Managing soft-tissue sarcomas in dogs and cats (Proceedings)

Soft tissue sarcomas (STS) – hemangiopericytoma, fibrosarcoma, neurofibrosarcoma, Schwannoma, peripheral nerve sheath tumor, malignant fibrous histiocytoma, liposarcoma, myxosarcoma, myxofibrosarcoma, spindle cell sarcoma, anaplastic/undifferentiated sarcoma – exhibit similar biological behavior, and hence can be dealt with in most cases with a similar therapeutic approach. Although these tumors are classified as malignant, their metastatic rate is generally low. However, due to a high degree of local infiltration, recurrence after conservative excision is common.

Diagnosis

Most animals with STS will present with the complaint of a palpable mass. Occasionally, the presenting complaint may be pain or lameness, or a mass may be detected during a routine physical examination. These masses can occur anywhere on the body, and are usually solitary. They are often firm and can be poorly demarcated. If large, they may be adherent to deep structures and hence not freely movable. Most will be covered by normal appearing haired skin, but some may be ulcerated, or have a softer central area of necrosis.

STS may sometimes be tentatively diagnosed based on the results of fine needle aspiration cytology. Given that cells from STS may exfoliate poorly, it may be helpful to use a larger gauge needle (e.g. 18-20g) or employ suction from a 5 or 10-cc syringe if other techniques do not yield an adequate sample. A nondiagnostic sample or the presence of large amounts of blood should be an indication for further evaluation. Cytology of sarcomas will reveal a population of cells exfoliating individually or in disorganized clumps, often admixed with varying amounts of peripheral blood. The cells appear spindle-shaped, and may have trailing cytoplasmic extensions. Nuclear: cytoplasmic ratio is often high, and the nuclei may contain multiple variably sized nucleoli.

If needle aspiration cytology is insufficient to suggest STS, excisional biopsy may be performed if the mass is small and in a surgically accessible area. Alternatively, an incisional (e.g. wedge, punch, or needle-core/Tru-cut) biopsy may be used to attain a histodiagnosis and aid in the planning of further treatment. Many times, Tru-cut or punch biopsies can be obtained using local anesthetic or mild chemical restraint.

Staging

Although the metastatic rate of STS is low (generally less than 10% - see exceptions below), it is not zero. Metastatic rate may be somewhat higher (25-45%) in the poorly differentiated STS (anaplastic or undifferentiated), and potentially in liposarcomas, and in sarcomas in younger dogs. Tumors considered histologically "high grade" or "grade III" based on their microscopic appearance may likewise have a higher metastatic rate. Similarly, feline vaccine-associated sarcoma may have a metastatic rate between 5 and 25%, with recurrent tumors perhaps more likely to metastasize. The majority of histiocytic sarcomas in dogs are capable of metastasis. Thoracic radiographs should be offered in any STS case, especially prior to undertaking an aggressive or expensive procedure. These types of tumor metastasize infrequently through the lymphatic system. However, any enlarged lymph nodes should unquestionably be investigated cytologically for evidence of metastasis. Abdominal ultrasound should be offered for known histiocytic sarcomas, as involvement of liver and spleen is common. Standard preanesthetic tests should be performed as for any other surgical procedure.

Treatment

Surgery

The mainstay of treatment for STS in dogs and cats remains aggressive surgery with wide margins. Often, STS can appear to be encapsulated and to "shell out" at surgery, but this is often a pseudocapsule composed of compressed tumor cells. Hence, an attempt should be made to achieve at least 3 cm margins 360 degrees around the palpable tumor mass, and deep margins including at least one normal appearing fascial plane below the tumor bed. If in a surgically difficult area, the widest margins possible should be attained. The excised tissue should be submitted in toto for histological analysis, with special requests made if necessary to evaluate the surgical margins for the presence of tumor cells.

There are certain areas (face, distal limbs) where conservative surgery is unlikely to remove the entire tumor. In these cases, or in cases where surgical margins are histologically not free of residual tumor cells, the owners should be advised that recurrence is very likely without additional intervention, although the time to recurrence can be variable. Multiple marginal excisions as recurrence is noted are NOT advised, as the interval to recurrence typically shortens after each incomplete excision. There is some evidence (especially in cats) that recurrent tumors may have a more aggressive biologic behavior with attendant worse long-term prognosis, and hence the best chance for cure is at the tumor's first occurrence.

If an appropriately large surgery has been performed and the surgical margins are histologically free of disease, recurrence is unlikely and other types of therapy are not usually necessary. However, regular rechecks for recurrence ( metastasis checks with thoracic radiographs) should be considered. Our standard recheck schedule consists rechecks every 3 months for 1.5 years, then twice yearly thereafter. Thoracic radiographs are obtained at every visit.

If the surgical margins are not free of tumor, additional therapy is indicated immediately. If possible, the best treatment is additional surgery, encompassing the entire prior surgical scar and an additional 3 cm on all sides. Radical procedures (such as mandibulectomy/ maxillectomy, thoracic wall resection, en bloc resection of dorsal scapulae and/or spinous processes, or amputation) are reasonable to consider. If these types or surgery are not feasible, or are declined by an owner for cosmetic/other reasons, another aggressive local treatment modality such as radiation therapy can be considered.

Radiation therapy

Radiation therapy (RT) can be extremely useful for the control of local disease recurrence of STS after incomplete excision. The timing for the start of RT is important. The likelihood of permanent tumor control is greater if RT is employed while the residual tumor is still microscopic, i.e. before gross recurrence is noted. However, RT should not be started until the surgical excision is well healed. Optimally, we will begin RT approximately 2-3 weeks after surgery. RT can also be employed in the preoperative (neoadjuvant) setting, in an attempt to reduce the size of a tumor and sterilize tumor margins.

