifle joint, J Am Anim Hosp 29:81–83, 1993. 76. Baez JL, Hendrick MJ, Shofer FS, et al.: Liposarcomas in dogs: 56 cases (1989-2000), J Am Vet Med Assoc 224:887–891, 2004. 77. Forlani A, Roccabianca P, Palmieri C, et al.: Pathological characterization of primary splenic myxoid liposarcomas in three dogs, Vet Q 35:181–184, 2015. 78. Gower KL, Liptak JM, Culp WT, et  al.: Splenic liposarcoma in dogs: 13 cases (2002-2012), J Am Vet Med Assoc 247:1404–1407, 2015. 79. Masserdotti C, Bonfanti U, De Lorenzi D, et al.: Use of Oil Red O stain in the cytologic diagnosis of canine liposarcoma, Vet Clin Pathol 35:37–41, 2006. 80. Fuesrt JA, Reichle JK, Szabo D, et  al.: Computed tomographic findings in 24 dogs with liposarcoma, Vet Radiol Ultrasound 58:23– 28, 2017. 81. Brennan MF, Singer S, Maki RG, et  al.: Soft tissue sarcoma. In DeVita RT, Hellman S, Rosenberg SA, editors: Cancer: principles and practice of oncology, ed 8, Philadelphia, 2008, Lippincott Williams & Wilkins, pp 1741–1789. 82. Chang HR, Hajdu SI, Collin C, et  al.: The prognostic value of histologic subtypes in primary extremity liposarcoma, Cancer 64:1514–1520, 1989. 83. Choong PFM, Pritchard DJ: Common malignant soft-tissue tumors. In Simon MA, Springfield D, editors: Surgery for bone and soft-tissue tumors, Philadelphia, 1998, Lippincott-Raven, pp 539–551. 84. Avallone G, Roccabianca P, Crippa L, et al.: Histologic classification and immunohistochemical evaluation of MDM2 and CDK4 expression in canine liposarcoma, Vet Pathol 53:773–780, 2016. 85. Cooper BJ, Valentine BA: Tumors of muscle. In Meuten DJ, editor: Tumors in domestic animals, Ames, IA, 2002, Iowa State Press, pp 319–363. 86. Caserto BG: A comparative review of canine and human rhabdomyosarcoma with emphasis on classification and pathogenesis, Vet Pathol 50:806–826, 2013. 87. Scott EM, Teixeira LB, Flanders DJ, et  al.: Canine orbital rhabdomyosarcoma: a report of 18 cases, Vet Ophthalmol 19:130–137, 2016. 88. Kobayashi M, Sakai H, Hirata A, et  al.: Expression of myogenic regulating factors, myogenin and MyoD, in two canine botryoid rhabdomyosarcomas, Vet Pathol 41:275–277, 2004. 89. Russell HV, Pappo AS, Nuchtern JG, et al.: Solid tumors of childhood. In DeVita RT, Hellman S, Rosenberg SA, editors: Cancer: principles and practice of oncology, ed 8, Philadelphia, 2008, Lip­ pincott Williams & Wilkins, pp 2043–2074. 90. Curran KM, Halsey CH, Worley DR: Lymphangiosarcoma in 12 dogs: a case series (1998-2013), Vet Comp Oncol 14:181–190, 2016. 91. Halsey CH, Worley DR, Curran K, et al.: The use of novel lymphatic endothelial-cell specific immunohistochemical markers to differentiate cutaneous angiosarcomas in dogs, Vet Comp Oncol 14:236–244, 2016. 92. Spangler WL, Culbertson MR, Kass PH: Primary mesenchymal (nonangiomatous/nonlymphomatous) neoplasms occurring in the canine spleen: anatomic classification, immunohistochemistry, and mitotic activity correlated with patient survival, Vet Pathol 31:37– 47, 1994. 93. McDonald RK, Helman RG: Hepatic malignant mesenchymoma in a dog, J Am Vet Med Assoc 188:1052–1053, 1986. 94. Hahn KA, Richardson RC: Use of cisplatin for control of metastatic malignant mesenchymoma and hypertrophic osteopathy in a dog, J Am Vet Med Assoc 195:351–353, 1989. 95. Carpenter JL, Dayal Y, King NW, et al.: Distinctive unclassified mesenchymal tumor of the digit of dogs, Vet Pathol 28:396–402, 1991. 96. Watson AD, Young KM, Dubielzig RR, et al.: Primary mesenchymal or mixed-cell-origin lung tumors in four dogs, J Am Vet Med Assoc 202:968–970, 1993.

