Soft Tissue Sarcomas

• They tend to appear as pseudoencapsulated soft-to-firm tumors but have poorly defined histologic margins or infiltrate through and along fascial planes, and they are locally invasive.

• Local recurrence after conservative surgical excision is common.

• Sarcomas tend to metastasize hematogenously in up to 20% of cases.

• Regional lymph node metastasis is unusual (except for synovial cell sarcoma).¹⁰

• Histopathologic grade is predictive of metastasis, and resected tumor margins predict local recurrence.¹⁶

• Measurable or bulky (>5 cm in diameter) tumors generally have a poor response to chemotherapy and radiation therapy (RT).

Tumors of Fibrous Origin

Tumors of the Peripheral Nerves

Histiocytic Disorders

The reader is referred to Chapter 33, Section F, for a complete discussion of histiocytic disorders because the biology, nomenclature, and management of this collection of benign and malignant conditions continue to evolve. Malignant fibrous histiocytoma as a histopathologic diagnosis, however, is considered to be more consistent with soft tissue sarcomas in general and is managed with guidelines discussed later in this chapter.

Tumors of Adipose Tissue

Tumors of Smooth Muscle

Tumors of Skeletal Muscle

Tumors of Vascular and Lymphatic Tissue

Tumors of Synovial Tissue

Tumors of Uncertain Histogenesis

Surgery

Soft tissue sarcomas are locally aggressive tumors that grow along paths of least resistance and invade surrounding tissue, resulting in the formation of a pseudocapsule of compressed viable tumor cells.²⁴ The pseudocapsule gives the false impression of a well-encapsulated tumor. However, surgical removal of the encapsulated mass without adequate margins will result in incomplete resection and a high risk of local tumor recurrence.¹⁶ The minimum recommended margins for surgical resection are 3 cm lateral to the tumor and one fascial layer deep to the tumor (Figure 21-7).^121,122 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 surgical margins and local tumor control. Alternatively, planned multimodal therapy with marginal surgical excision and postoperative RT may be limb sparing and reduce patient morbidity.

The resected tumor should be pinned out to the original dimensions to prevent shrinkage during formalin fixation (Figure 21-8)¹²³; 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. Surgical margins and tumor grade are important in determining the need and type of further treatment. For instance, tumor grade is important in deciding whether a soft tissue sarcoma resected with complete but close surgical margins (i.e., 1 to 3 mm) will require further local treatment because surgical margins may be adequate with a low-grade soft tissue sarcoma but not with a high-grade soft tissue sarcoma.^121,122

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 recurrences, and decreases survival time.^{111,121,124-128} Traditionally, if a soft tissue sarcoma had been incompletely resected, then the surgical scar was managed with either a second aggressive surgery or RT because the entire surgical wound was considered contaminated and neoplastic.¹²¹ However, recent evidence suggests that this may not necessarily be true and a more conservative approach may be employed, particularly for low-grade soft tissue sarcomas. In one study, histologic evidence of residual tumor was identified in only 22% of 39 dogs with incompletely excised tumors.¹²⁹ Following excision of the surgical scar in these dogs with 0.5- to 3.5-cm margins, the local recurrence rate was 15%.¹²⁹ In a study of 104 canine soft tissue sarcomas managed with surgery alone in nonreferral practices, fewer than 10% were excised with 3-cm margins and local tumor recurrence was reported in 28% of dogs.¹³⁰ In a similar pathologic study, 75% of 139 canine subcutaneous soft tissue sarcomas were incompletely excised and the local tumor recurrence rate was significantly associated with histologic grade, with local tumor recurrence reported in only 7% of dogs with grade I soft tissue sarcomas compared to 34% and 75% of dogs with grade II and III tumors, respectively.¹³¹ This was further supported by another study in which 11% of 35 dogs with low-grade soft tissue sarcomas of the extremities (below the elbow and stifle) had local tumor recurrence following marginal excision.¹³² Thus, based on this evidence, dogs with incompletely excised soft tissue sarcomas, especially grade I and perhaps grade II tumors, can be managed with either active surveillance (i.e., frequent observation for local tumor recurrence and appropriate treatment if the tumor recurs) or a staging surgery. Staging surgery is a decision-making surgery. The surgical scar is excised with minimal margins (0.5 to 1.0 cm) with the aim being to determine if there is histologic evidence of residual tumor cells.¹²⁹ 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 soft tissue sarcomas, 3 cm lateral to the tumor and one fascial layer deep to the tumor,^{117,121,126,127} or the entire surgical scar should be irradiated.^126,127 Surgery is preferred to RT for management of incompletely resected soft tissue sarcomas in humans because local tumor control is better with repeat surgical resection than adjunctive RT alone.^126,127 Another option for the management of dogs with incompletely excised soft tissue sarcomas may include metronomic (i.e., low-dose continuous) chemotherapy. The administration of piroxicam and low-dose cyclophosphamide in 30 dogs with incompletely excised soft tissue sarcomas resulted in a significantly prolonged DFI when compared to a nonrandomized control group of 85 dogs with incompletely excised soft tissue sarcomas and no metronomic chemotherapy.¹³³ Additional studies are needed to confirm this treatment alternative.

