Everyone at Hope was so nice and compassionate. Strangers I met in the lobby consoled me. You knew everyone who stepped through Hope's doors loved animals.
Ilona and Bill
An eight-year-old neutered male retriever mix dog diagnosed with osteosarcoma of the mid-left ulna in February of 2016, had a partial mid-ulnectomy with clean margins and had been doing well. No adjuvant chemotherapy or radiation therapy were administered post-operatively. Four months after the mid-ulnectomy, a small growth on the lateral aspect of left forelimb was noted and had been getting larger. Radiographs (see below) show a mass (approximately 2×2 cm) in the soft tissues where the partial ulnectomy was performed. The mass was nonpainful and firm. A fine needle aspirate of the mass was obtained and submitted for cytologic evaluation.
Submitted slides were moderately to very highly cellular and consist of few to many red blood cells and a nucleated cell population predominated by individual round to spindle shaped cells (osteoblasts) with few scattered leukocytes in proportions consistent with peripheral blood. The osteoblasts had a small to moderate amount of basophilic cytoplasm that rarely contained pink granules and occasionally exhibited a small perinuclear clear area (Golgi). The nuclei were eccentric, round to oval, and had finely stippled chromatin pattern and 1-3 prominent nucleoli. Anisokaryosis was moderate; mitotic figures were frequently noted; binucleated cells were occasionally noted. Cellular aggregates were occasionally associated with a very small to moderate amount of pink extracellular matrix. The cytologic diagnosis was osteosarcoma.
Unlike many types of sarcoma, osteosarcoma can often be diagnosed definitively via cytology. While most of sarcomas consist of numerous of spindle-shaped cells, the osteoblasts that comprise osteosarcomas are more round to irregular in shape with a characteristic large oval, eccentrically-placed nucleus coupled with a perinuclear clear area (a characteristic that osteoblasts share with plasma cells). Many, but not all, osteoblasts also contain many fine intracytoplasmic pink matrix granules. Aside from these characteristics that identify their cell of origin, the malignant osteoblasts of osteosarcomas commonly exhibit many easily discernible criteria of malignancy (anisokaryosis, multiple prominent nucleoli).
Although the biopsy of the tumor was reported to have clean margins, recurrence of osteosarcoma at the amputation site suggests neoplastic osteoblasts were left behind within the soft tissues of the distal forelimb, where achieving wide soft tissue surgical margins are often difficult or impossible. A recent retrospective study of ulnar osteosarcoma (n = 30 cases) suggests that prognosis was no worse for these dogs compared to dogs with osteosarcoma involving other appendicular sites, although a variety of different treatment strategies were employed in this case series.1 Partial ulnar ostectomy was associated with a low complication rate and good to excellent function post-operatively, but may be associated with an increased risk of local tumor recurrence given the challenges of achieving wide surgical margins in the distal forelimb. The role of adjuvant chemotherapy in delaying tumor progression in ulnar osteosarcoma remains undefined, although most veterinary oncologists would likely advocate for its use in these cases given the high likelihood of metastasis.
- Ulnar osteosarcoma in dogs: 30 cases (1992–2008). Ramesh K.Sivacolundhu, Jeffrey J. Runge, Taryn A. Donovan, Lisa G. Barber, Corey F. Saba, Craig A. Clifford, Louis-Philippe de Lorimier, Stephen W. Atwater, Lisa DiBernardi, Kim P. Freeman, Philip J. Bergman, JAVMA 2013; Jul 1; 243(1):96-101).
Image 1: Lateral radiograph of the left forelimb. Note the mid-forelimb radiopacity in line of where the ulna had previously resided.
Image 2: 50x objective. Cytology of the mid-forelimb mass. Several round to irregularly-shaped malignant osteoblasts with the typical eccentric nucleus, basophilic cytoplasm, and a perinuclear clear area within the cytoplasm. Also, note the anisokaryosis, prominent nucleoli, and binucleation. A small amount of extracellular pink matrix is in the center of the photo.
Image 3: 50x objective. Cytology of the mid-forelimb mass. Several round to irregularly-shaped malignant osteoblasts with the typical eccentric nucleus and a perinuclear clear area within the cytoplasm.