428

PA RT I V     Specific Malignancies in the Small Animal Patient

97. Robinson TM, Dubielzig RR, McAnulty JF: Malignant mesenchymoma associated with an unusual vasoinvasive metastasis in a dog, J Am Anim Hosp Assoc 34:295–299, 1998. 98. Murphy S, Blunden AS, Dennis R, et al.: Intermandibular malignant mesenchymoma in a crossbreed dog, J Small Anim Pract 47:550–553, 2006. 99. Gomez-Laguna J, Barranco I, Rodriguez-Gomez IM, et al.: Malignant mesenchymoma of the heart base in a dog with infiltration of the pericardium and metastasis to the lung, J Comp Pathol 147:195–198, 2012. 100. Weishaar KM, Edmonson EF, Thamm DH, et al.: Malignant mesenchymoma with widespread metastasis including bone marrow involvement in a dog, Vet Clin Pathol 43:447–452, 2014. 101. Machida N, Kobayashi M, Tanaka R, et  al.: Primary malignant mixed mesenchymal tumour of the heart in a dog, J Comp Pathol 128:71–74, 2003. 102. Ghisleni G, Roccabianca P, Ceruti R, et al.: Correlation between fine-needle aspiration cytology and histopathology in the evaluation of cutaneous and subcutaneous masses from dogs and cats, Vet Clin Pathol 35:24–30, 2006. 103. Hohenhaus AE, Kelsey JL, Haddad J, et al.: Canine cutaneous and subcutaneous soft tissue sarcoma: an evidence-based review of case management, J Am Anim Hosp Assoc 52:77–89, 2016. 104. Perry JA, Culp WT, Dailey DD, et al.: Diagnostic accuracy of pretreatment biopsy for grading soft tissue sarcomas in dogs, Vet Comp Oncol 12:106–113, 2014. 105. Postorino NC, Berg RJ, Powers BE, et al.: Prognostic variables for canine hemangiopericytoma: 50 cases (1979-1984), J Am Anim Hosp Assoc 24:501–509, 1988. 106. Affolter VK, Moore PF: Localized and disseminated histiocytic sarcoma of dendritic cell origin in dogs, Vet Pathol 39:74–83, 2002. 107. Sugiura H, Takahashi M, Katagiri H, et al.: Additional wide resection of malignant soft tissue tumors, Clin Orthop 394:201–210, 2002. 108. Loh ZH, Allan GS, Nicoll RG, et al.: Ultrasonographic characteristics of soft tissue tumours in dogs, Aust Vet J 87:323–329, 2009. 109. Greene FL, Page DL, Fleming ID, et al.: AJCC cancer staging manual, New York, 2002, Springer. 110. Dernell WS, Withrow SJ, Kuntz CA, et al.: Principles of treatment for soft tissue sarcoma, Clin Tech Small Anim Pract 13:59–64, 1998. 111. Avallone G, Boracchi P, Stefanello D, et  al.: Canine perivascular wall tumors: high prognostic impact of site, depth, and completeness of margins, Vet Pathol 51:713–721, 2014. 112. Russell DS, Townsend KL, Gorman E, et al.: Characterizing microscopical invasion patterns in canine mast cell tumours and soft tissue sarcomas, J Comp Path 157:231–240, 2017. 113. Banks T, Straw R, Thomson M, et al.: Soft tissue sarcomas in dogs: a study correlating optimal surgical margin with tumour grade, Aust Vet Pract 34:158–163, 2004. 114. Bray JP: Soft tissue sarcoma in the dog – part 1: a current review, J Small Anim Pract 57:510–519, 2016. 115. Pratschke KM, Atherton MJ, Sillito JA, et  al.: Evaluation of a modified proportional margins approach for surgical resection of mast cell tumors in dogs: 40 cases (2008-2012), J Am Vet Med Assoc 243:1436–1441, 2013. 116. Monteiro B, Boston S, Monteith G: Factors influencing complete tumor excision of mast cell tumors and soft tissue sarcomas: a retrospective study in 100 dogs, Can Vet J 52:1209–1214, 2011. 117. Stefanello D, Morello E, Roccabianca P, et al.: Marginal excision of low-grade spindle cell sarcoma of canine extremities: 35 dogs (1996-2006), Vet Surg 37:461–465, 2008. 118. McSporran KD: Histologic grade predicts recurrence for marginally excised canine subcutaneous soft tissue sarcomas, Vet Pathol 46:928–933, 2009. 119. Reimer SB, Séguin B, DeCock HE, et al.: Evaluation of the effect of routine histologic processing on the size of skin samples obtained from dogs, Am J Vet Res 66:500–505, 2005.