Surgery and Radiation Therapy

RT can be used as an adjunct to surgery following either planned marginal resection or unplanned incomplete resection. Marginal surgical resection combined with full-course postoperative RT is an attractive alternative to limb amputation for extremity soft tissue sarcoma (Figure 21-9). This multimodality approach requires additional planning and expense 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. Migration of the radiopaque clips has been reported but does not significantly influence the planned radiation field.¹³⁴

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.¹³⁵ Full-course 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.^136,137 The optimal fractionation and total dose schemes for canine soft tissue sarcoma have not been determined, but cumulative doses greater than 50 Gy are recommended, and local tumor control is better with higher cumulative doses.¹³⁶ Acute side effects of RT such as moist desquamation are relatively mild and transient.¹³⁷

Local tumor control and survival time are excellent when incompletely resected soft tissue sarcomas are treated with postoperative RT. The median time to local recurrence is 700 days to more than 798 days, with local tumor recurrence reported in 5% to 30% of dogs by 1 year and 16% to 60% of dogs in the long term (Figure 21-10).^111,136-140 The overall MST for incompletely resected nonoral soft tissue sarcomas treated with postoperative RT is 2270 days with 2-, 4-, and 5-year survival rates of 87%, 81%, and 76%, respectively (Figure 21-11).^136,137

Radiation Therapy

RT can be employed along with surgery in the treatment of soft tissue sarcomas with a curative intent, either preoperatively or postoperatively, or as a sole treatment for pain palliation. Radiotherapy alone as a single modality treatment using doses of 50 Gy resulted in 1-year tumor control rates of 50% that dropped to 33% at 2 years.¹⁴¹ Measurable and palpable (i.e., macroscopic) soft tissue sarcomas are resistant to long-term control with conventional doses of irradiation alone (40 to 48 Gy).^142,143 Although one study reported a 30% complete response rate with RT alone,¹⁴⁴ these tumors do not rapidly regress after radiation, or if there is significant tumor shrinkage, it is not a durable response. As a single modality, RT is generally considered palliative with control defined as a slowly regressing or stable-in-size tumor mass. Palliative radiation, with 4 fractions of 8 Gy for a total dose of 32 Gy, has recently been investigated with similar results to full-course radiation with a 50% response rate in 16 dogs with measurable soft tissue sarcomas, median time to progression of 155 days, and a MST of 309 days.¹⁴⁵

Inadequate durable tumor control using RT as a single modality resulted in the development of combination therapies using RT with hyperthermia and surgery, yielding superior control rates.* Current results of therapeutic clinical studies in dogs demonstrate that RT is the best treatment for incompletely resected soft tissue sarcomas.^{15,136,137,149}

Although higher doses of irradiation will have higher control rates, the chances of normal tissue complications will also increase. In some studies, hyperthermia combined with irradiation showed promise for improved control versus irradiation alone and may also decrease the time to recurrence.^144,146,147 The median duration of local control with RT plus hyperthermia is 750 days and significantly greater than the 350 days with RT alone. Difficulty in homogeneous heating of large tumors limits the routine use of hyperthermia for treating soft tissue sarcoma in conjunction with radiation. Addition of whole-body hyperthermia does not improve response rate when compared to RT and local hyperthermia and may have increased the risk for metastasis.¹⁴⁸ The response rate and survival time in dogs treated with irradiation and hyperthermia may be predicted with dynamic contrast-enhanced MRI of soft tissue sarcomas before and after the first hyperthermia.¹⁵⁰

