Canine Soft Tumour Sarcomas: Brief overview and recommended therapeutic approaches.
Radiation Oncology VCA West Los Angeles Animal Hospital 1900 S. Sepulveda Boulevard
Los Angeles, CA 90025 P 310-473-2951 | F 310-979-5400 VCAwestlaspecialty.com
Etiology/Pathophysiology
Soft tissue sarcomas are a group of tumors that arise from mesenchymal tissues and can originate from visceral and non-visceral sites. Tumors within this group tend to have different morphologic and histologic features, but there biological behavior is similar; therefore they are often treated as one. Several important biologic features have been described that these tumors have in common:
1. Ability to arise from any anatomical site
2. Appear as pseudoencapsulated, but tend to infiltrate through and along fascial planes
3. Metastasize hematogenously in up to 20% cases, but regional lymph node metastasis is unusual
4. Local recurrence after conservative surgery is common
5. Gross tumors generally have a poor response to chemotherapy and radiation therapy
Not all lesions arising from the subcutaneous space are malignant, and many are often benign or inflammatory. Soft tissue sarcomas comprise approximately 15% of all skin and subcutaneous tumors in dogs. Though histologic distinction is not clinically important in the treatment of these tumors, the nomenclature given to soft tissue sarcomas is determined by the connective tissue (muscle, adipose, fascial, fibrous, and neurovascular) from which they arise. Tumors classified as soft tissue sarcomas include fibrosarcoma, peripheral nerve sheath tumor, myxosarcoma, liposarcoma, undifferentiated sarcoma, rhabdomyosarcoma, and malignant fibrous histiocytoma. Other tumors also arising from connective tissue such as osteosarcoma, chondrosarcoma, hemangiosarcoma, and synovial cell sarcoma are not classified as soft tissue sarcomas as they have a higher propensity for metastasis.
Lauren Askin, DVM DACVR (Radiation Oncology) Veterinary Specialist
Epidemiology/Signalment
Soft tissue sarcomas tend to occur in middle aged to older dogs with no specific breed or sex
predilection; however, medium and large breed dogs do seem to be overrepresented. In dogs,
sarcomas have been associated with radiation, trauma, foreign bodies, implants, and the
parasite Spirocerca lupi.
History and Clinical Signs
Soft tissue sarcomas generally present as firm, fixed, slow
growing masses most commonly affecting the trunks,
extremities, or oral cavity. Many times they are initially
noted when they are small, but go untreated as they are
assumed to be benign. The skin overlying these tumors is
often moveable and the many times the tumor palpates as
an encapsulated mass due to the presence of a
psuedocapsule. A pseudocapsule is tissue that has formed
from compression of peritumoral connective tissue and
may or may not be confluent with tumor cells. When
tumors are small, they are non-painful; but as they grow they invade into the deeper tissues
which can result in the tumor becoming ulcerated and infected. Clinical signs manifested from
the tumor are dependent on the site from where it originates. For example, sarcomas
originating in the mouth may cause halitosis, difficulty eating, and salivation; whereas tumors
on a limb may result in lameness.
Diagnosis
A fine needle aspirate is always warranted on detection of any new mass or lesion. With soft
tissue sarcomas, cytology can be beneficial in helping to rule out cysts or other tumor types
(mast cell tumors), but it is always important to keep in mind that cytology is not sufficient for a
definitive diagnosis of a soft tissue sarcoma. These tumors do not readily exfoliate and can
contain areas of inflammation and necrosis. The presence of inflammatory cells and necrosis
in the absence of neoplastic cells on cytology does not rule out a soft tissue sarcoma. A study
conducted on FNA’s of 40 soft tissue sarcomas reported that only 62.5% of the cases yielded
an accurate diagnosis, while 15% of the cases were incorrectly diagnosed.
Biopsy and histopathology are needed for definitive diagnosis of a soft tissue sarcoma. There
are two approaches to tumor biopsy which include pre-treatment biopsy and post-treatment
biopsy. Pretreatment biopsy methods are the preferred methods and include needle core (Trucut),
wedge or incisional, and punch biopsy. All biopsies performed should be positioned so
that the biopsy tract can be included in the curative intent treatment. Post-treatment biopsy
refers to an excisional biopsy, where the diagnosis is made after removal of the gross tumor.
Many times this method is attractive to clinicians because it allows for treatment and diagnosis
in one step; but unfortunately, post-treatment biopsies are rarely curative. Also, the
subsequent surgery following an excisional biopsy is many times required to be more
aggressive than the surgery required following a pre-treatment biopsy. An excisional biopsy
should only be performed when it is possible to take a 2-3 cm margin around the tumor.