120. Kamstock DA, Ehrhart EJ, Getzy DM, et  al.: Recommended guide-lines for submission, trimming, margin evaluation, and reporting of tumor biopsy specimens in veterinary surgical pathology, Vet Pathol 48:19–31, 2011. 121. Eward WC, Mito JK, Eward CA, et  al.: A novel imaging system permits real-time in  vivo tumor bed assessment after resection of naturally occurring sarcomas in dogs, Clin Orthop Relat Res 471:834–842, 2013. 122. Holt D, Parthasarathy AB, Okusanya O, et al.: Intraoperative nearinfrared fluorescence imaging and spectroscopy identifies residual tumor cells in wounds, J Biomed Opt 20:76002, 2015. 123. Fidel J, Kennedy KC, Dernell WS, et al.: Preclinical validation of the utility of BLZ-100 in providing fluorescence contrast for imaging spontaneous solid tumors, Cancer Res 75:4283–4291, 2015. 124. DeWitt SB, Eward WC, Eward CA, et al.: A novel imaging system distinguishes neoplastic from normal tissue during resection of soft tissue sarcomas and mast cell tumors in dogs, Vet Surg 45:715–722, 2016. 125. Cabon Q, Sayag D, Texier I, et  al.: Evaluation of intraoperative fluorescence imaging-guided surgery in cancer-bearing dogs: a prospective proof-of-concept phase II study in 9 cases, Transl Res 170:73–88, 2016. 126. Ramanathan RC, A’Hern R, Fisher C, et al.: Prognostic index for extremity soft tissue sarcomas with isolated local recurrence, Ann Surg Oncol 8:278–289, 2011. 127. Stojadinovic A, Leung DHY, Hoos A, et al.: Analysis of the prognostic significance of microscopic margins in 2,084 localized primary adult soft tissue sarcomas, Ann Surg 235:424–434, 2002. 128. Zagars GK, Ballo MT, Pisters PWT, et al.: Prognostic factors for patients with localized soft-tissue sarcoma treated with conservative surgery and radiation therapy: an analysis of 1225 patients, Cancer 97:2530–2543, 2003. 129. Zagars GK, Ballo MT, Pisters PWT, et al.: Surgical margins and reresection in the management of patients with soft tissue sarcoma using conservative surgery and radiation therapy, Cancer 97:2544– 2553, 2003. 130. Eilber FC, Rosen G, Nelson SD, et al.: High-grade extremity soft tissue sarcomas: factors predictive of local recurrence and its effect on morbidity and mortality, Ann Surg 237:218–226, 2003. 131. Elmslie RE, Glawe P, Dow SW: Metronomic chemotherapy with cyclophosphamide and piroxicam effectively delays tumor recurrence in dogs with incompletely resected soft tissue sarcomas, J Vet Intern Med 22:1373–1379, 2008. 132. Spugnini EP, Vincenzi B, Citro G, et  al.: Adjuvant electrochemotherapy for the treatment of incompletely excised spontaneous canine sarcomas, Vivo 21:819–822, 2007. 133. McEntee MC, Samii VF, Walsh P, et al.: Postoperative assessment of surgical clip position in 16 dogs with cancer: a pilot study, J Am Anim Hosp Assoc 40:300–308, 2004. 134. Henry CJ, Stoll MR, Higginbotham ML, et al.: Effect of timing of radiation initiation on post-surgical wound healing in dogs, Proc Vet Cancer Soc 23:52, 2003. 135. Forrest LJ, Chun R, Adams WM, et al.: Postoperative radiotherapy for canine soft tissue sarcoma, J Vet Intern Med 14:578–582, 2000. 136. McKnight JA, Mauldin GN, McEntee MC, et al.: Radiation treatment of incompletely resected soft-tissue sarcomas in dogs, J Am Vet Med Assoc 217:205–210, 2000. 137. Heller D, Stebbins ME, Reynolds T, et al.: A retrospective study of 87 cases of canine soft tissue sarcoma 1986–2001, Int J Appl Res Vet Med 3:81–87, 2005. 138. Simon D, Ruslander DM, Rassnick KM, et  al.: Orthovoltage radiation and weekly low dose of doxorubicin for the treatment of incompletely excised soft-tissue sarcomas in 39 dogs, Vet Rec 160:321–326, 2007. 139. Graves GM, Bjorling DE, Mahaffey E: Canine hemangiopericytoma: 23 cases (1967-1984), J Am Vet Med Assoc 192:99–102, 1988.