Most current "curative-intent" RT protocols (15-19 treatments given over 3-4 weeks to a total radiation dose of 50 Gray, or 5700 rads) affords a roughly 85% 3-year local control rate when used to treat incompletely resected canine STS. Permanent local control is less likely if multiple prior surgeries have been performed, or if gross disease is irradiated. Similar RT protocols utilized in cats with VAS (with or without doxorubicin chemotherapy) afford median disease-free intervals in the 600-day range, which is a vast improvement over surgery alone. A recent study evaluating coarsely fractionated or "palliative" radiation therapy (once-weekly treatments for 4 weeks) for unresectable canine STS reported onjective tumor shrinkage in 50% of patients and a median progression-free inrterval of 5 months.

Although RT in animals requires multiple anesthetic procedures, each treatment is very short in duration and most animals tolerate this very well. Acute side effects are limited to the area being irradiated, and consist primarily of varying degrees of cutaneous erythema, alopecia, and pruritus, sometimes accompanied by a serous exudate (moist desquamation). This typically begins the third or fourth week of treatment and resolves 3-4 weeks after the completion of RT. A similar reaction can occur in the oral cavity when oral tumors are irradiated. Late side effects consist primarily of some degree of permanent alopecia, cutaneous hyperpigmentation, or change in hair color. Less common are skin or muscle fibrosis, bone necrosis, and sequestrum or fistula formation. Effects specific to the eye, if within the radiation field, include acute blepharitis/conjunctivitis and keratoconjunctivitis sicca, which may resolve with time, and vascular changes in the retina, cataracts, or chromic keratitis, which can occur over many months.

Chemotherapy

Chemotherapy may be offered in the surgical adjuvant setting if a STS falls into the "high-risk" group for metastasis (histologically high-grade or undifferentiated tumors, unfavorable histotypes), or if palliation of unresectable or metastatic disease is attempted. Chemotherapy can also be offered for those patients where curative therapy (aggressive surgery or RT) has been declined. Chemotherapy alone is unlikely to provide a cure for most STS, but is typically employed with the intent of delaying the onset of recurrence or metastasis in the setting of microscopic disease, or arresting or slowing the progression of existing gross disease. Objective response rates are reported to be in the 50% range, but response duration is often short.

Doxorubicin as a single agent or doxorubicin-containing protocols appear to have the greatest efficacy in the treatment of canine and feline STS. Carboplatin also appears to be an active drug for the management of feline VAS. In the adjuvant setting, a total of 4-5 treatments are typically given. If treating gross disease, a minimum of two treatments is usually administered, with further treatment dictated by response to therapy. Doxorubicin is an extreme vesicant if extravasated, and the practitioner must be aware of the unique cumulative toxicities associated with doxorubicin administration. Specifically, doxorubicin may cause cardiotoxicity in dogs, and nephrotoxicity in cats. The reader is directed to more general texts for further discussion of the administration of and toxicities associated with doxorubicin administration.

Recently, post-operative doxorubicin chemotherapy has been shown to significantly prolong disease-free intervals in cats with VAS, when compared to cats receiving surgery alone (median disease-free interval 415 days vs. 90 days, respectively). It appears that both doxorubicin chemotherapy and RT can be effective adjunctive treatments for feline VAS, but these should not be viewed as substitutes for appropriately aggressive surgical procedures.

Another recent study evaluated the efficacy of postoperative therapy with low-dose, continuous (metronomic) cyclophosphamide and piroxicam in dogs with incompletely resected STS. The well-tolerated protocol appeared to delay recurrence compared with dogs receiving no additional therapy, and may be a reasonable consideration in dogs with STS where additional aggressive local therapy (e.g. wide-margin surgery, RT) is declined or not feasible.

In conclusion, the take-home message is that the vast majority of STS can be dealt with effectively with early and appropriately aggressive surgery. Other therapies can be applied as necessary if surgery is insufficient or declined. Definitive therapy is best employed at the time of the first tumor occurrence.

Selected references

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Barber LG, et al. Combined doxorubicin and cyclophosphamide chemotherapy for nonresectable feline fibrosarcoma. JAAHA 36(5): 416-21, 2000.

Bregazzi VS, et al. Treatment with a combination of doxorubicin, surgery, and radiation versus surgery and radiation alone for cats with vaccine-associated sarcomas: 25 cases (1995-2000). JAVMA 218(4): 547-50, 2001.

Forrest LJ, et al. Postoperative radiotherapy for canine soft tissue sarcoma. JVIM. 14 (6): 578-82, 2000.

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Poirier VJ, et al. Liposome encapsulated doxorubicin (Doxil) and doxorubicin in the treatment of vaccine associated sarcoma in cats. JVIM 16: 726-731, 2002.

Lawrence J, et al. Four-fraction radiation therapy for macroscopic soft-tissue sarcomas in 16 dogs. JAAHA 44:100-108, 2008.

Elmslie RE, et al. Metronomic therapy with cyclophosphamide and piroxicam effectively delays tumor recurrence in dogs with incompletely resected soft tissue sarcomas. JVIM 22: 1373-1379, 2008.

Selting KA, et al. Outcome of dogs with high-grade soft tissue sarcomas treated with and without adjuvant doxorubicin chemotherapy: 39 cases. JAVMA 227 (9): 1442-1448, 2005.