Soft Tissue Sarcomas

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RADIATION ONCOLOGY

SOFT TISSUE SARCOMAS G. Neal Mauldin, DVM

The soft tissue sarcomas reportedly constitute approximately 15% of all canine and 7% of all feline skin and subcutaneous tumors. 31 The soft tissue sarcomas of the oral cavity form a distinct group of tumors and are discussed in another article. The annual incidence is about 35/100,000 for dogs and 17/ 100,000 for cats. 6 Soft tissue sarcomas (STS) are tumors that arise from a variety of mesenchymal tissues. The characteristics of this family of tumors have best been summarized by Withrow and MacEwen: 19 • They may arise from any anatomic site in the body. • They tend to appear as pseudoencapsulated fleshy tumors but have poorly defined histologic margins or infiltrate through facial planes. • Local recurrence after conservative surgical excision is common. • Sarcomas tend to metastasize through hematogenous methods in up to 25% of cases; regional lymph node metastasis is unusual (except for synovial cell sarcoma). • They generally have a poor response to chemotherapy and radiation therapy for measurable disease. The soft tissue sarcomas represent a group of biologically similar but pathologically distinct tumors including fibrosarcomas, nerve sheath tumors (neurofibrosarcomas), malignant fibrous histiocytomas, and hemangiopericytomas.U· 12• 21 Other tumor types that are sometimes included under the heading of STS are myxofibrosarcoma, liposarcoma, rhabdomyosarcoma, leiomyosarcoma, and, less frequently, mesenchymoma and synovial cell sarcoma.7 • 16• 17• 25• 28• 30• 32 All of these tumors share

From The Animal Medical Center, and The Donaldson-Atwood Cancer Clinic, New York, New York VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE VOLUME 27 • NUMBER 1 • JANUARY 1997

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the characteristics outlined above, with the most important being a lowto-moderate rate of metastasis. Mesenchymal tumors such as osteosarcoma, chondrosarcoma, hemangiosarcoma, and lymphangiosarcoma are not usually included under the heading of soft tissue sarcoma because of their histiogenesis and higher incidence of metastasis. This distinction of low versus high metastatic potential is of prime concern when formulating a treatment plan for a patient with a soft tissue sarcoma. Those animals with a sarcoma of low metastatic potential may be cured with locally aggressive therapies, whereas those with tumors that have a high incidence of metastasis require systemic adjunctive therapy in the form of chemotherapy. This article deals with the soft tissue sarcomas of low metastatic potential. Table 1 details the histiogenesis and metastatic potential of the common soft tissue sarcomas. Environmental factors, including radiation exposure, trauma, and parasitic infection with Spirocerca lupi have been associated with soft tissue sarcoma development in dogs and may be stressors in cats as well. 6• 13• 20 Retroviral infection with feline leukemia virus may lead to a syndrome of multiple fibrosarcoma development if the cat is concurrently infected with feline sarcoma virus.14 Cats with this disease warrant an extremely grave prognosis. Recently, a phenomenon of postvaccinal fibrosarcoma has been described in cats, most probably related to the aluminum adjuvant in the vaccine inducing an aberrant inflammatory response.8• 15• 18 Whether vaccination is an environmental factor for fibrosarcoma induction in dogs is not known but such a link has not been identified.

Table 1. HISTIOGENESIS AND METASTATIC POTENTIAL OF THE COMMON SOFT TISSUE SARCOMAS Tissue of Origin Fibrous tissue and histiocyte Fibrous tissue Myxomatous tissue Pericyte of blood vessel (?) Vessels Adipose tissue Nerve Synovial cell Skeletal muscle Smooth muscle Unknown/primitive Miscellaneous

Benign Fibroma Myxoma Hemangiopericytoma Lymphangioma Hemangioma Lipoma Synovioma Rhabdomyoma Leiomyoma

Malignant Fibrous histiocytoma Fibrosarcoma Myxosarcoma Hemangiopericytoma Lymphangiosarcoma Hemangiosarcoma Liposarcoma Neurofibrosarcoma Malignant Schwannoma Synovial cell sarcoma Rhabdomyosarcoma Leiomyosarcoma Anaplastic sarcoma Mesenchymoma Soft tissue OSA

Metastatic Potential*

+

+I + + +I + + + ++ + ++

+I++ +

++ ++ + i ++ t

++I + ++ + ++ +

.. + ... low, + + = moderate, + + + = high; low implies a metastatic rate of s = 15% tApplies to blood vessel smooth muscle only, not leiomyosarcomas arising from visceral organs Modified from MacEwen EG, Withrow SJ: Soft tissue sarcomas. In Withrow SJ, MacEwen EG (eds): Small Animal Clinical Oncology, ed 2. Philadelphia, WB Saunders, 1996, p 211. OSA = osteosarcoma