CHAPTER 22  Soft Tissue Sarcomas

140. Demetriou JL, Brearley MJ, Constantino-Casas F, et  al.: Intentional marginal excision of canine limb soft tissue sarcomas followed by radiotherapy, J Small Anim Pract 53:174–181, 2012. 141. Kung MBJ, Poirier VJ, Dennis MM, et al.: Hypofractionated radiation therapy for the treatment of microscopic canine soft tissue sarcoma, Vet Comp Oncol 14:135–145, 2016. 142. McChesney SL, Withrow SJ, Gillette EL, et al.: Radiotherapy of soft tissue sarcomas in dogs, J Am Vet Med Assoc 194:60–63, 1989. 143. Hilmas DE, Gillett EL: Radiotherapy of spontaneous fibrous connective-tissue sarcomas in animals, J Natl Cancer Inst 56:365–368, 1976. 144. Banks WC, Morris E: Results of radiation treatment of naturally occurring animal tumors, J Am Vet Med Assoc 166:1063–1064, 1975. 145. Richardson RC, Anderson VL, Voorhees WD, et al.: Irradiationhyperthermia in canine hemangiopericytomas: large-animal model for therapeutic response, J Natl Cancer Inst 73:1187–1194, 1984. 146. Lawrence J, Forrest L, Adams W, et  al.: Four-fraction radiation therapy for macroscopic soft tissue sarcomas in 16 dogs, J Am Anim Hosp Assoc 44:100–108, 2008. 147. Plavec T, Kessler M, Kandel B, et  al.: Palliative radiotherapy as treatment for non-resectable soft tissue sarcomas in the dog – a report of 15 cases, Vet Comp Oncol 4:98–103, 2006. 148. Cancedda S, Marconato L, Meier V, et al.: Hypofractionated radiotherapy for macroscopic canine soft tissue sarcoma: a retrospective study of 50 cases treated with a 5 x 6 Gy protocol with or without metronomic chemotherapy, Vet Radiol Ultrasound 57:75–83, 2016. 149. Tollett MA, Duda L, Brown DC, et al.: Palliative radiation therapy for solid tumors in dogs: 103 cases (2007-2011), J Am Vet Med Assoc 248:72–82, 2016. 150. McDonald C, Looper J, Greene S: Response rate and duration associated with a 4 Gy 5 fraction palliative radiation protocol, Vet Radiol Ultrasound 53:358–364, 2012. 151. Kalnicki S, Bloomer W: Radiation therapy in the treatment of bone and soft tissue sarcomas, Philadelphia, 1992, Saunders. 152. MacLeod DA, Thrall DE: The combination of surgery and radiation in the treatment of cancer. A review, Vet Surg 18:1–6, 1989. 153. Cheng EY, Dusenbery KE, Winters MR, et al.: Soft tissue sarcomas: preoperative versus postoperative radiotherapy, J Surg Oncol 61:90–99, 1996. 154. O’Sullivan B, Davis AM, Turcotte R, et  al.: Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial, Lancet 359:2235–2241, 2002. 155. Al-Absi E, Farrokhyar F, Sharma R, et al.: A systematic review and meta-analysis of oncologic outcomes of pre- versus postoperative radiation in localized resectable soft-tissue sarcoma, Ann Surg Oncol 17:1367–1374, 2010. 156. Selting KA, Powers BE, Thompson LJ, et al.: Outcome of dogs with high-grade soft tissue sarcomas treated with and without adjuvant doxorubicin chemotherapy: 39 cases (1996-2004), J Am Vet Med Assoc 227:1442–1448, 2005. 157. Payne SE, Rassnick KM, Northrup NC, et al.: Treatment of vascular and soft-tissue sarcomas in dogs using an alternating protocol of ifosfamide and doxorubicin, Vet Comp Oncol 1:171–179, 2003. 158. Sarcoma Meta-Analysis Collaboration: Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data, Lancet 350:1647–1654, 1997. 159. Komdeur R, Hoekstra HJ, van den Berg E, et  al.: Metastasis in soft tissue sarcomas: prognostic criteria and treatment perspectives, Cancer Metastasis Rev 21:167–183, 2002. 160. Burton JH, Mitchell L, Thamm DH, et  al.: Low-dose cyclophosphamide selectively decreases regulatory T cells and inhibits angiogenesis in dogs with soft tissue sarcomas, J Vet Intern Med 25:920–926, 2011. 161. de Queiroz GF, Dagli ML, Fukumasu H, et al.: Vascular endothelial growth factor expression and microvascular density in soft tissue sarcomas in dogs, J Vet Diagn Invest 22:105–108, 2010.

