General Considerations
Soft tissue sarcoma (STS) is a catch-all classification referring to tumors that arise from the embryonic mesoderm and, as such, can occur anywhere in the body. The term is most commonly used in reference to subcutaneous tissues, with other sites such as the alimentary and urogenital tracts being less frequently affected. This variable distribution leads to a huge range of histopathological subtypes. Generally, they are classified by histopathology or immunohistochemistry according to the cell of origin such as fibrosarcoma (FSA), peripheral nerve sheath tumor (PNST), myxosarcoma, liposarcoma, or leiomyosarcoma. Sometimes these distinctions are not clear and the generic term soft tissue sarcoma or spindle cell sarcoma are employed. Tumors within this group, however, are often treated as one, as they tend to have similar biological behavior.
Some tumors of mesoderm behave in a much more aggressive and less predictable fashion and have a much higher rate of metastasis. These tend not to be included in STS, and examples include rhabdomyosarcoma, synovial cell sarcoma, visceral hemangiosarcoma, chondrosarcoma, and osteosarcoma.
Etiology and Pathogenesis
Many subcutaneous soft-tissue lesions are benign or inflammatory, but STS comprise 15% of all skin and subcutaneous tumors in dogs and 7–9% in cats (Theilen, Madewell 1979; Miller et al. 1991). No consistent sex or breed predisposition in dogs has been found, although spayed females were over-represented in one study (Baker-Gabb et al. 2003). Medium- to old-aged dogs of medium to large breeds seem to be most commonly affected. STS are less common in cats, but since 1991 there has been an increase in the number of feline sarcomas, particularly at anatomic sites used for vaccination. This was coincident with the shift from modified-live to killed rabies vaccine products. Links with feline leukemia virus vaccines, vaccination for other feline infectious diseases, and non-vaccine injections in general have also been postulated.
Many STS feel encapsulated and distinct from surrounding tissues. This is because they are surrounded by a pseudocapsule, which creates an easy plane of cleavage between tumor and surrounding tissues, allowing the masses to be 'shelled-out.' The pseudocapsule arises, however, because expanding tumors are histologically surrounded by a poorly defined reactive zone, consisting of some or all of a vascular response (new blood vessels), mesenchymal response (to physical presence of the tumor and abnormal local tissue forces), and an inflammatory response (to necrosis/hemorrhage). This reactive zone may be fractions of a millimeter wide in small low-grade tumors, but significantly wider in rapidly expanding high-grade tumors. This reactive zone creates a visible and palpable 'edge' to the tumor, mimicking a fascial plane, but microscopically or immunohistochemically it is a three-dimensional 'halo' of malignancy. Dissections within the reactive zone (i.e., shelling-out) are therefore marginal excisions which commonly result in tumor cells extending to the edges of the resected tissue, or satellite deposits of tumor cells in the reactive zone are left in the wound.
Presentation and Clinical Signs
History
Many STS are found when still small in size but are often not investigated, as the owner or clinician assume them to be benign. They are typically non-painful masses, and although they may be firm and attached to deeper tissues, many are soft and mobile, mimicking lipomas or other benign masses. Hemangiopericytomas in particular are slow-growing and may contain fluid pockets creating 'soft spots' on palpation. A study of insured dogs in the UK identified lipomas in 318 per 100,000 dogs, with STS at 142 per 100,000 (Dobson et al. 2002). It is this greatly increased incidence of benign lipomas that leads to incorrect assumptions that soft subcutaneous masses are not malignant, and many go undiagnosed until they change their behavior, cause clinical signs, or cause concern for the owner. A history of a mass on the body wall or extremities slowly growing over several years is not uncommon.
Feline vaccine-associated sarcomas (VAS) are seen 2–10 months after vaccination and are on average 4 cm in diameter at diagnosis, often with a history of rapid growth. Most vaccine reactions resolve in 30–90 days - only those that persist longer than 4 months should be investigated and possibly removed.