A 33.7 kg, 10-year-old neutered male mixed breed presented to his local emergency service for acute onset of anorexia, restlessness, and mild dyspnea. At presentation, he had evidence of abdominal fluid and CBC/chemistry panel revealed hypercalcemia of 7.2 (reference range 9-12.2 mg/dL) and hypoproteinemia of 4.7 (reference range 5.5-7.6 g/dL). Ultrasonographic examination of his abdomen and thorax revealed a 6.9 x 5.2 cm solid mass along the right cranial aspect of the heart along with a moderate amount of free fluid in the pleural space (see figure 1). The dog was prescribed Lasix 40 mg twice a day after abdominocentesis was performed. Thoracocentesis was not performed. Given the solid nature of the mass and the location at the heart base, a presumptive diagnosis of a chemodectoma was made. Other differentials, in this case, were hemangiosarcoma, thyroid tumor, lymphoma or hemangiosarcoma. Because of the proximity of the mass to normal heart and lung tissue, the recommendation was made for stereotactic radiation therapy.
Figure 1. A still image from the original thoracic ultrasound. The four small white “x” mark the edges of the mass along the heart base. The mass initially measured 6.9 x 5.2 cm. Image courtesy of Dr. Anna Caceres.
Stereotactic radiation therapy is the use of a few hundred to a few thousand beams of radiation that are precisely targeted to a tumor, with a steep dose gradient in the few millimeters outside of the defined target volume. Typically, stereotactic radiation therapy treatments will entail 1-5 treatments, or fractions, that are given over a relatively short time period (typically one week or less). Large doses of radiation are prescribed, with emphasis put on highly accurate dose delivery. In cases such as this, the CyberKnife stereotactic radiation therapy unit employs the use of Synchrony, which is a camera system that establishes a pattern of respiration for a patient, thus “tracking” the tumor in real time as it changes position in space with respiratory motion. The Synchrony camera established a respiratory pattern in this patient’s case with the aid of ficucial markers, which are small gold seeds that were placed inside the tumor with ultrasound guidance approximately 1 week prior to treatment with CyberKnife. In conjunction with Synchrony, orthogonal x-ray sources use kilovoltage x-ray images to localize the fiducial markers, therefore allowing submillimeter accuracy for dose delivery.
The dog received 3 fractions of CyberKnife stereotactic radiation therapy. Each individual fraction size was 10 Gy for a total dose of 30 Gy of radiation that was delivered to the PTV (planning target volume) in a one-week time period. In accordance with well-established human guidelines for maximum tolerance of cardiac tissue, the maximum dose that the heart received was 23.8 Gy. These guidelines, although not well-established in veterinary medicine, are useful in radiation therapy in order to avoid unwanted toxicity in normal, healthy tissue that may surround a tumor (see figure 2).
Figure 2. These images are from the radiation treatment plan, which was created with specialized software that utilized these CT images. The top image shows an axial view of the thorax. The green crosshairs are centered on the gold fiducial markers, which were placed in the center of the tumor, outlined in red. A portion of the normal heart can be seen adjacent to the tumor, outlined in light blue. The bottom image is a sagittal view of the tumor outlined in red with fiducial markers and the adjacent heart, outlined in light blue.
No acute side effects of radiation were observed in the weeks following treatment. The dog did experience mild lethargy and inappetence approximately 3 months after his treatment, but these symptoms were considered unrelated. The dog had 2 repeat thoracic ultrasounds after treatment; the first ultrasound which was 2 months after radiation treatment revealed stable disease. The second ultrasound, which was 4 months after treatment, revealed a tumor size of 5.9 x 3.1. The dog’s Lasix was also weaned over a period of several weeks after radiation therapy; the by cavitary effusion previously noted in the thorax and abdomen was not noted in subsequent exams and all presenting clinical signs resolved.
There is a paucity of information in the veterinary literature regarding non-surgical treatment of heart base tumors1,2. The use of radiation therapy in the treatment of these tumors is becoming more widely accepted, especially with the growing availability of stereotactic radiation therapy. It has been reported that dogs with chemodectomas may enjoy several years of survival after treatment with conformal radiation therapy, as the metastatic rate for this tumor is reportedly very low. The reported response time of these tumors after treatment with radiation therapy are typically very slow, over several months1. This case report documents the successful treatment of a heart base tumor with stereotactic radiation therapy.