Once a diagnosis of soft tissue sarcoma has been made, it is important to determine the
clinical stage or extent of disease. Knowledge of the clinical stage of the tumor will help
determine the appropriate treatment. Diagnostic tests that should be performed prior to
beginning definitive treatment include 3-view thoracic radiographs, as the lungs are the most
common site of metastasis for soft tissue sarcomas. Also, careful palpation of the regional
lymph nodes is important. If the draining lymph node palpates enlarged, a fine needle aspirate
or biopsy of the lymph node should be performed. Careful palpation of the mass is necessary
to determine the tumor size and fixation to surrounding tissues. Advanced imaging with the
use of computed tomography or magnetic resonance imaging can be helpful to evaluate the
extent and invasiveness of larger tumors, tumors in the head or neck, or tumors within a body
cavity.
Surgery
Local tumor control accomplished with wide, surgical excision is considered the treatment of
choice for soft tissue sarcomas, and advances in reconstructive techniques have significantly
expanded surgical options for aggressive resection with good functional and cosmetic
outcomes The surgical approach for soft tissue sarcomas has been classified according to the
extent of the wound margins as intracapsular (when the tumor is surgically penetrated);
marginal (when the tumor is excised just outside, or at, the pseudocapsule); wide (when a
portion of normal tissue is left around the tumor); and
radical (when an entire anatomic segment is removed,
for example, amputation). The minimum recommended
margins for surgical resection are 3 cm lateral to the
tumor and one fascial plane or 3 cm deep to the tumor.
However, if the tumor has attached to the muscle layer
or fascial layer, the entire layer may be compromised
and should not be considered a clean margin. Also, fat
and connective tissue do not serve as good tumor
barriers, so if the tumor overlies these structures, the 3
cm rule for margins should be utilized. Biopsy tracts and
any areas of fixation to surround tissue should also be resected en bloc with the tumor, as
these areas are considered to be contaminated.
Soft tissue sarcomas are typically surrounded by a pseudocapsule, which creates an easy
plane of cleavage between the tumor and surrounding tissues allowing the tumor to be
“shelled out” and submitted for histologic evaluation. Unfortunately, this type of marginal
excision commonly results in tumor cells extending to the edges of the resected tissue. Any
surgical procedure involving margins <2 to 3 cm in all directions must be considered an
incomplete excision even if no macroscopic tumor is evident after removal.
Histopathology of the tumor and surrounding tissue following surgery is important as it
provides surgical margins and tumor grade; and both are necessary in determining whether
further treatment including surgery or radiation therapy is necessary. Following removal of the
tumor, surgical margins should be clearly marked on the specimen and completeness of
excision should be evaluated. The resected tumor should be pinned out to the original
dimensions to prevent shrinkage during formalin fixation. It has been recommended that the
following terminology be used for margin evaluation:
1. Incomplete margins: Neoplastic cells are continuous with at least one surgical
margin in any plane.
2. Close margins: Distance between surgically created tissue edge and neoplastic
cells is less than 3 mm thickness, or surgical margins do not contain normal tissue
outside the pseudocapsule.
3. Complete margins: Distance between surgically created tissue edge and
neoplastic cells is at least 3 to 5 mm.
Marginal and incomplete surgeries are usually associated with a higher risk of local
recurrence (26-60%) and dogs with incomplete margins are 10.5 times more likely to develop
local recurrence than dogs with complete margins. Studies have also shown that the first
surgery provides the best opportunity for local tumor control, as subsequent surgeries
increase morbidity, treatment costs, and the risk of further local tumor recurrences, while
decreasing survival time. If a second surgery is performed following inadequate resection, a
margin of healthy tissue of 3 cm in all directions is recommended, including removal of normal
appearing subcutaneous fat and underlying fascia. The entire surgical wound is contaminated
and should be considered neoplastic. In a study evaluating scar re-excisions, local recurrence
was reported in 15% of dogs and residual tumor was identified in 22% of the resected scars.
Surgery and Radiation Therapy
Prior to the routine availability of radiation treatment, radical and often disfiguring surgery was
the mainstay treatment for soft tissue sarcomas which resulted in 1-year control rates of 70-
80%. Although soft tissue sarcomas have historically been considered radiation resistant
when compared to other tumor types, a multimodality approach of surgery and radiation
therapy has proven to help prevent local recurrence.
The sequencing of radiation and surgery is
based on multiple factors and should be
determined on an individual basis. There are
several advantages and disadvantages to both
preoperative and postoperative radiation
therapy. The rationale for administering
postoperative radiation therapy is that the
radiation kills or prevents the multiplication of
any microscopic tumor cells left behind. Some
advantages of postoperative radiation include 1)
wound complications are rare in tissues that are
irradiated after the first inflammatory phase of
wound healing; 2) removal of a larger tumor with necrotic regions or infections may make the
patient and patient’s family more comfortable; and 3) postoperative treatment planning may be
simpler than preoperative planning in patients in which the size or shape of a tumor creates
Varian 2100 EX Linear Accelerator (LINAC)
Radiation Oncology
difficulty in achieving a uniform dose distribution. Disadvantages of post operative radiation
include 1) increased radiation field sizes; 2) damage to vasculature, which may lead to
hypoxia decreasing the effectiveness of radiation; and 3) potential delays in the start of
radiation therapy if post-surgical wound complications occur. Post-operative radiation is
generally started within 7-14 days after surgery.
