Injection site sarcomas in cats (Proceedings)

Soft tissue sarcomas of the cat come in several forms.  Injection site sarcomas/Vaccine associated sarcomas are the most common sarcomas seen in feline patients today.  Non-injection site sarcomas are not as common, but do occur.  Feline sarcoma virus is extremely rare in the cat and requires co-infection with FeLV in order to cause disease. This talk will focus mostly on Injection site sarcomas (ISS/VAS) with supplementary information on the other types of sarcomas in the cat.

Epidemiology and risk factors

• History of Injection Site Sarcomas in America

• Mid 1980's- The development of two new vaccines occurred: a killed rabies vaccine licensed for subcutaneous administration in the cat was developed as well as a killed vaccine for Feline Leukemia Virus (FeLV).

• 1987 – Law in Pennsylvania enacted to require rabies vaccinations in cats due to an increase in the prevalence of rabies in felines.

• 1991- Paper published by Drs. Hendrick and Goldschmidt (pathologists at the University of Pennsylvania) linking vaccines to soft tissue sarcomas in cats. 

• Epidemiology

• Strong association between the administration of inactivated feline vaccines, such as FeLV and rabies, and the development of soft tissue sarcomas.

• Incidence increases with number of vaccines given in one area simultaneously.

• Incidence between 1/1000 and 1/10,000.

• Incidence for soft tissue sarcomas of non-vaccine areas is 20/100,000.

• Time from vaccination to development of a tumor can be as little as 4 weeks or as long at 10 years.

• These tumors can be caused by other vaccines and even other types of injections allowing for a more inclusive name of Injection site sarcomas rather than Vaccine Associated Sarcomas.

• Pathogenesis

• Post vaccination or injection reactions lead to uncontrolled fibroblast and myofibroblast proliferation and eventual tumor formation.

• This process may occur alone or there may be immunologic factors that play a role in the process.

• This theory is supported by histology report of a transition zone from inflammation to sarcoma and areas of microscopic sarcoma mixed in with granulomatous inflammation.

• Similar to ocular sarcomas that develop in the feline eye after trauma or chronic uveitis.

• Growth factors associated with healing can help to promote malignant transformation.

• Growth factors thought to play a role in malignant transformation include- Epidermal growth factor (EGF), Platelet derived growth factor (PDGF), basic fibroblastic growth factor (bFGF) and transforming growth factor β (TGFβ).

• Non-vaccine associated sarcomas rarely express these growth factors or their receptors.

• Mutations of p53 are also common in these tumors.

• Injection site sarcomas and non-injection site sarcomas are not associated with a positive retroviral status.

• Feline sarcoma virus requires a co-infection with FeLV before tumors are established.    

Pathology

• Tumors that develop after vaccination are typically mesenchymal and include:

• Fibrosarcoma

• Rhabdomyosarcoma

• Malignant fibrous histiocytoma

• Undifferentiated sarcoma

• Extraskeletal Osteosarcoma

• These tumors are not significantly different from non-ISS/VAS in the cat based upon histologic types seen.

• ISS/VAS in the cat has a more aggressive biologic behavior than non-ISS/VAS.

• 60% of these tumors are considered grade III and only 6% of them are grade I.

• In the dog only up to 20% of soft tissue sarcomas tumors are considered grade III tumors.

Diagnosis and work up

• The diagnosis and work up are the same regardless of the cause of the sarcoma.

• Often a diagnosis can be achieved with a fine needle aspirate of the mass.

• Often these masses are cystic so using a core technique with your finger over the hub of the needle can help prevent dilution of the sample.

• Aspiration may be required if a core technique does not work because these tumors do not exfoliate well.

• A biopsy of the lesion can be performed if a fine needle aspirate does not provide a diagnosis.  The biopsy should be taken on the edge of the tumor as the center is likely necrotic.  It is best to include the junction between normal and abnormal tissue in the biopsy.

• Excisional biopsy should be avoided.  The Vaccine-Associated Feline Sarcoma Task Force (VAFSTF) recommends a diagnostic biopsy before surgery is attempted.  They also strongly recommend against “shelling out” one of these tumors.  If there is a chance that this mass could be an ISS/VAS, then it is important to get a diagnosis before the major surgery is performed for planning.

• Thoracic radiographs should be performed in all cats with sarcomas.

• The metastatic rate for cats with ISS/VAS is about 25% initially and goes up with each recurrence.

• The metastatic rate for cats with non-ISS/VAS is about 5-15%.

• This tumor spread hematogenously – therefore, the lungs are the most likely location.

• Advanced Imaging is an important part of the surgical planning and work-up for these cats.  These tumors often invade locally by dissecting through various tissue planes.  Therefore, what you see on the outside may be only the beginning (the proverbial tip of the iceberg).

• CT scans are recommended in most cats because therapy often includes radiation.

• MRI is also an acceptable modality for determining the extent of the tumor.

• Contrast agents should be used in either modality.

Treatment

• When to intervene: The VAFSTF recommends

• Treating any mass that has persisted more than 3 months post-injection.