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DIAGNOSIS

Most patients with soft tissue sarcomas share a common presentation: that of an animal with a slowly growing mass arising from somewhere on or in the body. These tumors may be superficial or deeply attached, freely moveable or infiltrative. A past history of a slowly changing mass present for weeks to months, followed by a rapid growth phase and ulceration or abscessation is not unusual. As these tumors enlarge, the portion of the mass furthest from the capillary blood supply will become hypoxic or anoxic, resulting in necrosis, ulceration, and secondary infection. Animals with soft tissue sarcomas involving the abdominal or thoracic viscera may show systemic signs related to the organ involved. Because the STS all share common characteristics and clinical presentations, a biopsy is necessary to arrive at a definitive diagnosis. Either a needle biopsy or incisional biopsy is generally considered to be the preferred sampling method for these types of tumors. 19 The biopsy allows a definitive diagnosis to be made without undue risk of compromising further therapies, such as aggressive surgical resection and radiotherapy. However, care must be taken to avoid contamination of tissue planes due to poor biopsy technique and to position the biopsy site so that it may be either easily excised during a later definitive surgery or included in a radiotherapy field without causing unacceptable normal tissue toxicity. Fine-needle aspiration of the STS is generally an unrewarding experience because STS exfoliate extremely poorly and may mimic benign or inflammatory lesions on cytologic examination. Although needle aspiration may be of benefit in differentiating such cutaneous tumors as mastocytomas, lymphomas, or histiocytomas from the STS, a negative fine-needle aspirate should not be interpreted as meaning that the aspirated mass is either nonneoplastic or benign. Excisional biopsy may be performed as both a diagnostic and therapeutic procedure, provided that the lesion is in a location that makes surgical resection easy. An excisional biopsy that is not curative may require that further therapy be much more aggressive than would have been necessary had an incisional or needle biopsy been performed, followed by the definitive treatment once a diagnosis had been established. The histopathology report for a patient diagnosed with a soft tissue sarcoma should be evaluated for tumor grade, presence of hemolymphatic invasion, degree of normal tissue invasion, and adequacy of margins (if an excisional biopsy was attempted). The characteristics that help determine the grade (high versus low) of malignancy for soft tissue sarcomas include cellularity, degree of differentiation, vascularity, presence or absence of necrosis, and number of mitoses per high power field that are seen in the biopsy specimen. Animals with a high histologic grade of malignancy may be at greater risk of early local failure and distant metastases and may benefit from adjuvant chemotherapy. Routine staging should be done before recommending a definitive course of therapy for any animal suspected of having an STS, especially

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if aggressive surgery or adjunct radiotherapy is contemplated. This staging should include a complete blood count and differential, biochemical profile, chest radiograph, and radiographs of the affected body part as indicated. A coagulation profile may also be warranted, especially if aggressive surgery is contemplated or if the tumor type may be hemangiosarcoma. Advanced imaging techniques such as computed tomography (CT) or magnetic resonance imaging (MRI) scans may also be of benefit, especially as a noninvasive prelude to an aggressive resection/reconstruction (Fig. 1). If a CT /MRI scan shows that a complete gross resection is impossible, you may rteed to reevaluate your treatment plan for that individual patient. You should question the appropriateness of an aggressive reconstruction with possible cosmetic and functional defects if a resection to at least microscopic disease is not a possibility. A cure is rarely possible in animals with gross residual disease because both radiotherapy and chemotherapy are ineffective at gaining long-term control for patients with a measurable tumor burden. Table 2 presents a modified T-N-M staging system for the soft tissue sarcomas.

TREATMENT The mainstay of treatment for the soft tissue sarcomas is complete surgical resection. 2-4 Advances in reconstructive and closure techniques have helped redefine what is meant by resectable in veterinary cancer patients. However, the extremely invasive nature of these tumors, com-

Figure 1. CT scan of a dog with a pelvic canal mass. Note the large mass ventral to the sacrum. This patient presented with difficulty in defecation, which was progressive over several months. Surgery alone is unlikely to result in adequate margins in this patient.