As mentioned previously, the combination of radiation and surgery provides long-term local control. Postoperative irradiation may be utilized if surgical removal is incomplete and further surgery is not feasible. Irradiation of microscopic tumors after excision is generally superior to radiation of measurable tumors. Control rates for adjuvant radiation after histologically incomplete resection of soft tissue sarcomas are 80% to 95% at 1 year and 72% to 91% at 2 years, with an expected 3-year and 5-year survival rate of 68% to 76%, respectively.^136,137,151 Dogs with soft tissue sarcomas with a mitotic rate greater than 9/10 HPF were more likely to have local tumor recurrence and shorter survival times in one study of 39 dogs treated with orthovoltage and doxorubicin as a radiation sensitizer.¹⁵¹ Although not statistically significant, dogs with hemangiopericytoma had a 3-year survival rate of 92% in one retrospective study.¹³⁶

Preoperative RT is becoming commonplace in veterinary oncology. The rationale and advantage of administering RT prior to surgery are that (1) the radiation field is smaller because, after surgery, the entire surgical site must be included in the field 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 reduction may make surgical resection less difficult.^15,152-154 In a study of 112 human patients with soft tissue sarcomas, it was noted that there was no significant difference between preoperative or postoperative radiotherapy in terms of relapse-free survival, local control, or overall survival. However, wound complications were significantly more frequent in preoperative radiotherapy patients.¹⁵⁴ A subsequent review supported these findings.¹⁵⁵ Lower doses of preoperative radiotherapy (less than 50 Gy) are used to reduce the risk of surgical complications. The therapeutic goal of preoperative radiotherapy is to eradicate the microscopic tumor cells at the peripheral margins. Generally, preoperative radiotherapy is reserved for initially inoperable tumors as an alternative to radical surgery.

Chemotherapy

The role of chemotherapy in the management of dogs with soft tissue sarcoma is not yet known. The metastatic rate for cutaneous soft tissue sarcoma is grade dependent and varies from less than 15% for grade I and II soft tissue sarcoma to 41% for grade III soft tissue sarcoma.¹⁶ Metastasis often occurs late in the course of disease, with a median time to metastasis of 365 days,¹⁶ and this may minimize the beneficial effects of postoperative chemotherapy on the development of metastatic disease. However, there are clinical situations in which postoperative chemotherapy should be considered, including dogs with grade III soft tissue sarcoma, metastatic disease, intraabdominal soft tissue sarcoma (e.g., leiomyosarcoma and splenic sarcoma), and histologic subtypes with a higher rate of metastasis, such as histiocytic sarcomas, hypodermal HSAs (stage II or III), synovial cell sarcomas, rhabdomyosarcomas, and lymphangiosarcomas.^{24,88,156-159}

Doxorubicin-based protocols, either alone or in combination with cyclophosphamide, have shown the most promise in dogs with soft tissue sarcoma with an overall response rate of 23%.¹⁶⁰ The need to combine cyclophosphamide with doxorubicin is debatable because single-agent doxorubicin has been shown to be equally as effective in the management of dogs with HSAs as doxorubicin combined with either cyclophosphamide or cyclophosphamide and vincristine.¹⁶¹ Mitoxantrone, a chemotherapeutic drug related to doxorubicin, has a variable effect against soft tissue sarcomas in dogs, with the response rate varying from 0% in 6 dogs to 33% in 12 dogs.^162,163 Ifosfamide has also shown some potential with a complete response rate of 15% (2 dogs) in 13 dogs with solid sarcomas of the skin, bladder, and spleen.¹⁶⁴ Doxorubicin and ifosfamide are the most effective single agents in the management of soft tissue sarcoma in humans, but response rates are less than 30% and metaanalyses show single- and multiple-agent chemotherapy protocols do not significantly increase overall survival times compared to surgery alone.^165,166 A similar finding of no improvement in survival times has been reported in dogs with grade III soft tissue sarcomas treated with surgery alone compared to those treated with surgery and adjuvant doxorubicin.¹⁶⁷

Postoperative systemic chemotherapy has also been shown to significantly improve disease-free survival times, but not overall survival time, in humans with soft tissue sarcomas, regardless of histologic grade.^165,166 Adjuvant chemotherapy has not shown the same effect on local tumor control in dogs with soft tissue sarcomas,¹⁶⁷ but metronomic and local chemotherapy protocols may be effective in decreasing the rate of local tumor recurrence and improving DFIs in dogs with soft tissue sarcomas. Metronomic chemotherapy with piroxicam and low-dose cyclophosphamide significantly prolongs DFI in a small group of dogs with incompletely excised soft tissue sarcomas.¹³³ Local release of cisplatin from a biodegradable polymer implanted into the surgical bed of incompletely resected soft tissue sarcomas may also decrease the risk of local tumor recurrence, with a 31% rate of local tumor recurrence in 32 dogs at a median of greater than 640 days postoperatively.¹⁶⁸