Clinical Signs
STS are typically in the subcutaneous space, and the skin overlying the mass is often freely mobile. They present as non-painful masses on the trunk or extremities, but as they grow, they invade the skin and deeper tissue, causing them to become more fixed and often superficially ulcerated or infected. Curative-intent surgery for large, fixed tumors may be difficult or impossible, and cross-sectional imaging such as CT is recommended to plan surgery appropriately in these cases. Palliative surgery to remove the bulk of the tumor can also be offered to improve the patient's quality of life. When sarcomas are confined within anatomic spaces, patients present with signs of pain due to increased compartmental pressure. Examples include STS contained within muscle bellies, or expansile intermuscular tumors compressing neurovascular structures - e.g., thigh masses compressing the sciatic nerve.
Feline VAS are also locally invasive with an infiltrative growth pattern and will regrow following inadequate surgery. There are often centrally located micro- or macro-abscesses giving rise to a cystic center, yielding fluid on fine-needle aspiration.
Clinical Approach
Diagnostic investigation of a possible STS has 3 aims:
1. To accurately diagnose the tumor before treatment
2. To define the anatomical relations of the primary tumor for surgery and/or radiation planning
3. To identify the presence or absence of metastatic disease
Biopsy
Fine-needle aspirates have an important role in ruling out other subcutaneous differentials - for example, lipomas, mast cell tumors, or inflammatory lesions, all of which exfoliate cells easily. Although STS are compact tumors, only a few mesenchymal cells need to be aspirated to make a diagnosis. In a university setting, fine-needle aspirates of STS yielded a correct diagnosis in 62.5% cases, were nondiagnostic in 22.5% cases, and an incorrect diagnosis was made in 15% (Baker-Gabb et al. 2003). If an aspirate of a subcutaneous mass fails to yield many cells on the slide, your index of suspicion for a STS should be raised and prompt a Tru-Cut biopsy.
Percutaneous core biopsies (e.g., Tru-Cut) are possibly the best technique for achieving a safe and accurate diagnosis and can easily be performed with local anesthesia and sedation. Tru-Cut biopsies will reliably differentiate benign from malignant disease and in most cases will also give a good indication of grade. The simplicity and accuracy of core biopsy for STS mean incisional biopsies are infrequently indicated and come with the added concerns of location and direction of scar, and tumor dissemination from post-incisional biopsy hematoma.
Evaluation of Primary Tumor and Possible Metastasis
A complete blood count and biochemistry are performed prior to anesthesia as patients are typically older and may have coexisting systemic disease. Radiographs of the mass may yield some information regarding local behavior (especially whether invasion of overlying bone is evident), but often only confirm the mass is of soft tissue density. Ultrasound (especially Doppler) can be useful to ascertain degree of local vascularity, but if available, cross-sectional imaging (CT or MRI) is the imaging of choice and is typically supportive of the diagnosis, in addition to accurately identifying the relationship of the mass to local vital structures. Whereas MRI is traditionally regarded as superior for soft tissue detail, CT (especially contrast CT) offers a fast, simple, and accurate alternative for all but the most complex STS. It is often cheaper, more intuitive to interpret if inexperienced, and it has the added advantage that imaging the thorax for metastatic disease can easily be performed at the same time.
STS metastasize hematogenously and lymphatic involvement is unusual. Any firm, irregular, or enlarged regional lymph nodes should be evaluated by fine-needle aspirate, Tru-Cut biopsy, or excisional biopsy.
Grading
STS are graded into low (I), intermediate (II), and high (III) grade tumors, taking into account histologic features such as mitotic rate, extent of necrosis, cellular differentiation, and cellular pleomorphism. Grading of STS in dogs is considered more important for prognosis than the cell of origin, because grade significantly affects likelihood of metastasis (Powers 1995; Kuntz 1997). Reported metastatic rates for the dog are grade I (13%), grade II (7%), and grade III (41%) (Kuntz et al. 1997). Immunohistochemical staining has demonstrated that increased AgNOR count in tissue specimens is a significant prognostic indicator for decreased survival time (Ettinger et al. 2006) and on the strength of this, AgNORs may become part of routine evaluation of malignancy of STS along with histologic grading.