Siobhan Haney, VMD, MS, DACVR (RO), MBA
Hope Veterinary Specialists and the Veterinary CyberKnife Cancer Center
Use of three-dimensional conformal radiation therapy for treatment of a heart base chemodectoma in a dog.
J Am Vet Med Assoc. August 15, 2012;241(4):472-6.
Nicholas J Rancilio1; Takashi Higuchi; Jerome Gagnon; Elizabeth A McNiel
Radiation therapy of thoracic and abdominal tumors
Semin Vet Med Surg (Small Anim). August 1995;10(3):190-6. 32 Refs
S M LaRue1; S M Gillette; J M Poulson
Splenic hemangiosarcoma is a malignant neoplasm of vascular endothelial origin which occurs more frequently in dogs than in any other species1. It is diagnosed in middle aged to older dogs with the following breeds over-represented in published studies: German Shepherds, Golden Retrievers, Labrador Retrievers1.
Increasing evidence suggests that dysregulation of molecular pathways leading to overexpression of angiogenic growth factors and their receptors, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor, and angiopoietins, is important in the pathogenesis of this malignancy1.
The most common primary tumor site in the dog is the spleen. Other commonly reported primary tumor sites include: right atriums, skin/subcutis, liver. Hemangiosarcoma is the most common splenic neoplasm but it is by no means the only differential for splenomegaly or splenic masses in dogs. Generally in veterinary oncology we follow the double two-thirds rule for canine splenic masses in which approximately two-thirds of dogs with splenic masses will have malignant tumor, and approximately two-thirds of these malignant tumors will be hemangiosarcoma1. Other benign splenic masses can have similar gross and ultrasonographic appearance including hematoma and hemangioma1. One study reported that large masses may be more likely benign than malignant1. Due to its close association with endothelial cells, extravasation and angiogenesis of metastatic clones prevails, lending to very aggressive biologic behavior. The most common metastatic sites include: lungs, omentum, liver1.
When a splenic mass is suspected, diagnostic work-up recommended includes: comprehensive physical exam, CBC/Chemistry/PT/PTT, abdominal ultrasound, cardiac ultrasound to evaluate for right atrial masses, three view thoracic radiographs. If effusion is noted then diagnostic abdominocentesis is recommended which will often yield non-clotting blood with PCV similar or higher than the peripheral blood PCV.
A definitive diagnosis of splenic hemangiosarcoma requires surgical biopsy and histopathology. Needle aspiration cytology of suspicious masses, although simple and cost effective, may be of low diagnostic utility due to the hemodilution that usually accompanies sampling1. Needle core biopsies, as well as needle aspirates in some instances, may increase the risk of hemorrhage and subsequent seeding of tumor cells throughout the abdomen. In many cases, if there is high suspicion for malignancy, or in the case of hemoabdomen, splenectomy is recommended. Submission of large samples of the mass for histopathology is preferred to help maximize the likelihood of definitive diagnosis. In some instances, when only a small sample of the lesion is submitted, histopathology may reveal blood clots or other non-specific findings due to tumor heterogeneity (i.e. the mass lesion is not uniform, rather there are pockets of tumor cells, pockets of necrotic tissue, and blood clots throughout the mass).
Treatment of choice for splenic hemangiosarcoma is splenectomy to remove primary tumor and source for potential bleeding then chemotherapy to help slow metastatic progression. The chemotherapeutic regimen prescribed may depend on patient factors and clinician preference. Multiple protocols have been described, the majority of which utilize doxorubicin, in combination with other chemotherapeutic drugs or as single agent.1 In general dogs experience good quality of life while undergoing chemotherapy treatment. Adverse events including gastrointestinal deviations 2-5 days after treatment occur in 20-30% of dogs and myelosuppression 7-10 days after treatment occur in 15-25% of dogs1. These adverse events are typically transient and mild. Approximately 20% of dogs receiving doxorubicin chemotherapy may develop irreversible cardiomyopathy due to cumulative free radical damage to the cardiac muscle. Previous reports suggested that dogs receiving lifetime cumulative doses ranging from 180-240mg/m2 or more are at risk1. The protocols published and used by the majority of clinical oncologists are well below this cumulative dose, further reducing the risk of this adverse event.