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Table 2. MODIFIED STAGING SYSTEM FOR THE SOFT TISSUE SARCOMAS*

T

N M Stage I Stage II Stage Ill

Primary tumor T1 <2 em diameter T2 2-5 em diameter T3 > 5 em diameter T4 Tumor invading muscle, cartilage, or bone Regional lymph nodes NO No histologically verified nodal metastases N1 Histologically verified nodal metastases Distant metastases MO No distant metastases M1 Distant metastases Ia lb

T1 NO MO T2 NO MO

IIa T3 NO MO lib T4 NO MO lila Any T N1 MO Ilib Any T Any N M1

•Animals with Slage-l or Stage·ll disease still have a chance of cure with locally aggressive treatments. Animals with Stage-Ill disease may benefit from systemic chemotherapy, but warrant a grave prognosis. From MacEwen EG, Withrow SJ: Soft tissue sarcoma. In Withrow SJ, MacEwen EG (eds): Small Animal Clinical Oncology, ed 2. Philadelphia, WB Saunders, 1996, p 215.

bined with the fact that they may occur in areas where aggressive surgery is not realistic, often makes complete resection impossible. When performing definitive surgery, care should be made to include any prior biopsy sites in the resection. Any areas of deep attachment should be removed as part of the primary resection and submitted en bloc with the rest of the tissue. The adage of "cut wide, cut deep" holds especially true for patients diagnosed with STS. A common pitfall during the definitive procedure is to mistake the pseudocapsule mentioned above for a true capsule. The pseudocapsule consists of a layer of compressed cancer cells and normal tissue that is produced as the tumor expands. Shelling or peeling out the tumor at the level of this pseudocapsule will almost certainly result in a marginal resection and residual tumor volume. Any description of the tumor being "shelled out" at the time of surgery should serve as a warning that residual, although perhaps microscopic, disease was left behind and that recurrence is almost a certainty. Any patient with a soft tissue sarcoma having surgery at the Animal Medical Center has some type of metal radiotherapy marker placed at the time of the definitive resection (Fig. 2). These metal markers (usually hemaclips or stainless steel suture) allow the radiotherapist to identify a tumor volume after the patient has recovered from surgery. Because aggressive reconstruction and grafting techniques often result in suture lines that are not a good representation of the original tumor volume or location, some method of identifying the site of tumor resection for the

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Figure 2. Simulation film of a cat following resection for a fibrosarcoma. Note the extensive dissection required. The metal clips allow for better tumor volume and target volume definition in this patient, hopefully decreasing the amount of unnecessary radiation delivered to normal tissues.

radiotherapist is necessary. The hemaclips should be placed in all planes of the dissection, so that a three-dimensional picture of the target can be reconstructed radiographically. This allows the radiotherapist to direct radiation to a three-dimensional anatomic site that should be tumor specific, rather than treating a two-dimensional surgical scar that may not be a true representation of residual tumor distribution. This technique also allows the radiotherapist to confine the radiation to as small a target volume as possible, thereby decreasing normal tissue exposure and toxicity. Radiation therapy becomes necessary when complete resection is impossible or when the surgical procedure necessary for complete resection is refused by the owner. For example, many owners choose marginal resection followed by radiotherapy for residual disease rather than amputation for a pet with an STS of an extremity, even though amputation is almost certainly a curative procedure. Because we are dealing with the STSs of low metastatic potential, a decision for amputation can usually be made later if radiotherapy fails. The mesenchymal tumors are considered the most radioresistant of the three "families" of neoplasia. This is due to a multitude of reasons, including a low growth fraction, a relatively long doubling time, and the tendency to develop hypoxic regions within the tumor parenchyma. Tumor hypoxia is a major cause of radioresistance and treatment failure in patients treated with radiotherapy for malignant tumors. Resection to

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microscopic disease should alleviate the problem with hypoxia and may address the other issues by resulting in an increased growth fraction and shortened doubling time. For these reasons, the majority of patients with STS treated with radiotherapy at the Animal Medical Center receive radiation after their definitive surgery. One school of thought holds that, in some instances, radiotherapy prior to surgery may be of benefit.26 Though some theoretical benefits from preoperative radiotherapy exist, the majority of patients treated with a combination of surgery and radiotherapy undergo surgical resection first. No objective data exists from which to compare the response, control, and complication rates for pre- versus postoperative radiotherapy in patients with STS. Table 3 summarizes the results of radiotherapy for canine and feline soft tissue sarcomas. The optimal cumulative dose and fractionation scheme for dogs anci cats with soft tissue sarcomas has yet to be determined. However, several of the studies mentioned in Table 3 did demonstrate a positive correlation between cumulative dose and disease-free interval. As a

Table 3. SUMMARY RESULTS OF RADIOTHERAPY FOR THE TREATMENT OF SOFT TISSUE SARCOMAS IN DOGS AND CATS Species (II)

Cumulative Dose & Fractionation

Results (Reference)

STS; extremity and head and neck

Canine (26) Canine (73)