• Treating any lesion greater than 2 cm in diameter.

• Treating any tumor that is increasing in size after 1 month post-injection.

• Injection site sarcomas are very invasive tumors and multi-modal therapy is often required.

• Surgery:

• These tumors are very locally invasive, non-encapsulated tumors that extend along fascial planes far beyond what the naked eye can see.

• If they look like they will just “shell out”, avoid the temptation.  It is not true.  They cannot be shelled out.

• The VAFSTF task force recommends at least 2 cm margins in all directions including deep.  Here at TAMU we recommend up to 5 cm lateral margins and at least 2 fascial planes deep. 

• Complete resection is achieved < 50% of time using the VAFSTF guidelines.

• Using the TAMU guidelines 97% of the tumors are complete removed based on histologic evaluation and only 11 % experienced local recurrence. With 74% of cats still alive at 3 years.

• A good rule of thumb is that once you think you have taken enough, go back and some more, then you might be ok.

• The first surgery is the best chance to achieve long term survival. Disease free intervals (DFI) go down with marginal surgeries and repeated surgeries.

• DFI for marginal resections is 79 days.

• DFI for radical surgery is 325-419 days.

• Experience of the surgeon plays a role as well:

• General practitioners have a DFI after surgery alone of 66 days, versus a boarded surgeon who has a DFI after surgery alone of 274 days.

• Any biopsy tracts or areas of fixation (including bone) should be removed en bloc with the tumor.

• Often includes dorsal spinous processes, scapula, ischium, ileum, etc…

• Body wall resection for truncal tumors is common

• Masses high on the thigh may require amputation plus hemipelvectomy to achieve the necessary margins.

• For Surgery alone the overall DFI for 1 year and 2 years are 35% and 9% respectively (quite disappointing)!

• For completely resected tumors the MST is greater than 16 months

• Surgery plus Radiation Therapy (RT)

• Combination therapy including RT and surgery is often considered essential for the treatment of this disease in many cats.  Especially those with intrascapular and body wall lesions.

• Full course RT generally consists of 3-4 weeks of daily radiation to a total of 48-57 gray.

• Radiation can be delivered before or after surgery.

• Preoperative radiation therapy

• Advantages

• Greater anti-tumor effect because blood supply to the tumor has not be disrupted- i.e. fewer hypoxic cells

• Possible reduction in tumor size may make surgery easier

• Decreased risk of disseminating tumor cells during surgery

• Disadvantages

• Increased risk of surgical complications such as dehiscence

• Postoperative Radiation therapy

• Advantages

• May provide better tumor control because RT is best when used against microscopic disease

• Does not delay definitive surgery

• Disadvantages

• Surgery increases the size of the RT field

• Altered local blood supply may create more hypoxic cells

• Tumor cells may repopulate during the time between surgery and the onset of RT

• Disease free intervals for combination therapy:

• For all cats 40-45% had local recurrence at a DFI of 398-584 days post therapy.

• For cats with complete surgical removal – DFI was 700-986 days after therapy.

• For cats with incomplete margins- DFI was 112-292 days.

• The numbers are about the same whether preoperative or post operative RT was done.

• One study that combined chemotherapy with surgery and postoperative RT demonstrated a recurrence rate of 28% and a DFI of 661 days.

• The role of Chemotherapy in ISS/VAS and non-ISS/VAS

• Metastatic rate is 12-26% for the 2 diseases.

• Median time to metastasis is 265 days

• In a gross disease setting between 39-50% of cats will have a measurable response to Doxorubicin alone or in combination with cyclophosphamide. This is a short lived response of 80-120 days.

• Chemotherapy has minimal impact on the overall survival time of cats treated with surgery and radiation therapy.

• Miscellaneous therapies:

• Irridium implants have been used here. They have a 1 year disease free rate of 61% and only require 7 days of treatment.  However this also requires 7 days of isolation therapy.

• IL-2 therapy has shown some promise when combined with other therapies, but more work needs to be done.

Prognosis

• Using traditional guidelines of surgery alone carries a poor prognosis for this disease.

• Outcomes improve with extremely aggressive surgery including 5 cm margins and 2 fascial planes deep and will multi-modality therapy.

• Outcomes are also improved when cats are treated with aggressive therapy from the start, rather than after recurrence.

• Combination therapy of surgery and RT lead to DFI of 13-19 months and MST of 23 months.

Prevention and guidelines

• Vaccinations should be given as low as possible on the limb.

• Decrease the use of polyvalent vaccines.

• Use non-adjuvanted vaccines in cats.

• Increase the interval between vaccines for as long as is safe.

• VAFSTF recommendations:

• Rabies given distally in the right pelvic limb

• FeLV given distally in the left pelvic limb

• All other vaccines should be given in the right shoulder

• The location of each injection, type of vaccine, the manufacturer and serial number of the vaccine should be documented in the patient records.

• IM injections can also lead to injection site sarcomas but may be harder to feel and take longer to discover.  Therefore, it is recommended that vaccines be given SC.