In general splenic hemangiosarcoma is a highly malignant tumor with rapid clinical course. Median survival time of dogs receiving surgery alone is 19-86 days, while surgery with doxorubicin-based chemotherapy yields a median survival time of 141-179 days1.
Given the bleak outlook with current treatment protocols, novel adjunctive therapies are being explored. Therapy directed against angiogenesis is a hot area of research, given the endothelial derivation of this disease. Metronomic (low dose, continuous) chemotherapy is based on the fact that blood vessel endothelial cells are highly sensitive to continuous exposure to low doses of chemotherapeutic drugs2-7. There are several proposed mechanisms for the anti-angiogenic effects of metronomic chemotherapy including: (1) targeting the drug-sensitive endothelial cells of tumors, (2) inhibiting the mobilization of endothelial precursors from the bone marrow, and (3) stimulating the production of thrombospondin-1, an endogenous anti-angiogenic protein5-7. Metronomic chemotherapy has also been shown to alert the immune system of the tumor and exert anti-tumor immunity through inhibition of regulatory T cells (Tregs)8. Tregs are a subset of CD4+ lymphocytes that normally function to keep the immune system in check and prevent autoimmunity. Several studies have documented a high level of circulating Tregs in both human and canine cancer patients9-10. In these cases, Tregs prevent the patient’s endogenous immune system from attacking and destroying the cancer cells. Studies have shown that the administration of metronomic cyclophosphamide in both human and canine cancer patients selectively decreases circulating Treg numbers, thereby promoting the host immune response to destroy tumor cells(8-10). Several studies have evaluated metronomic chemotherapy treatment in dogs with hemangiosarcoma3-4,6
Yunnan Baiyao (YB), a Chinese herbal developed in the Yunnan Province of China in 1902, may also have anti-tumor properties against hemangiosarcoma. It gained popularity among Chinese soldiers during World War II for use as a haemostatic agent on the battlefield. It is composed of a variety of herbal components with one of its major components as ginseng root. Studies (human) have shown it improves clotting and enhances platelet function. There is a vast body of literature demonstrating in vitro anti-tumor activity of various cell lines (human melanoma, human colorectal, human cervical) through tumor cell inhibition and apoptosis for various components of YB. There have been no studies (human or vet) to date evaluating YB in whole form. A recent veterinary study evaluated the in vitro effects of YB on canine hemangiosarcoma cell lines. These cell lines were exposed to increasing concentration of YB in vitro. Results showed dose dependent and time dependent exposure caused significant decrease in hemangiosarcoma cell proliferation by induction of cell apoptosis11.
Medicinal mushrooms may also play a role in hemangiosarcoma treatment. Polysaccharopeptide (PSP), the bioactive agent in the medicinal mushroom Coriolus versicolor, has been shown to have anti-tumor effect in both in vitro and human clinical trials. A recent study demonstrated benefit in 15 dogs with splenic hemangiosarcoma12.
A 7 year old, castrated male, Rottweiler mix, presented to the Emergency Services at Hope Vet Specialists for acute onset of weakness and lethargy. He was reportedly normal up until the day of presentation. He had no other prior medical concerns other than mild osteoarthritis for which he received glucosamine-chondroitin. He was adopted as a puppy and had no history of travel outside NJ/PA.
Upon triage it was noted that he was tachycardic, tachypneic, had pale mucous membranes and abdominal distension with palpable fluid wave. A cursory ultrasound confirmed abdominal effusion and suspected splenic mass. A diagnostic abdominocentesis confirmed non-clotting blood with PCV of 40%. Peripheral blood PCV was 32%.
The clients elected for further stabilization and diagnostics. The patient was stabilized with IV fluids and blood transfusion. Vital signs, EKG and blood pressure were continuously monitored. CBC revealed anemia with Hct of 29%, no other significant changes. Chemistry panel revealed no abnormalities. PT/PTT were normal. Three view thoracic radiographs were negative for overt pulmonary metastasis, cardiac silhouette appeared normal size and shape. Full abdominal ultrasound revealed 8cm splenic mass, abdominal effusion, no other abnormalities. Cardiac ultrasound was negative for masses associated with the heart.