Grade plays an important role in tumors of the upper limb, chest wall, and flank where wide excisions with tumor-free margins can be taken, but may have a lesser role when tumors involve the head and neck, retroperitoneum or distal limbs, where specific anatomical restraints at these sites prevent wide curative-intent excision. In these locations, the amount of tumor excised/excisable may prove to be more important than grade.
Histologic Subtypes
Peripheral Nerve Sheath Tumor (PNST)
This is a large group of tumors, containing neurofibrosarcomas, malignant schwannomas, and somewhat contentiously, hemangiopericytomas. As a group, they tend to be locally invasive, but metastasize rarely, especially hemangiopericytomas. PNSTs arise predominantly in the distal extremities, and they can become large and adherent to the overlying skin. Infiltration between the flexor and extensor tendons is common, making many of these excisions marginal at best, leaving residual tumor disease behind. These tumors can also be derived from peripheral nerves close to the spinal column, most commonly in the brachial plexus. These dogs will present with muscle wasting, single forelimb lameness, and a firm painful mass deep in the axilla. Electromyography to demonstrate muscle denervation and CT or MRI to plan surgery are recommended. Many cases have spinal cord invasion, and amputation combined with a laminectomy may be necessary. Invasion into the spinal cord is also possible in cats but represents <5% cases (Marioni-Henry et al. 2008).
Fibrosarcoma (FSA)
Originating from neoplastic fibroblasts, these tumors have a low-moderate metastatic rate. They occur most commonly on the flanks (dermal, subcutaneous, and deep fascia) and oral cavity. Non-oral FSA behaves like a STS. A specific type of FSA, the 'Hi-Lo,' is encountered in the mouth of young dogs, commonly Golden Retrievers. This is a biologically high-grade, but histologically low-grade tumor - i.e., the biopsy can be misleading in terms of clinical behavior and prognosis. Aggressive surgical excision and fractionated radiation therapy of a 'Hi-Lo' may still result in local recurrence and/or distant metastasis. FSA in the cat is covered as a separate condition.
Myxosarcoma
A mesenchymal malignancy characterized by production of mucinous matrix, these can grossly appear wet when biopsied or sectioned, and are generally softer to the touch than other STS. They otherwise behave biologically in a similar fashion to other STS.
Leiomyosarcoma
A STS with rare involvement of the skin or subcutaneous tissues. These are tumors arising from smooth muscle cells and are predominantly found in the walls of the alimentary and urogenital tract, where they result in clinical signs due to their physical presence (luminal obstruction/organ deviation), or through ulceration (vaginal bleeding, melena). Small-intestinal leiomyosarcoma treated by resection-anastomosis with 3- to 5-cm margins usually results in tumor-free margins, but the draining mesenteric lymph nodes should be carefully inspected and biopsied or removed if firm or enlarged. Leiomyosarcoma of the oesophagus presents late in the course of the disease but appears to be low grade and has been treated with marginal excision with long-term resolution of clinical signs (Farese et al. 2007). Leiomyosarcoma in the vagina may be managed by episiotomy and resection, and occasionally total vaginectomy if extensive disease is present.
Adipose Tumors
1. Lipoma
Well-circumscribed soft masses within a thin capsule, which can occasionally grow to considerable size. Although the subcutaneous site is the most common, they have been diagnosed in the thoracic and abdominal cavities and pelvic canal. Indications for removal include sudden rapid growth, recent change in texture, bothering the dog, bothering the owner, or interfering with normal function. Lipomas in cats are rare.