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 requiring rabies vaccinations for cats in Pennsylvania in 1987.¹⁷¹ 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). Two pathologists, M. J. Hendrick and M. H. Goldschmidt, and their colleagues at the University of Pennsylvania School of Veterinary Medicine were the first to recognize the increased incidence of reactions and formation of sarcomas at sites of rabies vaccinations.^172-174 Epidemiologic studies have shown a strong association between the administration of inactivated feline vaccines, such as FeLV and rabies, and subsequent development of soft tissue sarcoma at vaccine sites.^172-176 Additionally, some authors report reaction to vaccines was additive and this increased the likelihood of sarcoma development with multiple vaccines given at the same site simultaneously.¹⁷⁵ The development of soft tissue sarcoma at sites of vaccine administration of FeLV or rabies is believed by some to be as high as 1/1000,^177,178 whereas others report a prevalence between 1 and 3.6/10,000 cases.^176,179,180

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 a soft tissue sarcoma.¹⁷⁶ However, two large epidemiologic studies did not provide evidence that aluminum-containing vaccines pose a greater risk.^165,182 Thus it remains unclear whether nonadjuvant vaccines are safer. A multicenter study of cats in the United States and Canada found that no single vaccine manufacturer or vaccine type had a higher or lower association with the development of soft tissue sarcoma.¹⁸² Additionally, vaccine 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.¹⁸²

The hypothesis that postvaccination inflammatory reactions lead to uncontrolled fibroblast and myofibroblast proliferation and eventual tumor formation either alone or along with immunologic factors is a popular theory.^183-188 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. A similar phenomenon of intraocular sarcoma development exists in cats after trauma or chronic uveitis.^189-191

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. Immunohistochemical identification and localization of growth factors and their receptors are being investigated in vaccine-associated sarcomas. Through immunohistochemical study of growth factors and their receptors, Hendrick has found that vaccine-associated sarcomas are immunoreactive for platelet-derived growth factor (PDGF), epidermal growth factor (EGF) and its receptors, and transforming growth factor-β (TGF-β). Conversely, non–injection-site fibrosarcomas are negative or faintly positive.^192,193 Hendrick also found that lymphocytes in vaccine-associated sarcomas are positive for PDGF, but lymphocytes in non–injection-site fibrosarcomas and normal lymph nodes are negative.¹⁹² 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 vaccine-associated sarcomas may secrete PDGF, recruit macrophages, and lead to fibroblast proliferation.^192,193 The expression of C-jun, a proto-oncogene coding for the transcriptional protein AP-1, has also been examined in vaccine-associated sarcomas. C-jun was found to be strongly positive in vaccine-associated sarcomas and not expressed in non–injection-site fibrosarcomas.^192,193 It appears that FeLV and the feline sarcoma virus are not involved in the pathogenesis of feline vaccine-associated sarcomas. Using immunohistochemical analysis and polymerase chain reaction (PCR) techniques, FeLV was not detected in vaccine-associated sarcomas.¹⁹⁴

p53 mutations have been evaluated in feline vaccine-associated sarcomas.^195-198 p53 is a tumor suppressor gene that encodes a nuclear protein critical in the regulation of the cell cycle. Normal or wild-type p53 will increase in response to DNA damage resulting in cell arrest at the G1 interphase, allowing for DNA repair before replication or apoptosis if damage is irreparable. Cells lacking normal p53 proceed through the cell cycle unregulated, leading to aberrant clones and possible malignancy.¹⁸⁶ Anti-p53 antibodies have immunoreactivity in feline sarcomas and may play a role in predicting clinical outcome.¹⁹⁸

Recent papers continue to link growth factors with development of vaccine-associated sarcomas in cats. Continued immunohistochemical probing of feline vaccine-associated sarcomas document expression of growth-regulating proteins: p53 protein, basic fibroblast growth factor β (bFGF-β), and TGF-α.¹⁹⁸ Researchers recently concluded that PDGF and its receptor play an important role in the in vitro growth of vaccine-associated sarcoma cell lines, both alone and in the presence of chemotherapeutic agents. Furthermore, they found that a signal transduction inhibitor, imatinib mesylate, inhibits the PDGF-dependent cell growth in a dose-dependent manner.¹⁹⁹

The term vaccine-associated sarcoma has been used interchangeably with injection-site sarcoma because sarcomas arising at sites of injections other than vaccines, such as lufenuron and microchips, have been reported.^200-202 Vaccine-associated sarcoma has been used in this chapter because of the overwhelming prevalence of vaccines as a cause of these injection-site sarcomas.