The rationale behind preoperative radiation therapy is to inactivate the large number of
peripheral tumor cells reducing the contamination of the surgical site. Advantages to
preoperative radiation include 1) a smaller radiation field; 2) possible shrinkage of the tumor
making surgical excision with wide margins less difficult; and 3) undisturbed tumor bed and
blood supply increasing effectiveness of radiation. While disadvantages to preoperative
radiation include the possibility of poor or delayed wound healing in the irradiated field.
Generally, preoperative radiation is reserved for tumors that are initially determined to be
inoperable.
Radiation therapy is commonly is used as an adjunct to surgery. Radiation seems to have the
greatest efficacy when it is used to treat remaining microscopic disease following surgical
cytoreduction of a soft tissue sarcoma; and it is less effective when used to treat bulky, gross
disease. Marginal surgical resection combined radiation therapy is an attractive alternative to
limb amputation for a soft tissue sarcoma on an extremity. It also can be used following a
planned marginal resection when wide surgical resection is not possible such as with tumors
of the head or neck. In these cases, removal of all grossly visible tumor is completed.
Radiopaque clips are often placed during surgery marking the lateral, proximal, and distal
extent of the tumor to aid in radiation planning.
Several studies have been done evaluating radiation
therapy for incompletely excised soft tissue sarcomas in
dogs. Studies have shown that similar local control and
survival rates are attained with a better functional and
cosmetic outcome by performing marginal surgical
excisions plus adjuvant radiotherapy compared to radical
surgery alone. A prospective study was performed which
evaluated 48 dogs with soft tissue sarcomas treated with
surgery to decrease disease to <3 cm followed by full
course radiation therapy to a total dose of 63 Gy. This study Basic set up for an incompletely
excised STS treated with electrons.
reported a 5 year survival rate at 76% and a recurrence rate of 16%. The median time to
recurrence was 23.3 months. Another study evaluating 35 dogs with soft tissue sarcomas that
were excised to microscopic disease followed by daily radiation to a total dose of 42-57 Gy
reported an overall median survival of 61.7 months.
A recent study completed in 2012 evaluated intentional marginal excision of canine soft tissue
sarcomas of the limb followed by a coarsely fractionated radiation protocol consisting of four 8
to 9 Gy fractions at 7- day intervals. Fifty-six dogs were included in the study. The results of
this study compared favorably to studies using more fractionated “definitive” protocols, as the
1-, 2-, and 3- year disease-free intervals were 82, 74, 70%, respectively, and a local
recurrence rate of 18%. The main disadvantages of using coarsely fractionated protocols are
reduced efficacy and the increased risk of late radiation toxicity, which may be significant and
include bone necrosis and radiation induced tumors at the site. This study supports, however,
that in the postoperative setting coarsely fractionated radiation protocols can give good control
and that the risk of late radiation side effects is low when the fraction size does not exceed 8
Gy.
Radiation Therapy
If surgical excision of a soft tissue sarcoma is
impossible because of tumor location or size of
the tumor, primary radiation therapy can be
applied; however, measureable and bulky tumors
tend to have a poor long term response to primary
radiotherapy. Long term control of soft tissue
sarcomas with conventional doses of radiation
alone (40-48 Gy) are difficult to obtain because of
their low growth fraction, relatively long doubling
time, and tendency to develop hypoxic regions
within the tumor parenchyma. Reported 1-year
control rates are 30% at 35 Gy (10 x 3.5 Gy), 35%
at 40 Gy (10 x 4 Gy), 48% at 45 Gy (10 x 4.5 Gy)
and 67% at 50 Gy (10 x 5 Gy). At 2 years, control
rates vary from 12% at 40 Gy and 33% at 50 Gy.
Radiation Oncology
As a single modality, radiation is generally considered palliative for soft tissue sarcomas with
control defined as a slowly regressing or stable-in-size tumor mass. The goal of palliative or
coarsely fractionated radiation therapy is alleviate pain, swelling, and inflammation associated
with the tumor, in hopes to improve quality of life. Typical palliative protocols involve large
radiation doses (5-10 Gy) delivered as a few fractions once or twice weekly. The delivery of a
small fraction size once per week is unlikely to lead to a durable response because tumor
cells have a significant amount to time to repair damage and proliferate between treatments.