2. Infiltrative lipoma
Most commonly reported in the limbs and flank, these are poorly demarcated tumors, with the macroscopic appearance of mature fat, but microscopically the fat is dispersed with infiltrated muscle fibres. There is no obvious tumor capsule, and CT is necessary to adequately plan surgery and identify potential risks (McEntee et al. 2001). Infiltration between muscle bellies and around neurovascular structures makes surgery an intralesional dissection. Cobalt radiation therapy has been used with some success to control local disease following debulking surgery, with a median survival of 40 months reported (McEntee et al. 2000). These tumors do not metastasize.
3. Liposarcoma
A malignant mesenchymal tumor derived from adipocytes, these tumors can occur equally on the flanks and the limbs. They are locally invasive, and median size at presentation is 4 cm. Recent work has indicated their metastatic potential may be lower than previously believed. A wide excision is associated with a median survival of 1188 days, compared to 649 days for a marginal excision (Baez et al. 2004).
Hemangiosarcoma (HSA)
Dermal HSA behaves biologically very differently to the more aggressive visceral form seen in internal organs. It is reported more frequently in breeds such as Irish Wolfhounds, Whippets, Salukis, Bloodhounds, and Pointers. Lightly pigmented, sparsely haired dogs (Beagles, White Bulldogs, English Pointers, and Dalmatians) have also been reported as predisposed to the development of cutaneous and subcutaneous HSA (Hargis et al. 1992). It is possible that unpigmented skin in cats may also be predisposed to developing dermal HSA. It has been suggested cutaneous hemangiomas may undergo malignant transformation to HSA - this appears less likely with the subcutaneous form (Hargis et al. 1992). Most cutaneous HSA are well-defined superficial masses that are amenable to local excision and metastasize slowly, if at all. Subcutaneous HSA tends to be a more locally invasive, problematic tumor, and infiltrative tumors, plus those with hypodermal or muscular involvement in dogs, seem to have a high recurrence rate and incidence of metastasis.
In cats, dermal and subcutaneous HSA are more common than the visceral form and are treated primarily by surgery. Attaining a tumor-free margin following surgery is more likely with a well-defined dermal mass, and this translates into a longer recurrence-free interval, whereas margins of normal tissue can be difficult to identify with subcutaneous HSA because of localized bleeding and bruising. In one study, 50% cats with subcutaneous HSA suffered local recurrence following surgery, while none of the cats with dermal HSA had recurrence (Johannes et al. 2007). Subcutaneous HSA is particularly difficult to manage when it arises in the ventral or inguinal areas, as these tumors are often too large to treat by the time of diagnosis (McAbee et al. 2005). A high mitotic count (>3/10 hpf) is associated with a poorer survival in cats (Johannes et al. 2007). It is likely that metastatic rate of subcutaneous HSA is higher than previously thought (Kraje et al. 1999).
Radiation therapy for unresectable or incompletely excised HSA has been poorly reported in dogs and cats, and its impact is unknown. Chemotherapy for subcutaneous tumors has been described with commonly used agents being doxorubicin, vincristine, and cyclophosphamide; but there is little evidence to show any benefit.
Whereas the prognosis for dermal HSA in both dogs and cats is good, no difference in overall survival in dogs has been found between visceral and subcutaneous HSA, unlike in cats where the subcutaneous form is less aggressive than the visceral form (Sorenmo et al. 1993; Johannes et al. 2007). Stage I HSA (tumor <5 cm, does not invade beyond dermis) has a long median survival time with surgery alone of 780 days in dogs and 36 months in cats. Stage 2 (invades subcutaneous tissue) and stage 3 (invades adjacent muscle) carry a poorer prognosis (Ward et al. 1994).
Lymphangiosarcoma
In addition to behaving like any STS where older patients are more at risk, lymphangiosarcoma can also affect younger dogs and cats, often with soft fluctuant swellings arising along the ventral body wall, the inguinal area, or around the proximal thigh. The masses are soft and easily compressible, sometimes adopting the feel of 'bubble wrap.' Clear transudate can be easily expressed from any skin puncture - e.g., through a needle tract for Tru-Cut biopsy. Due to anatomical location, often wide excision means amputation with myocutaneous flaps. The prognosis is guarded due to risk for local recurrence at the amputation site, and reportedly increased risk of metastasis. There is no known benefit to giving chemotherapy.