3&-45 Gy; 10 fractions M·W·F 35-50 Gy (RT) or 40-55 Gy (RT + WR2721 ) 10 fractions M·W·F

Hemangiopericytoma; extremity & trunk

Canine (20)

40-50 Gy; 10 fractions M·W·F

Hemangiopericytoma; extremity, trunk Hemangiopericytoma; site not indicated STS, most of extremity

Canine (8) Canine (5) Canine (42)

40-45 Gy, 10 fractions M·W· F 24-40 Gy, 4 Gy/fraction 35-50 Gy, 10 fractions M·W·F

STS; extremity, trunk, head and neck STS, extremity and trunk

Canine (18) Canine (21)

48.-52.2 Gy, 3.2-3.4 Gy/ fraction 63 Gy, 3 Gy/fraction M· W·F

27% 1 year; dose response seen (10) TCD-50 at 1 year = 52 Gy for both groups; WR2721" not protective for normal tissue (23) DFI of 0.5, 1, and 2 years = 81.8%, 59.1%, and 40.9% (9) Median survival = 13.5 months (29) No survival data, 60% recurrence ( t2) TCD-50 at 1 year = 45.3 Gy; dose response for 1 year control (24) > 50% DFI at 1 year (1)

FSA, site not indicated

Feline (37)

FSA; trunk and extremity

Feline (9)

45.6- 57 Gy, 12- 19 fractions; randomized to RT alone vs. RT followed by surgery 63 Gy, 3 Gy/iraction M· W·F

Tumor Type/Site FSA; site not indicated

1 year control of 95%; 2, 3, and 4 year control rates of 91%, 91%, and 86% (22) RT alone, median DFS = 137 days; RT + surgery, median DFS = 280 days (9) Median survival = 343 days, median DFI = 256 days (27)

*WR272 1 is a sulfhydryl compound being investigated because of its radioprotective properties DFI = disease-free interval; FSA "" fibrosarcoma; M-W-F = Monday, Wednesday, and Friday treatment schedule; DFS = disease-free survival; AT = radiotherapy; STS = soft tissue sarcomas; TCD-50 = median tissue culture dose

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Figure 3. CT scan of a cat with a rapidly progressing mass over the left flank. This mass appeared shortly after the cat was vaccinated for feline leukemia virus. Note the dense white pseudocapsule surrounding the mass. This pseudocapsule often gives a false sense of security when dealing with these tumors.

general rule, disease-free survival increased as total cumulative dose increased. However, the types of radiotherapy (orthovoltage versus megavoltage) and wide variety of fractionation schemes make any direct comparisons of these studies impossible. For definitive conclusions to be made, a larger cohort of animals that is treated in a controlled fashion and observed until failure must be studied. Other adjunct therapies, such as hyperthermia, chemotherapy, and immunotherapy (including Acemannan) have not conclusively been shown to offer a survival advantage over surgery and radiotherapy alone. Hyperthermia may increase the complete response rate when compared to radiotherapy alone in animals with gross residual disease. The aggressive nature of the soft tissue sarcomas in cats, especially those occurring after vaccination, suggest that novel therapies should be investigated (Fig. 3). The current protocol for cats being treated for postvaccinal sarcomas at the Animal Medical Center is surgical resection followed by radiotherapy (63 Gy, 3 Gy /fraction Monday-WednesdayFriday) and carboplatin chemotherapy. References 1. Atwater SW, LaRue SM, Powers BE, et al: Adjuvant radiotherapy of soft tissue sarcomas in dogs. In Proceedings of the 12th Annual Veterinary Cancer Society Conference, 1992, p 41