429

162. Al-Dissi AN, Haines DM, Singh B, et al.: Immunohistochemical expression of vascular endothelial growth factor and vascular endothelial growth factor receptor in canine cutaneous fibrosarcoma, J Com Pathol 141:229–236, 2009. 163. Avallone G, Stefanello D, Boracchi P, et  al.: Growth factors and COX2 expression in canine perivascular wall tumors, Vet Pathol 52:1034–1040, 2015. 164. de Queiroz GF, Dagli MLZ, Meira SA, et al.: Serum vascular endothelial growth factor in dogs with soft tissue sarcomas, Vet Comp Oncol 11:230–235, 2013. 165. Dernell WS, Withrow SJ, Straw RC, et al.: Intracavitary treatment of soft tissue sarcomas in dogs using cisplatin in a biodegradable polymer, Anticancer Res 17:4499–4505, 1997. 166. Havlicek M, Straw RC, Langova V, et al.: Intra-operative cisplatin for the treatment of canine extremity soft tissue sarcomas, Vet Comp Oncol 7:122–129, 2009. 167. Bergman NS, Urie BK, Pardo AD, et al.: Evaluation of local toxic effects and outcomes for dogs undergoing marginal tumor excision with intralesional cisplatin-impregnated bead placement for treatment of soft tissue sarcomas: 62 cases (2009-2012), J Am Vet Med Assoc 248:1148–1156, 2016. 168. Marconato L, Comastri S, Lorenzo MR, et al.: Postsurgical intraincisional 5-fluorouracil in dogs with incompletely resected, extremity malignant spindle cell tumours: a pilot study, Vet Comp Oncol 5:239–249, 2007. 169. Bostock DE, Dye MT: Prognosis after surgical excision of canine fibrous connective tissue sarcomas, Vet Pathol 17:581–588, 1980. 170. Evans SM: Canine hemangiopericytoma: a retrospective analysis of response to surgery and orthovoltage radiation, Vet Radiol 28:13– 16, 1987. 171. Hauck M: Feline injection site sarcomas, Vet Clin North Am Small Anim Pract 33:553–557, 2003. 172. Hendrick MJ, Goldschmidt MH, Shofer FS, et  al.: Postvaccinal sarcomas in the cat: epidemiology and electron probe microanalytical identification of aluminum, Cancer Res 52:5391–5394, 1992. 173. Hendrick MJ, Goldschmidt MH: Do injection site reactions induce fibrosarcomas in cats? J Am Vet Med Assoc 199:968, 1991. 174. Hendrick MJ, Shofer FS, Goldschmidt MH, et  al.: Comparison of fibrosarcomas that developed at vaccination sites and at nonvaccination sites in cats: 239 cases (1991-1992), J Am Vet Med Assoc 205:1425–1429, 1994. 175. Kass PH, Barnes WG, Spangler WL, et al.: Epidemiologic evidence for a causal relation between vaccination and fibrosarcoma tumorigenesis in cats, J Am Vet Med Assoc 203:396–405, 1993. 176. Macy DW, Hendrick MJ: The potential role of inflammation in the development of postvaccinal sarcomas in cats, Vet Clin North Am Small Anim Pract 26:103–109, 1996. 177. Hendrick MJ, Kass PH, McGill LD, et al.: Postvaccinal sarcomas in cats, J Natl Cancer Inst 86:341–343, 1994. 178. Kass PH, Spangler WL, Hendrick MJ, et al.: Multicenter case-control study of risk factors associated with development of injectionsite sarcomas in cats, J Am Vet Med Assoc 223:1283–1292, 2003. 179. Dean R, Adams V, Whitbread T, et al.: Study of feline injection site sarcomas, Vet Rec 159:641–642, 2006. 180. Day MJ, Schoon HA, Magnol JP, et  al.: A kinetic study of histopathological changes in the subcutis of cats injected with nonadjuvanted and adjuvanted multi-component vaccines, Vaccine 25:4073–4084, 2007. 181. Shaw SC, Kent MS, Gordon IK, et al.: Temporal changes in characteristics of injection-site sarcomas in cats: 392 cases (1990-2006), J Am Vet Med Assoc 234:376–380, 2009. 182. Coyne MJ, Reeves NCP, Rosen DK, et al.: Estimated prevalence of injection sarcomas in cats during 1992, J Am Vet Med Assoc 210:249–251, 1997. 183. Gober GM, Kass PH: World Wide Web-based survey of vaccination practices, postvaccinal reactions, and vaccine site-associated sarcomas in cats, J Am Vet Med Assoc 2002 220:1477–1482, 2002.

430

PA RT I V     Specific Malignancies in the Small Animal Patient

184. Lester S, Clemett T, Burt A: Vaccine site-associated sarcomas in cats: clinical experience and a laboratory review (1982-1993), J Am Anim Hosp Assoc 32:91–95, 1996. 185. Kliczkowska K, Jankowska U, Jagielski D, et al.: Epidemiological and morphological analysis of feline injection site sarcomas, Pol J Vet Sci 18:313–322, 2015. 186. Doddy FD, Glickman LT, Glickman NW, et al.: Feline fibrosarcomas at vaccination sites and nonvaccination sites, J Comp Pathol 114:165–174, 1996. 187. Srivastav A, Kass PH, McGill LD, et al.: Comparative vaccine-specific and other injectable-specific risks of injection-site sarcomas in cats, J Am Vet Med Assoc 241:595–602, 2012. 188. Wilcock B, Wilcock A, Bottoms K: Feline postvaccinal sarcoma: 20 years later, Can Vet J 53:430–434, 2012. 189. Dubielzig RR, Hawkins KL, Miller P: Myofibroblastic sarcoma originating at the site of rabies vaccination in a cat, J Vet Diagn Invest 5:637–638, 1993. 190. Hendrick MJ: Feline injection-site sarcomas, Cancer Invest 17:273– 274, 1999. 191. McEntee MC, Page RL: Feline injection-site sarcomas, J Vet Intern Med 15:176–182, 2001. 192. McNiel EA: Vaccine-associate sarcomas in cats: a unique cancer model, Clin Orthop 382:21–27, 2001. 193. Morrison WB, Starr RM: Injection-site feline sarcoma task force: injection-site feline sarcomas, J Am Vet Med Assoc 218:697–702, 2011. 194. Séguin B: Injection site sarcomas in cats, Clin Tech Small Anim Pract 17:168–173, 2002. 195. Peiffer RL, Monticello T, Bouldin TW: Primary ocular sarcomas in the cat, J Small Anim Pract 29:105, 1988. 196. Dubielzig RR, Everitt J, Shadduck JA, et al.: Clinical and morphologic features of post-traumatic ocular sarcomas in cats, Vet Pathol 27:62–65, 1990. 197. Hakanson N, Forrester SD: Uveitis in the dog and cat, Vet Clin North Am Small Anim Pract 20:715–735, 1990. 198. Esplin DG, Bigelow M, McGill LD, et al.: Fibrosarcoma at the site of a lufenuron injection in a cat, Vet Cancer Soc Newsletter 23(8), 1999. 199. Buracco P, Martano M, Morello E, et al.: Vaccine-associated-like fibrosarcoma at the site of a deep nonabsorbable suture in a cat, Vet J 163:105–107, 2002. 200. Daly MK, Saba CF, Crochik SS, et  al.: Fibrosarcoma adjacent to the site of microchip implantation in a cat, J Feline Med Surg 10:202–205, 2008. 201. Carminato A, Vascellari M, Marchioro W, et al.: Microchip-associated fibrosarcoma in a cat, Vet Dermatol 22:565–569, 2011. 202. Munday JS, Banyay K, Aberdein D, et  al.: Development of an injection-site sarcoma shortly after meloxicam injection in an unvaccinated cat, J Feline Med Surg 13:988–991, 2011. 203. Martano M, Morello E, Iussich S, et al.: A case of feline injectionsite sarcoma at the site of cisplatin injections, J Feline Med Surg 14:751–754, 2012. 204. McLeland SM, Imhoff DJ, Thomas M, et al.: Subcutaneous fluid port-associated soft tissue sarcoma in a cat, J Feline Med Surg 15:917–920, 2013. 205. Hendrick MJ, Brooks JJ: Postvaccinal sarcomas in the cat: histology and immunohistochemistry, Vet Pathol 31:126–129, 1994. 206. Hendrick MJ: Feline injection-site sarcomas: current studies on pathogenesis, J Am Vet Med Assoc 213:1425–1426, 1998. 207. Ellis JA, Jackson ML, Bartsch RC, et  al.: Use of immunohistochemistry and polymerase chain reaction for detection of oncornaviruses in formalin-fixed, paraffin-embedded fibrosarcomas from cats, J Am Vet Med Assoc 209:767–771, 1996. 208. Nieto A, Sánchez MA, Martínez E, et  al.: Immunohistochemical expression of p53, fibroblast growth factor-b and transforming growth factor-α in feline injection-site sarcomas, Vet Pathol 40:651–658, 2003.