Therefore, larger doses of radiation are often delivered to optimize killing of tumor cells, with
the increased risk of late radiation toxicity accepted as part of the treatment. Since palliative
radiation therapy is administered to improve quality of life, not prolong life, patients will likely
live long enough to experience permanent late effects. Control rates for soft tissue sarcomas
treated with palliative protocols have been reported to be greater than 87% with time to
progression ranging from 5.2 months to 8.8 months.
A retrospective study completed in 2012 evaluated a palliative radiation protocol consisting of
4 Gy fractions given over 5 consecutive days, as the concern for clinically significant late
effects of palliative radiation protocols can be addressed by delivering lower doses of
radiation. In this study, 10 soft tissue sarcomas were treated. A measurable overall response
rate of 80% was reported with tumor control achieved in 100% of patients, and a median
progression free survival of 5.7 months. With this protocol, the risk for late side effects is about
half that of the traditional 8 Gy x 4 fraction protocol; therefore, retreatment with the 4 Gy x 5
fraction protocol may be considered without more concern for toxicity than a single traditional
8 Gy x 4 fraction protocol.
Chemotherapy
Adjuvant chemotherapy at times is useful in the treatment of soft tissue sarcomas. Chemotherapy
is best used when combined with radiation therapy and/or surgery. Chemotherapy
alone does not seem to be effective for measurable soft tissue sarcomas, with the exception
of providing palliation in some cases. Doxorubicin-based protocols, either alone or in
combination with cyclosphasmide have shown the most promise with an overall response rate
of 23%.
Despite the fact, that generally soft tissue sarcomas are slow to metastasize, the metastatic
rate for cutaneous soft tissue sarcoma is grade dependent and varies from less than 15% for
grade I and II soft tissue sarcomas to 41% for grade III soft tissue sarcomas. Due to the higher
metastatic rate of grade III soft tissue sarcomas, post-operative chemotherapy should be
considered as it may prevent or delay metastasis. Single-agent doxorubicin, mitoxantrone, or
combination protocols are most commonly used.
Metronomic chemotherapy, continuous administration of chemotherapy drugs at doses that
are significantly lower than conventional maximally tolerated dose therapy, has also been
evaluated in canine soft tissue sarcomas. A retrospective study was done in 2008 which
evaluated 85 dogs with incompletely resected soft tissue sarcomas. Thirty of the these dogs
received continuous Cyclophosphamide (10mg/m2) and standard dose piroxicam therapy (0.3
mg/kg) and 55 control dogs did not receive additional therapy. When comparing these two
groups, treated dogs had a disease free interval of 13.7 months which was significantly longer
when compared to 7.0 months for untreated dogs. Another study completed in 2011 evaluated
low-dose cyclophosphamide and its effects on T regulatory cells and tumor angiogenesis in
dogs with soft tissue sarcomas. This study found that those dogs receiving 15 mg/m2/d of
cyclophosphamide had significant decreases in the number and percent of T regulatory cells
as well as the microvessel density, further supporting that metronomic therapy may provide
antitumor effects.
Prognosis for Dogs
The overall prognosis for dogs with soft tissue sarcomas is good, but the range of biological
behavior for these tumors can be broad. The median survival time for dogs with soft tissue
sarcoma ranges from 3.9 years following surgery alone to 6.2 years with surgery and
adjunctive radiation. Overall, up to 33% of dogs eventually die of tumor-related causes.
Research has identified valuable prognostic information from histologic grade, mitotic index,
and completeness of surgical margins. Complete margins predict non-recurrence; and
recurrence appears to increase with grade. The metastatic rate for dogs with grade I or grade
II soft tissue sarcomas is less than 15% compared to 41% for grade III soft tissue sarcomas.
High mitotic index (> 9 mitotic figures per 10 high power fields) is prognostic for reduced
survival. Other factors, including markers of cellular proliferation, tumor dimension, tumor
location, histologic type, invasiveness, and cytogenetic profiles may be useful indicators of
prognosis, but presently require further investigation. ▪
Dr. Lauren Askin was born and raised in West Virginia. She attended
the University of Delaware where she received her Bachelor’s degree
in Animal Science in May 2005. She earned her DVM at the University
of Georgia in 2009. Following completion of Veterinary School, she
completed a one-year small animal medical and surgical internship at
VCA West Los Angeles. Dr. Askin completed a 2-year residency in
Radiation Oncology at North Carolina State University and is board
certified in veterinary radiation oncology. Dr. Askin’s interests include
advanced radiation therapy techniques to improve local tumor control
and reduce treatment related side effects.