Histiocytic Sarcoma
Arising from myeloid dendritic cells, these rare malignant tumors behave like other STS. They should not be confused with histiocytomas, which are benign cutaneous round cell tumors often seen in juvenile dogs that can undergo spontaneous regression within 3 months. Histiocytic sarcomas are localized masses arising in the subcutaneous tissues, but primary tumors affecting joints have also been described (Craig et al. 2002). They are locally invasive tumors, are graded according to STS guidelines, and are primarily treated surgically. They may represent an early form of the disseminated disease, malignant histiocytosis, which is a rapidly progressive systemic form most commonly seen in the Bernese Mountain Dogs, although Rottweilers and retrievers are also affected. Dogs present with anorexia, weight loss, and often pulmonary signs and are poorly responsive to therapy. It carries a grave prognosis (Fulmer et al. 2007).
Malignant Fibrous Histiocytoma (MFH)
These are often confused with histiocytic sarcomas but are a separate member of the STS family, reportedly arising in the subcutaneous tissues and spleen. Rottweilers and golden retrievers are more commonly affected (Goldschmidt, Hendrick 2002). Long-term local control is possible with surgery alone, or combined with radiation (McKnight et al. 2000).
Feline Sarcomas
Three types arise in cats:
1. Viral induced (feline sarcoma virus, FeSV)
Seen in cats also positive for FeLV, FeSV oncogenes transform fibroblasts and produce FSA. These are rare, accounting for 2% of FSA, are seen in young cats and typically multicentric. A rapid doubling time (12–72 hours) is possible. Surgery will not benefit these patients.
2. Non-viral, non-vaccine
Usually seen in older cats, these affect the head and neck.
3. Feline vaccine-associated sarcoma (VAS or injection-site sarcomas)
There is a statistical link to vaccination, particularly FeLV and rabies virus vaccines, enhancing the risk of VAS 2–5 fold. Cats are younger than the non-vaccine sarcoma group. There is an increased risk with increasing number of vaccinations, and with repeated vaccination at the same site (Kass 1993; Kass 2003). Tumors usually arise 2–10 months after vaccination, and a risk of 0.32 sarcomas/10,000 doses given is reported (Gobar, Kass 2002).
VAS are mostly fibrosarcomas, but rhabdomyosarcoma, osteosarcoma, chondrosarcoma, etc. are also seen (Hendrick 1994; Doddy 1996; Macy 1996). Median survival times for cats with FSA or PNST were significantly longer than median time for cats with MFH (Dillon et al. 2005). An inflammatory granuloma is seen in 11.8 times/10,000 doses, but it is not necessary to remove these masses unless malignant behavior is apparent or they persist over 4 months (Gobar, Kass 2002). VAS are not linked to FeLV or FIV infection, but the aluminum adjuvant may play a role in carcinogenesis.
They are graded from 1–3 depending on mitotic index, differentiation, and necrosis. Multinucleated giant cells are seen in the more malignant, and most have peritumoral lymphocyte inflammation and increased vascular density. Recent evidence has suggested a higher grade is associated with an increased risk of metastasis (Romanelli 2008).
Management and Prognosis
Surgical resection is the most effective treatment for primary localized STS, as they are relatively chemo-insensitive and radiotherapy is more effective at treating microscopic disease than unresectable gross disease. The aim of curative-intent surgery is to widely excise the primary tumor (3 cm wide and 3 cm or a fascial plane deep) and achieve negative histopathological margins.
The great variation in possible location, factored with variable size and grade, can present significant problems when making a treatment plan, and it is complicated by anatomical constraints, maintenance of local function, biological characteristics of the tumor, and length and cost of surgery and reconstruction.