209. Moore PF, Affolter VK: Canine and feline histiocytic diseases. In Ettinger SJ, Feldman EC, editors: Textbook of veterinary internal medicine, ed 6, St Louis, 2005, Elsevier Saunders, pp 779–782. 210. Ladlow J: Injection site-associated sarcoma in the cat: treatment recommendations and results to date, J Feline Med Surg 15:409– 418, 2013. 211. Hartmann K, Day MJ, Thiry E, et al.: Feline injection-site sarcoma: ABCD guidelines on prevention and management, J Feline Med Surg 17:606–613, 2015. 212. Heldmann E, Anderson MA, Wagner-Mann C: Feline osteosarcoma: 145 cases (1990-1995), J Am Anim Hosp Assoc 36:518–521, 2000. 213. Cohen M, Wright JC, Brawner WR, et  al.: Use of surgery and electron beam irradiation, with or without chemotherapy, for treatment of injection-site sarcomas in cats: 78 cases (1996-2000), J Am Vet Med Assoc 219:1582–1589, 2001. 214. Phelps HA, Kuntz CA, Milner RJ, et al.: Radical excision with fivecentimeter margins for treatment of feline injection-site sarcomas: 91 cases (1998-2002), J Am Vet Med Assoc 239:97–106, 2011. 215. Esplin DG, McGill LD, Meininger AC, et al.: Postvaccination sarcomas in cats, J Am Vet Med Assoc 202:1245–1247, 1993. 216. Madewell BR, Griffey SM, McEntee MC, et al.: Feline injectionsite fibrosarcoma: an ultrastructural study of 20 tumors (19961999), Vet Pathol 38:196–202, 2001. 217. Couto SS, Griffey SM, Duarte PC, et al.: Feline injection-site fibrosarcoma: morphologic distinctions, Vet Pathol 39:33–41, 2002. 218. Rousset N, Holmes MA, Caine A, et  al.: Clinical and low-field characteristics of injection site sarcomas in 19 cats, Vet Radiol Ultrasound 54:623–629, 2013. 219. Travetti O, di Giancamillo M, Stefanello D, et al.: Computed tomography characteristics of fibrosarcoma – a histological subtype of feline injection-site sarcoma, J Feline Med Surg 15:488–493, 2013. 220. Longo M, Modina SC, Bellotti A, et al.: Advances in the anatomic study of the interscapular region of the cat, BMC Vet Res 11:249, 2015. 221. Nemanic S, Milovancev M, Terry JL, et al.: Microscopic evaluation of peritumoral lesions of feline injection site sarcomas identified by magnetic resonance imaging and computed tomography, Vet Surg 45:392–401, 2016. 222. Zardo KM, Damiani LP, Matera JM, et al.: Recurrent and nonrecurrent feline injection-site sarcoma: computed tomographic and ultrasonographic findings, J Feline Med Surg 18:773–782, 2016. 223. Ferrari R, Di Giancamillo M, Stefanello D, et  al.: Clinical and computed tomography tumour dimension assessments for planning wide excision of injection-site sarcomas in cats: how strong is the agreement, Vet Comp Oncol 15:374–382, 2017. 224. Davidson EB, Gregory CR, Kass PH: Surgical excision of soft tissue fibrosarcomas in cats, Vet Surg 26:265–269, 1997. 225. Hershey AE, Sorenmo KU, Hendrick MJ, et al.: Prognosis for presumed feline injection-site sarcoma after excision: 61 cases (19861996), J Am Vet Med Assoc 216:58–61, 2000. 226. Romanelli G, Marconato L, Olivero D, et al.: Analysis of prognostic factors associated with injection-site sarcomas in cats: 57 cases (2001-2007), J Am Vet Med Assoc 232:1193–1199, 2008. 227. Cantatore M, Ferrari R, Boracchi P, et  al.: Factors influencing wound healing complications after wide excision of injection site sarcomas of the trunk of cats, Vet Surg 43:783–790, 2014. 228. Lidbetter DA, Williams FA, Krahwinkel DJ, et al.: Radical lateral body-wall resection for fibrosarcoma with reconstruction using polypropylene mesh and a caudal superficial epigastric axial pattern flap: a prospective clinical study of the technique and results in 6 cats, Vet Surg 31:57–64, 2002. 229. Bray J, Polton G: Neoadjuvant and adjuvant chemotherapy combined with anatomical resection of feline injection-site sarcoma: results in 21 cats, Vet Comp Oncol 14:147–160, 2016. 230. Wenk CHF, Ponce F, Guillermet S, et  al.: Near-infrared optical guided surgery of highly infiltrative fibrosarcomas in cats using an anti-αvβ3 integrin molecular probe, Cancer Lett 334:188–195, 2013.