Based on diagnostic work-up, a list of differential diagnoses was established and these possibilities discussed with the client. Differentials discussed included: splenic hemangiosarcoma with secondary hemoabdomen, other splenic malignancy (other forms of sarcoma like fibrosarcoma, extraskeletal osteosarcoma, etc), or benign splenic lesion (hematoma, extramedullary hematopoiesis). Our top concern was for hemangiosarcoma, given patient age, breed, and no prior history of trauma. As such an oncology consultation was recommended prior to surgery. Treatment options with associated prognosis were discussed including: abdominal exploratory surgery with chemotherapy (if malignancy confirmed on histopathology) with average survival time of 6-9 months vs surgery alone with average survival time of 1-3 months if malignant tumor vs palliative supportive care with IV fluids and blood transfusion which will provide merely a ‘band-aid’ of relief of symptoms for a period of hours to days vs humane euthanasia.
Clients elected for abdominal exploratory surgery. Once the patient was fully stabilized he was taken to surgery where a bleeding splenic mass was confirmed. Routine splenectomy was performed. The remainder of the abdomen was evaluated and negative for other lesions. Continuous EKG and blood pressure were monitored throughout the surgery and in the post op period for up to 36 hours. The patient recovered uneventfully with no signs of hypotension nor cardiac arrhythmia. Norton returned home with his family 48-hours after splenectomy surgery.
Histopathology confirmed splenic hemangiosarcoma. He returned to Hope Vet Specialists 10-days post op for suture removal and to start chemotherapy. Clients reported that the patient had returned to his normal routine and was fully recovered from surgery. Chemotherapy plan discussed with clients included multi-agent treatment utilizing doxorubicin chemotherapy given every 2 weeks for 5 treatments, metronomic (low dose) oral chemotherapy (cyclophosphamide or chlorambucil) starting at the time of second doxorubicin treatment and continuing for six months, I’m Yunity (Colorius vericus mushroom supplement) starting at the time of third doxorubicin treatment, and Yunnan Bia Yao starting at the time of first doxorubicin treatment. The metronomic chemotherapy and supplements were staged in an effort to reduce risk of potential side effects from adding multiple therapeutics all at one time.
Routine CBC and PCV were monitored prior to each IV chemotherapy treatment. Recheck exams including CBC and Chemistry, three view thoracic radiographs, abdominal and cardiac ultrasound, to re-evaluate for metastasis and progression of the disease, were performed every 3 months. The patient tolerated the treatments well and he enjoyed an excellent quality of life with his family both during and after the treatments.
Twelve months (yes, 12-months) post diagnosis with hemangiosarcoma, routine restaging exam confirmed a new cavitated liver mass that had not been present on the ultrasound exam 3-months prior. The remainder of the staging tests (CBC and chemistry, three view thoracic radiographs and cardiac ultrasound) were normal. Due to concern for hemangiosarcoma metastasis, a needle aspirate of the liver mass was not performed in an effort to mitigate risk for mass rupture with subsequent bleeding and tumor cell seeding in the abdominal cavity. It is not common for a patient with hemangiosarcoma to present with just one metastatic lesion. It was discussed with the client that the new liver mass may be a separate issue unrelated to the hemangiosarcoma or there may be metastatic lesions present that are too small to be detected on routine radiography and ultrasound or the patient is lucky enough to have just one metastatic nodule. We discussed the following options including: more sensitive diagnostic imaging such as CT of the abdomen and thorax to potentially rule out smaller metastatic lesions or recheck focal ultrasound of the liver in 4 weeks. Clients elected to pursue CT scan which confirmed only 1 liver mass, the remainder of the abdomen and thorax were negative for lesions. Immediately after CT scan the patient was taken to abdominal exploratory surgery. The liver mass and associated liver lobe were removed, the remainder of the abdomen was negative for lesions. He recovered uneventfully from surgery.