Pathology

There are many similarities between the histologic subtypes and biologic behavior of soft tissue sarcomas in cats and dogs. The three principal exceptions in cats are vaccine-associated sarcomas, virally induced multicentric fibrosarcoma, and the relative rarity of PNST, synovial cell sarcoma, and histiocytic sarcoma.^188,203 There are significant differences between vaccine-associated sarcoma and non–vaccine-associated sarcoma. Tumors that develop after vaccination are typically mesenchymal in origin and include fibrosarcomas, rhabdomyosarcomas, malignant fibrous histiocytomas, undifferentiated sarcomas, and extraskeletal osteosarcomas and chondrosarcomas.^192,204,205 Vaccine-associated sarcomas have histologic features consistent with a more aggressive biologic behavior than non–vaccine-associated sarcomas, such as marked nuclear and cellular pleomorphism, increased tumor necrosis, high mitotic activity, and the presence of a peripheral inflammatory cell infiltrate consisting of lymphocytes and macrophages.^187,192,206 In a series of 91 cats with histologically confirmed and graded vaccine-associated sarcomas, the prevalence of high-grade lesions was substantially higher than reported in dogs,¹⁶ with 59% of cats diagnosed with grade III tumors and only 5% with grade I tumors.²⁰⁷ Microscopically, areas of transition between inflammation and tumor development are frequently observed in cats with vaccine-associated sarcoma.^161,192,208 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.¹⁸⁸ Aluminum hydroxide is one of several adjuvants used in currently available feline vaccines.¹⁸⁸ Injection-site sarcomas are histologically similar to mesenchymal tumors arising in the traumatized eyes of cats, which suggests a common pathogenesis of inflammation and the development of soft tissue sarcomas in these cats.^190-193 The presence of inflammatory cells, fibroblasts, and myofibroblasts in and adjacent to vaccine-associated sarcomas supports this hypothesis.^24,209,210

Diagnosis and Work-Up

The diagnostic techniques and clinical staging tests recommended for cats with suspected vaccine-associated sarcoma 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 (Figure 21-14).¹⁸⁸ The volume of tumor based on contrast-enhanced CT is approximately twice the volume measured using calipers during physical examination.¹⁸⁵ Accurate pretreatment knowledge of the extent of disease is important because vaccine-associated sarcomas 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 resected. Excisional biopsy of a suspected vaccine-associated sarcoma is not recommended because the risk of local tumor recurrence is increased, and DFI and survival time are significantly decreased.^211,212

Treatment

The Vaccine-Associated Feline Sarcoma Task Force has recommended that masses at vaccination sites be treated if the mass is still evident 3 or more months after vaccination, is larger than 2 cm in diameter, or is increasing in size more than 4 weeks after vaccine administration.¹⁸⁸ Vaccine-associated sarcomas are very invasive tumors, and aggressive treatment is required, with both wide surgical resection and full-course RT, to achieve adequate local control.

Prognosis

It has become clear that the prognosis for cats with vaccine-associated sarcomas treated with surgical excision alone, using traditional recommendations, can be poor with respect to tumor control, especially when the first surgery is marginal and multiple surgeries are employed as the method of treatment. However, long-term survival, even in the face of multiple recurrences, is the norm with this disease. The median time to first recurrence was 2 months for cats treated by conservative surgery (referring veterinarian) and 9 months for those cats treated by more aggressive surgery (referral institution); the overall survival time was 19 months.²¹² Another study of single modality surgical excision reported an overall DFI of 10 months, which increased to longer than 16 months when excision was complete.²¹¹ The prognosis with surgery alone is improved with aggressive surgical excision using 5-cm lateral margins and two fascial layers for deep margins.²⁰⁷ A recent study looked at 3D histologic margins in 48 cats with vaccine-associated sarcomas and evaluated the predictive value of histologic margins and tumor grading on local recurrence.²³³ Tumor margins were noninfiltrated in 32 cats and the remaining 16 cases had infiltrated margins. Overall, 6/32 (19%) tumors with noninfiltrated margins and 11/16 (69%) with infiltrated margins had tumor recurrence. Tumors with infiltrated margins recurred about 10 times more frequently compared to tumors with noninfiltrated margins.²³³ The degree of infiltration of tumor margins may provide an indication for the need for adjuvant RT following surgical excision.