Lauren Askin, DVM, DACVR (RO)
Veterinary Specialist
VCA West Los Angeles
Animal Hospital
Radiation Oncology
VCA West Los Angeles Animal Hospital
1900 S. Sepulveda Boulevard
Los Angeles, CA 90025
P 310-473-2951 | F 310-979-5400
Radiation Oncology VCA West Los Angeles Animal Hospital 1900 S. Sepulveda Boulevard
Los Angeles, CA 90025 P 310-473-2951 | F 310-979-5400 VCAwestlaspecialty.com
Etiology/Pathophysiology
Soft tissue sarcomas are a group of tumors that arise from mesenchymal tissues and can originate from visceral and non-visceral sites. Tumors within this group tend to have different morphologic and histologic features, but there biological behavior is similar; therefore they are often treated as one. Several important biologic features have been described that these tumors have in common:
1. Ability to arise from any anatomical site
2. Appear as pseudoencapsulated, but tend to infiltrate through and along fascial planes
3. Metastasize hematogenously in up to 20% cases, but regional lymph node metastasis is unusual
4. Local recurrence after conservative surgery is common
5. Gross tumors generally have a poor response to chemotherapy and radiation therapy
Not all lesions arising from the subcutaneous space are malignant, and many are often benign or inflammatory. Soft tissue sarcomas comprise approximately 15% of all skin and subcutaneous tumors in dogs. Though histologic distinction is not clinically important in the treatment of these tumors, the nomenclature given to soft tissue sarcomas is determined by the connective tissue (muscle, adipose, fascial, fibrous, and neurovascular) from which they arise. Tumors classified as soft tissue sarcomas include fibrosarcoma, peripheral nerve sheath tumor, myxosarcoma, liposarcoma, undifferentiated sarcoma, rhabdomyosarcoma, and malignant fibrous histiocytoma. Other tumors also arising from connective tissue such as osteosarcoma, chondrosarcoma, hemangiosarcoma, and synovial cell sarcoma are not classified as soft tissue sarcomas as they have a higher propensity for metastasis.
Lauren Askin, DVM DACVR (Radiation Oncology) Veterinary Specialist
Epidemiology/Signalment
Soft tissue sarcomas tend to occur in middle aged to older dogs with no specific breed or sex
predilection; however, medium and large breed dogs do seem to be overrepresented. In dogs,
sarcomas have been associated with radiation, trauma, foreign bodies, implants, and the
parasite Spirocerca lupi.
History and Clinical Signs
Soft tissue sarcomas generally present as firm, fixed, slow
growing masses most commonly affecting the trunks,
extremities, or oral cavity. Many times they are initially
noted when they are small, but go untreated as they are
assumed to be benign. The skin overlying these tumors is
often moveable and the many times the tumor palpates as
an encapsulated mass due to the presence of a
psuedocapsule. A pseudocapsule is tissue that has formed
from compression of peritumoral connective tissue and
may or may not be confluent with tumor cells. When
tumors are small, they are non-painful; but as they grow they invade into the deeper tissues
which can result in the tumor becoming ulcerated and infected. Clinical signs manifested from
the tumor are dependent on the site from where it originates. For example, sarcomas
originating in the mouth may cause halitosis, difficulty eating, and salivation; whereas tumors
on a limb may result in lameness.
Diagnosis
A fine needle aspirate is always warranted on detection of any new mass or lesion. With soft
tissue sarcomas, cytology can be beneficial in helping to rule out cysts or other tumor types
(mast cell tumors), but it is always important to keep in mind that cytology is not sufficient for a
definitive diagnosis of a soft tissue sarcoma. These tumors do not readily exfoliate and can
contain areas of inflammation and necrosis. The presence of inflammatory cells and necrosis
in the absence of neoplastic cells on cytology does not rule out a soft tissue sarcoma. A study
conducted on FNA’s of 40 soft tissue sarcomas reported that only 62.5% of the cases yielded
an accurate diagnosis, while 15% of the cases were incorrectly diagnosed.
Biopsy and histopathology are needed for definitive diagnosis of a soft tissue sarcoma. There
are two approaches to tumor biopsy which include pre-treatment biopsy and post-treatment
biopsy. Pretreatment biopsy methods are the preferred methods and include needle core (Trucut),
wedge or incisional, and punch biopsy. All biopsies performed should be positioned so
that the biopsy tract can be included in the curative intent treatment. Post-treatment biopsy
refers to an excisional biopsy, where the diagnosis is made after removal of the gross tumor.
Many times this method is attractive to clinicians because it allows for treatment and diagnosis
in one step; but unfortunately, post-treatment biopsies are rarely curative. Also, the
subsequent surgery following an excisional biopsy is many times required to be more
aggressive than the surgery required following a pre-treatment biopsy. An excisional biopsy
should only be performed when it is possible to take a 2-3 cm margin around the tumor.