Our understanding of margins for excising STS is based on Enneking's pioneering work in musculoskeletal tumors in humans, whereby he classified them as intralesional (intracapsular), marginal, wide, or radical.
An intracapsular margin is achieved by piecemeal removal ('debulking') of a lesion from within the capsule. This is also used if the capsule is accidentally entered during dissection, as the surgical field is now contaminated. Gross and/or microscopic disease remains. Examples include incisional biopsy and infiltrative lipomas.
A marginal margin is achieved by an extracapsular dissection through the reactive zone around the STS. Classically these are termed 'shell-outs' and involve peeling the mass out from its tissue bed and off local attachments. Both benign and malignant lesions may have extracapsular microextensions of disease, microsatellites (in the reactive zone), and 'skip' metastases of high-grade lesions (in normal tissue of the same compartment). These both have implications for marginal excisions in terms of potential for local recurrence.
A wide margin is achieved by en bloc removal of the lesion, its capsule and the surrounding reactive zone but always working in normal uncontaminated tissue within the compartment of the lesion. Non-neoplastic, non-reactive intracompartmental normal tissue is left at the margins, and there is the possibility of 'skip' metastases arising in the remaining portion of the compartment (e.g., high-grade STS).
A radical margin removes the lesion, reactive zone, and all the tissue of the associated compartment. There is no potential for residual neoplasm locally. The typical example is amputation, along with variants such as hemi-pelvectomy.
The abundance of skin on the neck and flanks of most patients means wide resections of the upper limb or flank are possible and complex reconstructive techniques are often only indicated in awkward anatomical locations, for example around the perineum. Radiation has a role if incomplete margins are found and if further revision surgery is declined.
This is a different situation in the distal limbs, however (at/below the stifle and at/below the elbow) where a wide surgical margin of skin is usually only achievable using free skin grafts or random flaps, and options such as amputation or marginal resection and radiation are considered. Both these options have drawbacks in terms of altered function, morbidity, and cost. Whereas it is expected that an amputation will cure the patient, the limb could be spared with marginal excision of the STS and radiation, but this is costly and results in a local recurrence rate of 19–35%.
Following excision, all cut edges of the tissue (skin margin and deep margin) should be stained with India Ink, left to dry, and then placed into 10% formalin to fix, at a ratio at least 1 part mass: 10 parts formalin. On processing and interpretation, identifying tumor cells in 'inked' tissue represents tumor at the wound edge, and so an incomplete excision. Larger tissue masses may need to be 'bread-loafed' prior to fixing, as the formalin cannot diffuse to a depth of >1 cm tissue. Alternatively, some surgeons prefer to tie small suture knots at locations where concern exists over the width of the normal tissue margin to encourage the pathologist to examine these areas more critically.
Treatment options for a histologically diagnosed extremity STS include:
1. Amputation
2. Curative-intent excision with reconstruction, plus radiation if tumor cells extend to the edge of resected tissue microscopically
3. Preoperative radiation (48 Gy) to sterilize tissue around the tumor with marginal excision of mass 4 weeks later
4. Planned marginal excision of mass, then postoperative radiation (57 Gy) to sterilize residual tumor in the wound bed 2 weeks later
5. Skin-sparing surgery - planned marginal excision to microscopic disease, including fascia where possible
Options 1–4 are curative-intent plans and local recurrence is unlikely. Option 5 is a palliative plan, and the owner accepts local recurrence is a possibility. For many geriatric patients, however, this is a viable option with the expectation the patient will die of something else before the tumor has a chance to recur or metastasize.
Without presurgical biopsies, inadvertent shell-out procedures on masses assumed to be benign that subsequently turn out to be malignant, represent an unfortunately common but easily avoidable clinical scenario.