Histopathology of liver mass confirmed metastatic hemangiosarcoma. It was discussed with client that while the patient’s disease had progressed, and metastatic lesions are often more aggressive than the primary lesion, the disease is not behaving as the typical hemangiosarcoma given that he had outlived the median survival time by 3-6 months and only one known metastatic nodule was apparent. Since he tolerated the first round of chemotherapy well and his disease seemed to be sensitive to therapy with a better than anticipated outcome, additional chemotherapy was encouraged. Due to potential dose accumulating cardiotoxic effect of doxorubicin, further treatment with this agent was limited. As such we discussed alternative chemotherapy protocols including carboplatin, given every 3 weeks for 4 treatments. This was combined with metronomic oral chemotherapy and Chinese herbal supplements (I’m Yunity and Yunnan Bia Yao). Routine CBC and PCV was performed prior to each treatment. He tolerated these treatments well with minimal adverse events. We continued to monitor for progression of disease with recheck three view thoracic radiographs as well as abdominal and cardiac ultrasound every 3 months.
Six months later (now 18-months post initial diagnosis with hemangiosarcoma), the presented to the Emergency Service for acute onset of lethargy and weakness. Cursory ultrasound and diagnostic abdominocentesis confirmed hemoabdomen. Full abdominal ultrasound confirmed one new liver mass, the remainder of the abdomen and thoracic radiographs were normal. Further treatment including CT scan with surgical exploratory surgery vs trial treatment with chemotherapy alone was discussed. Based on the course of his disease, the first metastatic lesion appeared 12 months after diagnosis and then second in about half that time 6 months later. From this information we estimated that further treatment with surgery and chemotherapy may provide an additional 3-4 months of remission. Clients however elected for no further treatment as the patient was also experiencing diminished mobility from arthritis and thus a decline in quality of life.
This case exemplifies the benefits of treatment for canine hemangiosarcoma. While this patient’s outcome was better than average, the majority of dogs undergoing treatment for this disease experience an excellent quality of life for an extended period of time beyond that which they would have without treatment.
Submitted by: Kate Vickery, VMD, MS, DACVIM (Oncology), CVA
- Hemangiosarcoma. In Withrow and MacEwen’s Small Animal Clinical Oncology. 5th ed. 2013. Pages 679-688.
- Buckstein, R, et al. High-dose celecoxib and metronomic ‘low-dose’ cyclophosphamide is an effective and safe therapy in patients with relapsed and refractory aggressive histology Non-Hodgkin’s Lymphoma. Clin Cancer Res 2006; 12(17): 5190-5198.http://www.ncbi.nlm.nih.gov/pubmed/?term=High-dose+celecoxib+and+metronomic+%E2%80%98low-dose%E2%80%99+cyclophosphamide+is+an+effective+and+safe+therapy+in+patients+with+relapsed+and+refractory+aggressive+histology+Non-Hodgkin%E2%80%99s+Lymphoma.+Clin+Cancer+Res+2006
- Leach TN, et al. Prospective trial of metronomic chlorambucil chemotherapy in dogs with naturally occurring cancer. Vet Comp Oncol. 2012 Jun;10(2):102-12. http://www.ncbi.nlm.nih.gov/pubmed/?term=Prospective+trial+of+metronomic+chlorambucil+chemotherapy+in+dogs+with+naturally+occurring+cancer.+Vet+Comp+Oncol.+2012
- Tripp CD, et al. Tolerability of metronomic administration of lomustine in dogs with cancer. J Vet Intern Med. 2011 Mar-Apr;25(2):278-84. http://www.ncbi.nlm.nih.gov/pubmed/?term=Tolerability+of+metronomic+administration+of+lomustine+in+dogs+with+cancer.+J+Vet+Intern+Med.+2011
- Elmslie RE, et al. Metronomic therapy with cyclophosphamide and piroxicam effectively delays tumor recurrence in dogs with incompletely resected soft tissue sarcomas. J Vet Intern Med. 2008 Nov-Dec;22(6):1373-9.http://www.ncbi.nlm.nih.gov/pubmed/?term=Metronomic+therapy+with+cyclophosphamide+and+piroxicam+effectively+delays+tumor+recurrence+in+dogs+with+incompletely+resected+soft+tissue+sarcomas.+J+Vet+Intern+Med.+2008