Once a diagnosis of soft tissue sarcoma has been made, it is important to determine the
clinical stage or extent of disease. Knowledge of the clinical stage of the tumor will help
determine the appropriate treatment. Diagnostic tests that should be performed prior to
beginning definitive treatment include 3-view thoracic radiographs, as the lungs are the most
common site of metastasis for soft tissue sarcomas. Also, careful palpation of the regional
lymph nodes is important. If the draining lymph node palpates enlarged, a fine needle aspirate
or biopsy of the lymph node should be performed. Careful palpation of the mass is necessary
to determine the tumor size and fixation to surrounding tissues. Advanced imaging with the
use of computed tomography or magnetic resonance imaging can be helpful to evaluate the
extent and invasiveness of larger tumors, tumors in the head or neck, or tumors within a body
cavity.
Surgery
Local tumor control accomplished with wide, surgical excision is considered the treatment of
choice for soft tissue sarcomas, and advances in reconstructive techniques have significantly
expanded surgical options for aggressive resection with good functional and cosmetic
outcomes The surgical approach for soft tissue sarcomas has been classified according to the
extent of the wound margins as intracapsular (when the tumor is surgically penetrated);
marginal (when the tumor is excised just outside, or at, the pseudocapsule); wide (when a
portion of normal tissue is left around the tumor); and
radical (when an entire anatomic segment is removed,
for example, amputation). The minimum recommended
margins for surgical resection are 3 cm lateral to the
tumor and one fascial plane or 3 cm deep to the tumor.
However, if the tumor has attached to the muscle layer
or fascial layer, the entire layer may be compromised
and should not be considered a clean margin. Also, fat
and connective tissue do not serve as good tumor
barriers, so if the tumor overlies these structures, the 3
cm rule for margins should be utilized. Biopsy tracts and
any areas of fixation to surround tissue should also be resected en bloc with the tumor, as
these areas are considered to be contaminated.
Soft tissue sarcomas are typically surrounded by a pseudocapsule, which creates an easy
plane of cleavage between the tumor and surrounding tissues allowing the tumor to be
“shelled out” and submitted for histologic evaluation. Unfortunately, this type of marginal
excision commonly results in tumor cells extending to the edges of the resected tissue. Any
surgical procedure involving margins <2 to 3 cm in all directions must be considered an
incomplete excision even if no macroscopic tumor is evident after removal.
Histopathology of the tumor and surrounding tissue following surgery is important as it
provides surgical margins and tumor grade; and both are necessary in determining whether
further treatment including surgery or radiation therapy is necessary. Following removal of the
tumor, surgical margins should be clearly marked on the specimen and completeness of
excision should be evaluated. The resected tumor should be pinned out to the original
dimensions to prevent shrinkage during formalin fixation. It has been recommended that the
following terminology be used for margin evaluation:
1. Incomplete margins: Neoplastic cells are continuous with at least one surgical
margin in any plane.
2. Close margins: Distance between surgically created tissue edge and neoplastic
cells is less than 3 mm thickness, or surgical margins do not contain normal tissue
outside the pseudocapsule.
3. Complete margins: Distance between surgically created tissue edge and
neoplastic cells is at least 3 to 5 mm.
Marginal and incomplete surgeries are usually associated with a higher risk of local
recurrence (26-60%) and dogs with incomplete margins are 10.5 times more likely to develop
local recurrence than dogs with complete margins. Studies have also shown that the first
surgery provides the best opportunity for local tumor control, as subsequent surgeries
increase morbidity, treatment costs, and the risk of further local tumor recurrences, while
decreasing survival time. If a second surgery is performed following inadequate resection, a
margin of healthy tissue of 3 cm in all directions is recommended, including removal of normal
appearing subcutaneous fat and underlying fascia. The entire surgical wound is contaminated
and should be considered neoplastic. In a study evaluating scar re-excisions, local recurrence
was reported in 15% of dogs and residual tumor was identified in 22% of the resected scars.
Surgery and Radiation Therapy
Prior to the routine availability of radiation treatment, radical and often disfiguring surgery was
the mainstay treatment for soft tissue sarcomas which resulted in 1-year control rates of 70-
80%. Although soft tissue sarcomas have historically been considered radiation resistant
when compared to other tumor types, a multimodality approach of surgery and radiation
therapy has proven to help prevent local recurrence.
The sequencing of radiation and surgery is
based on multiple factors and should be
determined on an individual basis. There are
several advantages and disadvantages to both
preoperative and postoperative radiation
therapy. The rationale for administering
postoperative radiation therapy is that the
radiation kills or prevents the multiplication of
any microscopic tumor cells left behind. Some
advantages of postoperative radiation include 1)
wound complications are rare in tissues that are
irradiated after the first inflammatory phase of
wound healing; 2) removal of a larger tumor with necrotic regions or infections may make the
patient and patient’s family more comfortable; and 3) postoperative treatment planning may be
simpler than preoperative planning in patients in which the size or shape of a tumor creates
Varian 2100 EX Linear Accelerator (LINAC)
Radiation Oncology
difficulty in achieving a uniform dose distribution. Disadvantages of post operative radiation
include 1) increased radiation field sizes; 2) damage to vasculature, which may lead to
hypoxia decreasing the effectiveness of radiation; and 3) potential delays in the start of
radiation therapy if post-surgical wound complications occur. Post-operative radiation is
generally started within 7-14 days after surgery.