The difference between planned and unplanned marginal excisions is:
In planned marginal excisions, typically in the distal extremities, the surgeon has biopsied the mass and is aware they are incompletely excising a STS. They anticipate local recurrence, and so attempt wherever possible to work outside the pseudocapsule to excise the infiltration of the tumor into the surrounding tissues. Wide margins are not possible without reconstructive techniques (which have been discussed and declined by the owner) and so the aim is to remove as much tumor as possible, but still close the skin over the wound. This skin-sparing surgery may still involve excising fascia beneath the mass. At some point during the surgery the pseudocapsule is entered (normally when peeling tumor off skin) and so the surgery is classified as marginal. A recurrence rate in dogs of 11% for this technique has been reported when performed by experienced surgeons, and all STS were grade 1 (Stefanello 2008).
An unplanned marginal excision is a true 'shell-out' working in the pseudocapsule of an unknown mass. Fascia is not taken, and small macroscopic disease may remain. As no attempt is made to reduce the chance of recurrence by wider dissection, local recurrence is considered likely.
If faced with an incompletely excised STS (so-called 'dirty margins'), treatment options include:
1. Amputation, if on a limb
This should be curative assuming the scar and previous tumor-contaminated surgical wound are not entered during amputation
2. Postoperative radiation to sterilize tumor bed
Several studies have reported the results of adjunctive radiotherapy in the management of STS with surgically incomplete margins, and its success has generally been measured by its long overall survival times. The effect on local tumor control, however, has been variable, with recurrence rates ranging from 17% to 31% (Forrest et al. 2000; McKnight et al. 2000).
3. Re-excision of scar with local closure techniques
Even in the distal limbs where there is little available soft tissue, re-excision of the scar with as wide a margin as possible (to still close wound primarily) can result in clean margins of excision in over 90% of cases and a local recurrence rate of 15%. Tumor may be found in only 22% of resected scars on histopathology, but its presence cannot be used to predict which dogs will have local recurrence (Bacon et al. 2007).
4. Wait and see
For many owners, this is an understandable choice. The failure rate for marginal excisions in dogs is historically quoted as 60–70% based on work performed 20–30 years ago on grade III sarcomas with unknown margin status, but much has changed since in terms of understanding tumor biology and especially earlier intervention by owners. Marginal excision of grade I sarcomas may have a local recurrence rate as low as 11%, so the rate for grade II tumors is likely somewhere between 11–70%.
Chemotherapy
STS are not considered chemosensitive. It is known that >40% of dogs with grade III STS will develop distant metastatic disease (Kuntz et al. 1997) and so the addition of conventional chemotherapy drugs to try to control this systemic spread is sensible. Little evidence exists, however, to show a beneficial effect of chemotherapy on overall survival. Doxorubicin as a single agent failed to improve disease-free interval or overall survival in dogs with grade III STS (Selting et al. 2005). Recent work following dogs with incompletely excised STS receiving daily oral low-dose cyclophosphamide (10 mg/m2) and full-dose piroxicam (0.3 mg/kg), showed it to be very effective at delaying local recurrence compared to a control population and could be considered in dogs with 'dirty' wounds (Elmslie et al. 2008).
Radiotherapy
Use of radiotherapy as a sole treatment for unresectable STS has received recent attention. Dogs with macroscopic STS receiving four fractions of radiation (total dose 32 Gy) in a palliative setting showed it to be well tolerated with an overall response rate of 50%, but this was a short-lived improvement as median time to progression was 155 days (Lawrence et al. 2008). Cobalt radiation was administered in three fractions (total dose 24 Gy) to dogs with non-resectable STS, and median time to progression was 263 days (Plavec et al. 2006).