- Lana S, et al. Continuous low-dose oral chemotherapy for adjuvant therapy of splenic hemangiosarcoma dogs. J Vet Intern Med. 2007 Jul-Aug;21(4):764-9.http://www.ncbi.nlm.nih.gov/pubmed/?term=Continuous+low-dose+oral+chemotherapy+for+adjuvant+therapy+of+splenic+hemangiosarcoma+dogs.+J+Vet+Intern+Med.+2007
- Kerbel RS. The anti-angiogenic basis of metronomic chemotherapy. Nature Reviews. Cancer 2004; 4: 423-436.http://www.nature.com/nrc/journal/v4/n6/full/nrc1369.html
- Burton JH, et al. Low-dose cyclophosphamide selectively decreases regulatory T cells and inhibits angiogenesis in dogs with soft tissue sarcoma. J Vet Intern Med. 2011 Jul-Aug;25(4):920-6.http://www.ncbi.nlm.nih.gov/pubmed/?term=Low-dose+cyclophosphamide+selectively+decreases+regulatory+T+cells+and+inhibits+angiogenesis+in+dogs+with+soft+tissue+sarcoma.+J+Vet+Intern+Med.+2011
- Wilke CM, et al. Prognostic significance of regulatory T cells in tumors. Int J Cancer 2010; 127: 748-758.http://www.ncbi.nlm.nih.gov/pubmed/?term=Prognostic+significance+of+regulatory+T+cells+in+tumors.+Int+J+Cancer+2010
- Biller, BJ. Use of FoxP3 expression to identify regulatory T cells in healthy dogs and dogs with cancer. Vet Immunol Immunopathol 2007; 116: 69-78.http://www.ncbi.nlm.nih.gov/pubmed/?term=Use+of+FoxP3+expression+to+identify+regulatory+T+cells+in+healthy+dogs+and+dogs+with+cancer.+Vet+Immunol+Immunopathol+2007
- Wirth, K, et al. In Vitro Effects of Yunnan Biayao on Canine Hemangiosarcoma Cell Lines. Vet Compar Onco 2014; 1-13. https://www.researchgate.net/publication/263511754_In_vitro_effects_of_Yunnan_Baiyao_on_canine_hemangiosarcoma_cell_lines
- Brown DC & Reetz J. Single Agent Polysaccharopeptide Delays Metatstases and Improves Survival in Naturally Occurring Hemangiosarcoma Evid Based Comp & Alt Med 2012; 1-8 http://www.hindawi.com/journals/ecam/2012/384301/abs/
Case report: August is an 11 year old female spayed Labradoodle that presented to the oncology service for consultation regarding a recently diagnosed soft tissue sarcoma. A semi-firm soft tissue mass was noted along the cranial aspect of her right distal radius and was thought to have shown moderate growth to a size of approximately 3-4 cm over the previous 4-5 months. She also had several other dermal and subcutaneous masses that were softer and previously diagnosed as lipomas. The right forelimb mass was marginally excised by her primary veterinarian and histologic evaluation of submitted tissue was consistent with an incompletely excised (both lateral and deep margins) grade II (mild to moderate anisocytosis/anisokaryosis, mitotic index = 7, <50% necrosis) soft tissue sarcoma (STS), thought most consistent with a hemangiopericytoma. At surgery, the mass was noted to have ill-defined deep extension that was adherent to the underlying tendons.
At oncology consultation, the incision was well healed and she appeared otherwise healthy aside from generally decreased mobility. Full blood work (CBC/Chemistry) was unremarkable and three-view thoracic radiographs were free of pulmonary metastatic disease. In light of the residual local disease following initial surgery, a discussion was had regarding the available options for follow up therapy, which included:
- Curative intent surgery (right forelimb amputation)
- Full course radiation therapy
- Conservative surgery (scar revision)
- Metronomic chemotherapy
- Monitoring without further therapy
The reported risk of local recurrence for marginally excised grade II STS is 34%1, therefore an incompletely excised tumor of this grade would be predicted to have an equal to or even higher risk of regrowth. The metastatic rate of grade II tumors is somewhat unclear, but reported to be anywhere from 7% to 33% across studies2-5, although it’s generally accepted that it’s more likely toward the lower end of that range (<20%). Therefore, less priority was given to therapeutically addressing the modest risk of metastasis for August’s tumor. However, additional local therapy was recommended.