The rationale behind preoperative radiation therapy is to inactivate the large number of
peripheral tumor cells reducing the contamination of the surgical site. Advantages to
preoperative radiation include 1) a smaller radiation field; 2) possible shrinkage of the tumor
making surgical excision with wide margins less difficult; and 3) undisturbed tumor bed and
blood supply increasing effectiveness of radiation. While disadvantages to preoperative
radiation include the possibility of poor or delayed wound healing in the irradiated field.
Generally, preoperative radiation is reserved for tumors that are initially determined to be
inoperable.
Radiation therapy is commonly is used as an adjunct to surgery. Radiation seems to have the
greatest efficacy when it is used to treat remaining microscopic disease following surgical
cytoreduction of a soft tissue sarcoma; and it is less effective when used to treat bulky, gross
disease. Marginal surgical resection combined radiation therapy is an attractive alternative to
limb amputation for a soft tissue sarcoma on an extremity. It also can be used following a
planned marginal resection when wide surgical resection is not possible such as with tumors
of the head or neck. In these cases, removal of all grossly visible tumor is completed.
Radiopaque clips are often placed during surgery marking the lateral, proximal, and distal
extent of the tumor to aid in radiation planning.
Several studies have been done evaluating radiation
therapy for incompletely excised soft tissue sarcomas in
dogs. Studies have shown that similar local control and
survival rates are attained with a better functional and
cosmetic outcome by performing marginal surgical
excisions plus adjuvant radiotherapy compared to radical
surgery alone. A prospective study was performed which
evaluated 48 dogs with soft tissue sarcomas treated with
surgery to decrease disease to <3 cm followed by full
course radiation therapy to a total dose of 63 Gy. This study Basic set up for an incompletely
excised STS treated with electrons.
reported a 5 year survival rate at 76% and a recurrence rate of 16%. The median time to
recurrence was 23.3 months. Another study evaluating 35 dogs with soft tissue sarcomas that
were excised to microscopic disease followed by daily radiation to a total dose of 42-57 Gy
reported an overall median survival of 61.7 months.
A recent study completed in 2012 evaluated intentional marginal excision of canine soft tissue
sarcomas of the limb followed by a coarsely fractionated radiation protocol consisting of four 8
to 9 Gy fractions at 7- day intervals. Fifty-six dogs were included in the study. The results of
this study compared favorably to studies using more fractionated “definitive” protocols, as the
1-, 2-, and 3- year disease-free intervals were 82, 74, 70%, respectively, and a local
recurrence rate of 18%. The main disadvantages of using coarsely fractionated protocols are
reduced efficacy and the increased risk of late radiation toxicity, which may be significant and
include bone necrosis and radiation induced tumors at the site. This study supports, however,
that in the postoperative setting coarsely fractionated radiation protocols can give good control
and that the risk of late radiation side effects is low when the fraction size does not exceed 8
Gy.
Radiation Therapy
If surgical excision of a soft tissue sarcoma is
impossible because of tumor location or size of
the tumor, primary radiation therapy can be
applied; however, measureable and bulky tumors
tend to have a poor long term response to primary
radiotherapy. Long term control of soft tissue
sarcomas with conventional doses of radiation
alone (40-48 Gy) are difficult to obtain because of
their low growth fraction, relatively long doubling
time, and tendency to develop hypoxic regions
within the tumor parenchyma. Reported 1-year
control rates are 30% at 35 Gy (10 x 3.5 Gy), 35%
at 40 Gy (10 x 4 Gy), 48% at 45 Gy (10 x 4.5 Gy)
and 67% at 50 Gy (10 x 5 Gy). At 2 years, control
rates vary from 12% at 40 Gy and 33% at 50 Gy.
Radiation Oncology
As a single modality, radiation is generally considered palliative for soft tissue sarcomas with
control defined as a slowly regressing or stable-in-size tumor mass. The goal of palliative or
coarsely fractionated radiation therapy is alleviate pain, swelling, and inflammation associated
with the tumor, in hopes to improve quality of life. Typical palliative protocols involve large
radiation doses (5-10 Gy) delivered as a few fractions once or twice weekly. The delivery of a
small fraction size once per week is unlikely to lead to a durable response because tumor
cells have a significant amount to time to repair damage and proliferate between treatments.