Management of Feline VAS
The presence of metastasis has been shown to significantly decrease survival time in cats with VAS (Cohen 2001; Sorensen 2004), underlying the importance of preoperative staging prior to radical surgery. Three-view chest radiographs are a minimum, and cross-sectional imaging such as contrast CT or MRI is recommended to delineate the tumor. Palpation may suggest a discrete mass, but post-contrast CT often shows the true extent of infiltrative disease, which cannot be appreciated by feel alone. Radical first excision of VAS yielded significantly longer median time to first recurrence (325 days) than did marginal first excision (79 days) (Hershey et al. 2000). Median survival time is significantly longer in cats with tumors <2 cm in diameter compared to those with tumors 2 cm in diameter (Dillon et al. 2005).
Surgery for VAS
The general approach of 2–3 cm margins wide, and one fascial plane deep to the tumor bed (Dernell 1998) has been adopted for VAS in cats, but even this may not be adequate considering historical rates of local recurrence. Some surgeons are suggesting more radical methods, including surgical margins of ≥3 cm and 1 to 2 fascial planes deep to the tumor, along with partial scapulectomy, osteotomy of spinous processes or hemipelvectomy when indicated (Al-Sarraf 1998; Hershey 2000; Cohen 2001; Seguin 2002; Kobayashi 2002; Davis 2007; Romanelli 2008). Currently, the Vaccine-Associated Sarcoma Task Force recommends multimodal treatment, including surgical resection with at least 2-cm margins in all planes, with mention of use of 3- to 5-cm surgical margins for excision (VASTF 2005). When such large surgeries are performed, epidural analgesia, local tissue infiltration with bupivacaine prior to closure, and a constant-rate infusion (CRI) of fentanyl or fentanyl patches should be used.
Chemotherapy for VAS
Although there are isolated reports of VAS responding to drugs such as doxorubicin, cyclophosphamide, mitoxantrone, and carboplatin, there is little evidence in larger numbers of cats with VAS that adjuvant chemotherapy improves overall survival (Bregazzi 2001; Martano 2005); however, it may delay local recurrence in cats also receiving curative-intent radiation therapy (Hahn 2007).
Radiation Therapy for VAS
Although VAS response to external beam radiation can be unpredictable, it plays an important role in large fixed tumors where CT shows achieving tumor-free margins by surgery alone will be difficult. Preoperative radiation will sterilize the reactive zone and surrounding 'clean' tissues and so allow for a potentially smaller resection to be performed. Postoperative radiation can be used when a curative-intent surgery was unsuccessful and residual tumor disease remains. The postoperative dose can be high (54–57 Gy) as treatment is started 10–14 days after surgery when the surgical site has already healed. The preoperative dose is often lower (48 Gy) to avoid overly damaging the skin and so reduce the risk of creating a non-healing wound following surgery.
Using preoperative cobalt 60 in combination with surgery, median time to recurrence was 2.7 years following complete excision and 0.8 years if incompletely excised (Kobayashi 2002). Surgery followed by megavoltage radiation gave median survivals of 23–24 months, but time to recurrence and survival was decreased when time to surgery and starting radiation was increased (Bregazzi 2001; Cohen 2001).
Reported rates of local recurrence range from 25–60% (Davidson 1997; Cronin 1998; Bregazzi 2001; Kobayashi 2002; Martano 2005; Banjeri 2006; Hahn 2007; Romanelli 2008) after various combinations of surgery, radiation (pre- or postoperative), and chemotherapy. Rates of metastasis range from 5.6% to 22.5% (Hershey 2000; Cohen 2001; Kobayashi 2002; Poirier 2002; Romanelli 2008). Pulmonary metastasis is most commonly reported, with other sites including regional lymph nodes, skin, intestine, spleen, epidural and ocular infiltration, or multi-organ involvement (Hershey 2002; Kobayashi 2002; Cohen 2003; Chang 2006).
Preventative measures include:
Not over vaccinating
Keeping detailed vaccination records
Vaccinating in locations that can be easily resected in the future (e.g., mid-distal thigh, treatable by amputation)
Excising or biopsying vaccine-site reactions that
Persist over 4 months,
Are >2 cm in diameter, or
Increase in size 1 month after vaccination (Hershey et al. 2000)