CHAPTER 22  Soft Tissue Sarcomas

231. Martano M, Morello E, Ughetto M, et  al.: Surgery alone versus surgery and doxorubicin for the treatment of feline injection-site sarcomas: a report on 69 cases, Vet J 170:84–90, 2005. 232. Cronin K, Page RL, Spodnick G, et al.: Radiation therapy and surgery for fibrosarcoma in 33 cats, Vet Radiol Ultrasound 39:51–56, 1998. 233. Bregazzi VS, LaRue SM, McNiel E, et al.: Treatment with a combination of doxorubicin, surgery, and radiation versus surgery and radiation alone for cats with injection-site sarcomas: 25 cases (1995-2000), J Am Vet Med Assoc 218:547–550, 2001. 234. Kobayashi T, Hauck ML, Dodge R, et  al.: Preoperative radiotherapy for injection-site sarcoma in 92 cats, Vet Radiol Ultrasound 43:473–479, 2002. 235. Eckstein C, Guscetti F, Roos M, et al.: A retrospective analysis of radiation therapy for treatment of feline vaccine-associated sarcoma, Vet Comp Oncol 7:54–68, 2009. 236. Mayer MN, Treuil PL, LaRue SM: Radiotherapy and surgery for feline soft tissue sarcoma, Vet Radiol Ultrasound 50:669–672, 2009. 237. Kleiter M, Tichy A, Willmann M, et al.: Concomitant liposomal doxorubicin and daily palliative radiation therapy in advanced feline soft tissue sarcomas, Vet Radiol Ultrasound 51:349–355, 2010. 238. Nolan MW, Griffin LR, Custis JT, et al.: Stereotactic body radiation therapy for treatment of injection-site sarcomas in cats: 11 cases (2008-2012), J Am Vet Med Assoc 15:526–531, 2013. 239. Williams LE, Banerji N, Klausner JS, et al.: Establishment of two injection-site feline sarcoma cell lines and determination of in vitro chemosensitivity to doxorubicin and mitoxantrone, Am J Vet Res 62:1354–1357, 2001. 240. Banerji N, Li X, Klausner JS, et al.: Evaluation of in vitro chemosensitivity of injection-site feline sarcoma cell lines to vincristine and paclitaxel, Am J Vet Res 63:728–732, 2002. 241. Hill J, Lawrence J, Saba C, et al.: In vitro efficacy of doxorubicin and etoposide against a feline injection-site sarcoma cell line, Res Vet Sci 97:348–356, 2014. 242. Barber LG, Sorenmo KU, Cronin KL, et al.: Combined doxorubicin and cyclophosphamide chemotherapy for nonresectable feline fibrosarcoma, J Am Anim Hosp Assoc 36:416–421, 2000. 243. Poirier VJ, Thamm DH, Kurzman ID, et  al.: Liposome-encapsulated doxorubicin (Doxil) and doxorubicin in the treatment of injection-site sarcomas in cats, J Vet Intern Med 16:726–731, 2002. 244. Saba CF, Vail DM, Thamm DH: Phase II clinical evaluation of lomustine chemotherapy for feline vaccine-associated sarcoma, Vet Comp Oncol 10:283–291, 2012. 245. Katayama R, Huelsmeyer MK, Marr AK, et al.: Imatinib mesylate inhibits platelet-derived growth factor activity and increases chemosensitivity in feline injection-site sarcoma, Cancer Chemother Pharmacol 54:25–33, 2004. 246. Lawrence J, Saba C, Gogal R, et al.: Mastinib demonstrates antiproliferative and pro-apoptotic activity in primary and metastatic feline injection-site sarcoma cells, Vet Comp Oncol 10:143–154, 2012. 247. Turek M, Gogal R, Saba C, et  al.: Masitinib mesylate does not enhance sensitivity to radiation in three feline injection-site sarcoma cell lines under normal growth conditions, Res Vet Sci 96:304–307, 2014. 248. Holtermann N, Kiupel M, Hirschberger J: The tyrosine kinase inhibitor toceranib in feline injection-site sarcomas: efficacy and side effects, Vet Comp Oncol 15:632–640, 2017. 249. Spugnini EP, Baldi A, Vincenzi B, et al.: Intraoperative versus postoperative electrochemotherapy in high grade soft tissue sarcomas: a preliminary study in a spontaneous feline model, Cancer Chemother Pharmacol 59:375–381, 2007.