Therefore, larger doses of radiation are often delivered to optimize killing of tumor cells, with
the increased risk of late radiation toxicity accepted as part of the treatment. Since palliative
radiation therapy is administered to improve quality of life, not prolong life, patients will likely
live long enough to experience permanent late effects. Control rates for soft tissue sarcomas
treated with palliative protocols have been reported to be greater than 87% with time to
progression ranging from 5.2 months to 8.8 months.
A retrospective study completed in 2012 evaluated a palliative radiation protocol consisting of
4 Gy fractions given over 5 consecutive days, as the concern for clinically significant late
effects of palliative radiation protocols can be addressed by delivering lower doses of
radiation. In this study, 10 soft tissue sarcomas were treated. A measurable overall response
rate of 80% was reported with tumor control achieved in 100% of patients, and a median
progression free survival of 5.7 months. With this protocol, the risk for late side effects is about
half that of the traditional 8 Gy x 4 fraction protocol; therefore, retreatment with the 4 Gy x 5
fraction protocol may be considered without more concern for toxicity than a single traditional
8 Gy x 4 fraction protocol.
Chemotherapy
Adjuvant chemotherapy at times is useful in the treatment of soft tissue sarcomas. Chemotherapy
is best used when combined with radiation therapy and/or surgery. Chemotherapy
alone does not seem to be effective for measurable soft tissue sarcomas, with the exception
of providing palliation in some cases. Doxorubicin-based protocols, either alone or in
combination with cyclosphasmide have shown the most promise with an overall response rate
of 23%.
Despite the fact, that generally soft tissue sarcomas are slow to metastasize, the metastatic
rate for cutaneous soft tissue sarcoma is grade dependent and varies from less than 15% for
grade I and II soft tissue sarcomas to 41% for grade III soft tissue sarcomas. Due to the higher
metastatic rate of grade III soft tissue sarcomas, post-operative chemotherapy should be
considered as it may prevent or delay metastasis. Single-agent doxorubicin, mitoxantrone, or
combination protocols are most commonly used.
Metronomic chemotherapy, continuous administration of chemotherapy drugs at doses that
are significantly lower than conventional maximally tolerated dose therapy, has also been
evaluated in canine soft tissue sarcomas. A retrospective study was done in 2008 which
evaluated 85 dogs with incompletely resected soft tissue sarcomas. Thirty of the these dogs
received continuous Cyclophosphamide (10mg/m2) and standard dose piroxicam therapy (0.3
mg/kg) and 55 control dogs did not receive additional therapy. When comparing these two
groups, treated dogs had a disease free interval of 13.7 months which was significantly longer
when compared to 7.0 months for untreated dogs. Another study completed in 2011 evaluated
low-dose cyclophosphamide and its effects on T regulatory cells and tumor angiogenesis in
dogs with soft tissue sarcomas. This study found that those dogs receiving 15 mg/m2/d of
cyclophosphamide had significant decreases in the number and percent of T regulatory cells
as well as the microvessel density, further supporting that metronomic therapy may provide
antitumor effects.
Prognosis for Dogs
The overall prognosis for dogs with soft tissue sarcomas is good, but the range of biological
behavior for these tumors can be broad. The median survival time for dogs with soft tissue
sarcoma ranges from 3.9 years following surgery alone to 6.2 years with surgery and
adjunctive radiation. Overall, up to 33% of dogs eventually die of tumor-related causes.
Research has identified valuable prognostic information from histologic grade, mitotic index,
and completeness of surgical margins. Complete margins predict non-recurrence; and
recurrence appears to increase with grade. The metastatic rate for dogs with grade I or grade
II soft tissue sarcomas is less than 15% compared to 41% for grade III soft tissue sarcomas.
High mitotic index (> 9 mitotic figures per 10 high power fields) is prognostic for reduced
survival. Other factors, including markers of cellular proliferation, tumor dimension, tumor
location, histologic type, invasiveness, and cytogenetic profiles may be useful indicators of
prognosis, but presently require further investigation. ▪
Dr. Lauren Askin was born and raised in West Virginia. She attended
the University of Delaware where she received her Bachelor’s degree
in Animal Science in May 2005. She earned her DVM at the University
of Georgia in 2009. Following completion of Veterinary School, she
completed a one-year small animal medical and surgical internship at
VCA West Los Angeles. Dr. Askin completed a 2-year residency in
Radiation Oncology at North Carolina State University and is board
certified in veterinary radiation oncology. Dr. Askin’s interests include
advanced radiation therapy techniques to improve local tumor control
and reduce treatment related side effects.
Lauren Askin, DVM, DACVR (RO)
Veterinary Specialist
VCA West Los Angeles
Animal Hospital
Radiation Oncology
VCA West Los Angeles Animal Hospital
1900 S. Sepulveda Boulevard
Los Angeles, CA 90025
P 310-473-2951 | F 310-979-5400