Outcomes are improved when cats with vaccine-associated sarcomas are treated with multimodality therapy, especially following surgical excision with less aggressive intent. Optimal outcome occurs when cats are treated aggressively initially and not after multiple failed resections.²²⁰ The combination of radiotherapy either preoperatively or postoperatively has improved the DFI and overall survival time in cats with vaccine-associated sarcomas. DFI and MSTs range from 13 to 37 months and 23 to 43 months, respectively.^205,215-218 Injection-site sarcomas are locally invasive; however, approximately 15% to 24% will metastasize to the lungs or other sites.^{207,208,212,216,217} Continued research into the treatment of vaccine-associated sarcomas is needed because there is room for improvement in outcomes.

Prognostic factors were investigated in one study of 42 cats with surgically resected nonvisceral soft tissue sarcomas, including 8 cats with presumed vaccine-associated sarcomas.²³⁴ The overall MST was 608 days. The margins of excision lateral and deep to the tumor were not reported, but excision was incomplete in 74% of cats and local tumor recurrence was reported in 62% of cats. The median time to recurrence was 261 days and the MST in cats with local tumor recurrence was 576 days. Metastasis was suspected in 14% of cats and the MST in cats with suspected metastasis was 562 days. Prognostic factors included tumor size and histologic type. Cats with soft tissue sarcomas smaller than 2 cm in diameter had a MST of 643 days, which was significantly longer than the 558 days for cats with tumors 2 to 5 cm in diameter and 394 days for cats with soft tissue sarcomas larger than 5 cm in diameter. The MSTs for cats with fibrosarcoma (640 days) and PNST (645 days) were significantly better than for cats with malignant fibrous histiocytoma (290 days). Tumor location and injection-site versus non–injection-site sarcomas were not prognostic factors in this study.²³⁴ Although these results are encouraging, the rates of incomplete excision and local tumor recurrence suggest that a more aggressive surgical approach and multimodal therapy with adjuvant RT should also be considered for cats with non–vaccine-associated sarcomas.

In two studies, one with 57 cats with vaccine-associated sarcomas treated primarily with wide surgical excision (4- to 5-cm lateral margins and one fascial layer for deep margins)²¹⁶ and the other with 91 cats treated with aggressive surgery alone (5-cm lateral margins and two fascial layers for deep margins),²⁰⁷ prognostic factors for survival included histologic grade, local tumor recurrence, and distant metastasis. Local tumor recurrence was reported in 39% of the cats and was not associated with tumor diameter, tumor location, or histologic grade.²¹⁶ The MST for cats with local tumor recurrence was 365 to 499 days compared to 1098 to 1461 days for cats without local tumor recurrence.^207,216 The MST for cats without distant metastasis was 929 to 1528 days compared to 165 to 388 days for the 20% to 21% of cats that developed distant metastasis.^207,216 Furthermore, distant metastasis was more likely in cats with grade III sarcomas, suggesting that chemotherapy should be considered for cats with high-grade vaccine-associated sarcomas.²¹⁶

Prevention

The recommendations on preventing vaccine-associated sarcomas in cats are controversial. These include changing the sites of vaccine administration, decreasing the use of polyvalent vaccines, using nonadjuvanted vaccines, avoiding the use of aluminum-based adjuvants, and increasing the interval between vaccinations.^{24,178,235,236}

The Vaccine-Associated Feline Sarcoma Task Force 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.²⁴ 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 vaccine-associated sarcomas. 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 vaccine-associated sarcomas.²⁴ Subcutaneous administration is preferred to intramuscular injection because vaccine-associated sarcomas developing from subcutaneous sites are more readily palpable and diagnosed earlier in the course of disease. The Vaccine-Associated Feline Sarcoma Task Force has recommended that masses at vaccination sites be treated 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 4 weeks after vaccine administration.¹⁸⁵ Unfortunately, feline vaccine-associated sarcomas are still occurring at sites not recommended by the Vaccine-Associated Feline Sarcoma Task Force and are often difficult to cure with surgery and RT.²³⁷

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.¹⁸⁸ Recently, 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.^238,239 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.¹⁸⁸ The Vaccine-Associated Feline Sarcoma Task Force has recommended that the administration of vaccines is a medicinal procedure and vaccination protocols should be customized for individual cats.¹⁸⁸ 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 vaccine-associated sarcomas and other adverse effects.¹⁸⁸

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