431

250. Spugnini EP, Renaud SM, Buglioni S, et al.: Electrochemotherapy with cisplatin enhances local control after surgical ablation of fibrosarcoma in cats: an approach to improve the therapeutic index of highly toxic chemotherapy drugs, J Transl Med 9:152, 2011. 251. Knapp DW, Richardson RC, DeNicola DB, et al.: Cisplatin toxicity in cats, J Vet Intern Med 1:29–35, 1987. 252. Jourdier TM, Moste C, Bonnet MC, et al.: Local immunotherapy of spontaneous feline fibrosarcomas using recombinant poxviruses expressing interleukin 2 (IL2), Gene Ther 10:2126–2132, 2003. 253. Jas D, Soyer C, De Fornel-Thibaud P, et al.: Adjuvant immunotherapy of feline injection-site sarcomas with the recombinant canarypox virus expressing feline interleukine-2 evaluated in a controlled monocentric clinical trial when used in association with surgery and brachytherapy, Trials Vaccinol 4:1–8, 2015. 254. Jahnke A, Hirschberger J, Fischer C, et  al.: Intra-tumoral gene delivery of feIL-2, feIFN-gamma and feGM-CSF using magnetofection as a neoadjuvant treatment option for feline fibrosarcoma: a phase I trial, J Vet Med A Physiol Pathol Clin Med 54:599–606, 2007. 255. H007.A Physiol Pathberger J, Jahnke A, et al: Neoadjuvant gene delivery of feline granulocyte-macrophage colony-stimulating factor using magnetofection for the treatment of feline fibrosarcomas: a phase I trial, J Gene Med 10:655–667, 2008. 256. Kent EM: Use of an immunostimulant as an aid in treatment and management of fibrosarcoma in three cats, Fel Pract 21(13), 1993. 257. King GK, Yates KM, Greenlace PG, et al.: The effect of acemannan immunostimulant in combination with surgery and radiation therapy on spontaneous canine and feline fibrosarcomas, J Am Anim Hosp Assoc 31:439–447, 1995. 258. Quintin-Colonna F, Devauchelle P, Fradelizi D, et al.: Gene therapy of spontaneous canine melanoma and feline fibrosarcoma by intratumoral administration of histoincompatible cells expressing human interleukin-2, Gene Ther 3:1104–1112, 1996. 259. Giudice C, Stefanello D, Sala M, et  al.: Feline injection-site sarcoma: recurrence, tumour grading and surgical margin status evaluated using the three-dimensional histological technique, Vet J 186:84–88, 2010. 260. Hahn KA, Endicott MM, King GK, et al.: Evaluation of radiotherapy alone or in combination with doxorubicin chemotherapy for the treatment of cats with incompletely excised soft tissue sarcomas: 71 cases (1989–1999), J Am Vet Med Assoc 231:742–745, 2007. 261. Porcellato I, Menchetti L, Brachelente C, et al.: Feline injection-site sarcoma: matrix remodeling and prognosis, Vet Pathol 54:204–211, 2017. 262. Dillon CJ, Mauldin GN, Baer KE: Outcome following surgical removal of nonvisceral soft tissue sarcomas in cats: 42 cases (19922000), J Am Vet Med Assoc 227:1955–1957, 2005. 263. Macy DW: Current understanding of vaccination site-associated sarcomas in the cat, J Feline Med Surg 1:15–21, 1999. 264. Martano M, Morello E, Buracco P: Feline injection-site sarcoma: past, present and future perspectives, Vet J 1888:136–141, 2011. 265. Hendricks CG, Levy JK, Tucker SJ, et al.: Tail vaccination in cats: a pilot study, J Feline Med Surg 16:275–280, 2014. 266. Scott FW, Geissinger CM: Duration of immunity in cats vaccinated with an inactivated feline panleukopenia, herpesvirus, and calicivirus vaccine, Fel Pract 25(12), 1997. 267. Scott FW, Geissinger CM: Long-term immunity in cats vaccinated with an inactivated trivalent vaccine, Am J Vet Res 60:652–658, 1999. 268. Jas D, Frances-Duvert V, Vernes D, et  al.: Three-year duration of immunity for feline herpesvirus and calicivirus evaluated in a controlled vaccination-challenge laboratory trial, Vet Microbiol 177:123–131, 2015.