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2. Bostock DE, Dye MT: Prognosis after excision of canine fibrous connective tissue sarcomas. Vet Pathol 17:581-588, 1980 3. Bostock DE, Dye MT: Prognosis after excision of fibrosarcomas in cats. JAm Vet Med Assoc 175:727-728, 1979 4. Brown NO, Patnaik AK, Mooney S, eta!: Soft tissue sarcomas in the cat. J Am Vet Med Assoc 173:744-749, 1978 5. Cronin KL, Page RL, Thrall DE: Radiation and surgery for treatment of feline fibrosarcomas. In Proceedings of the 14th Annual Veterinary Cancer Society Conference, 1994, p 22 6. Dorn ER: Epidemiology of canine and feline tumors. J Am Anim Hosp Assoc 12:307312, 1976 7. Doster AR, Tomlinson AJ, Mahaffey EA, eta!: Canine liposarcoma. Vet Pathol 23:8788, 1986 8. Esplin DG, McGill LD, Meininger A, et al: Postvaccinal sarcomas in cats. 1 Am Vet Med Assoc 202:1245-1247, 1993 9. Evans SM: Canine hemangiopericytoma: A retrospective analysis of response to surgery and radiotherapy. Vet Radio! 28:13, 1987 10. Gillette EL: Radiation therapy for canine and feline tumors. J Am Anim Hosp Assoc 12:359' 1976 11. Gleiser CA, Raulston GL, Jardine JH, et al: Malignant fibrous histiocytoma in dogs and cats. Vet Pathol16:199-208, 1979 12. Graves GM, Bjorling DE, Mahaffey E: Canine hemangiopericytoma (1967-1984). 1 Am Vet Med Assoc 192:99-102, 1988 13. Hardy WD Jr: The etiology of canine and feline tumors. J Am Anim Hosp Assoc 12:313-334, 1976 14. Hardy WD Jr: The feline sarcoma viruses. JAm Anim Hosp Assoc 17:981, 1981 15. Hendrick MJ, Kass PH, McGill LD, et a!: Postvaccinal sarcomas in cats. J Nat! Cancer Inst 86:341-343, 1994 16. Hullard TJ: Tumors of the muscle. I n Moulton JE (ed): Tumors in Domestic Animals, ed 3. Berkeley, University of California Press, 1990, pp 88-101 17. Kapatkin AS, Muller HS, Matthiesen DT, et al: Leiomyosarcoma in dogs: 44 cases (1983-88). JAm Vet Med Assoc 201:1077- 1086, 1992 18. Kass PH, Barnes WG, Spangler WL, eta!: Epidemiologic evidence for a causal relationship between vaccination and fibrosarcoma tumorigenesis in cats. JAm Vet Med Assoc 203:369-405, 1993 19. MacEwen EG, Withrow SJ: Soft Tissue Sarcomas. In Withrow SJ, MacEwen EG (eds): Small Animal Clinical Oncology, ed 2. Philadelphia, WB Saunders, 1996, pp 211-226 20. Madewell BR, Theilen GH: Etiology of cancer in animals. In Theilen GH, Madewell BR (eds): Veterinary Cancer Medicine. Philadelphia, Lea & Febiger, 1979, pp 13-25 21. Madewell BR, Munn RJ: The soft tissue sarcomas: Immunohistochemical and ultrastructural distinctions. In Proceedings of the 9th Annual Convention of the American College of Veterinary Internal Medicine, 1991, pp 717-729 22. Mauldin GN, Meleo KA, Burk RL: Radiation therapy for the treatment of incompletely resected soft tissue sarcomas in dogs: 21 cases. In Proceedings of the 13th Annual Veterinary Cancer Society Conference, 1993, p 111 23. McChesney SL, Gillette EL, Dewhirst MW, et a!: Influence of WR2721 on radiation response of canine soft tissue sarcomas. Int J Radial Oncol Bioi Phys 12:1957, 1986 24. McChesney SL, et a!: Radiotherapy of soft tissue sarcomas in dogs. J Am Vet Med Assoc 194:60, 1989 25. McClennon NH, Houlton JEF, Gorman NT: Synovial sarcoma in the dog- A review. J Small Anim Pract 29:139-152, 1988 26. McLeod DA, Thrall DE: The combination of surgery and radiation in the treatment of cancer: A review. Vet Surg 18:1-{), 1989 27. Meleo KA, Mauldin GN: Postoperative radiotherapy for the treatment of fibrosarcoma in 9 cats. Proceedings of the 14th Annual Veterinary Cancer Society Conference, 1994, p 127 28. Moore RW, Snyder SP, Houchen JW, et al: Malignant mesenchymoma in a dog. J Am Vet Med Assoc 19:187- 90, 1983

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29. Pastorino NC, et a!: Prognostic variables for canine hemangiopericytomas: 50 cases (1979-1984). J Am Anim Hosp Assoc 24:501, 1988 30. Pulley LT, Stannard AA: Tumors of skin and soft tissue. In Moulton JE (ed): Tumors in Domestic Animals, ed 3. Berkeley, University of California Press, 1990, pp 23--87 31. Theilen GH, Madewell BR: Tumors of the skin and subcutaneous tissues. In Theilen GH, Madewell BR (eds): Veterinary Cancer Medicine. Philadelphia, Lea & Febiger, 1979, pp 123-191 32. Vail OM, Powers BE, Getzy OM, eta!: Evaluation of prognosis for dogs with synovial sarcoma: 36 cases (1986-1991). JAm Vet Med Assoc 205:1300-1307, 1994

Address reprint requests to G. Neal Mauldin, DVM The Animal Med ical Center 510 East 62nd Street New York, NY 11021