Because of August’s age and concurrent orthopedic disease, as well as the recognition that local tumor regrowth was possible not a guarantee, an aggressive approach with full limb amputation was considered an over-treatment in this case, although it would certainly have the best chance at completely eradicating her residual disease. The next most aggressive adjuvant treatment option, full course radiation therapy, is also quite effective, with one study finding the rate of local control at 3 years to be 85% with the combination of surgery and adjuvant radiation, although 31% of dogs still had local tumor recurrence6. Another study found just a 17% risk of tumor regrowth with a median time to local tumor recurrence of 700 days7 after radiation for incompletely excised STS. However, the requirement for 15-18 consecutive daily anesthetic events for this therapy made adjuvant radiation an unfavorable option for this particular owner and dog.
The third option reviewed was the possibility for a second surgery that would be aimed at removing as much tissue around and underneath the scar as possible. The standard approach would be to remove 2-3 cm of normal tissue around the lateral margin and an intact fascial plane deep, but this is not always possible, especially with a second surgery. Evidence to suggest that re-excision surgery might be a favorable option for August stems from a 2008 study8 that examined the outcomes of dogs undergoing marginal excision of low-grade spindle cell sarcoma of the extremities. In this study, about 30% of dogs had clean excision, ~30% were clean but close, and ~30% of tumors had dirty margins. However, the local recurrence rate was only 10.8%. Thus, even if only narrow margins were achieved with a second surgery, it would likely lower August’s risk of local tumor recurrence overall.
It was discussed that there were a few possible disadvantages to this surgical approach. First, achieving clean margins may not be possible given the reported invasiveness of this tumor, particularly at the deep margin. This information would not be determined until the final biopsy report became available. Interestingly, a 2007 JAVMA study9 examined the outcomes of dogs undergoing primary re-excision after incomplete resection of soft tissue sarcomas and found that even though all tumors were initially incompletely excised (and thus should have contained residual tumor at the surgery site), only 22% had residual tumor identified in the second biopsy sample. This might be due to a couple of reasons. First, it can be difficult to identify small populations of residual neoplastic mesenchymal cells in beds of active granulation tissue, which are also composed of mesenchymal cells (fibroblasts). Additionally, in veterinary pathology, only a few sections (typically 4 or less) are typically examined as part of histologic analysis, and thus foci of residual tumor cells could be overlooked in a large biopsy. The local recurrence rate following a second surgery in the Bacon et al. JAVMA study was just 15%. The authors argued that a major advantage of such an approach is that for most dogs, a favorable long-term outcome was achieved without radiation therapy or amputation. Fifty-one percent (51%) of dogs in this study had their tumor located on a limb, like August.
A second possible disadvantage to a scar revision surgery was that secondary surgeries in this region sometimes leave an open wound that requires healing by second intention and even skin grafts because of the scarcity of excess tissue available for surgical wound closure. Nevertheless, a recent study10 evaluated second intention healing after wide local excision of soft tissue sarcomas in the distal aspects of the limbs of dogs and found that 93.5% of the wounds healed completely by second intention over a median time of 53 days, while just 6.5% of dogs required a free skin graft. Only 3.2% of dogs developed local tumor recurrence. The rates of short-term and long-term complications of wound healing were modest (22.6% and 9.7%, respectively) and all were managed conservatively.
For August, a scar revision surgery was elected and went without complication. Lateral margins of 2 cm were obtained along with resection of as much deep tissue as was possible without disrupting the normal tendon anatomy; en bloc resection of an intact fascial plane was not feasible because the deep tissue was already disturbed from the initial surgery. Fortunately, primary incisional closure was achieved. Histologic evaluation confirmed residual grade II STS (peripheral nerve sheath origin – i.e. hemangiopericytoma) with a low mitotic rate, but this time the lateral margins were clean by 4-5 mm and only the deep margin was considered incomplete in a few areas where cells extended to the edge of the section. August recovered very well and owner was pleased with the cosmetic and functional outcome of the second surgery. Although her tumor was still not completely excised, the second surgery was considered successful because it eradicated residual tumor that was large enough to be detected microscopically, and thus was likely enough to have led to local tumor regrowth if further therapy had not been pursued.
Following healing from the second surgery, adjuvant therapy was discussed and priority was given to metronomic chemotherapy, which involves the use of low dose daily oral therapy with either cyclophosphamide (Cytoxan) or chlorambucil (Leukeran), typically along with a non-steroidal anti-inflammatory drug (NSAID). Preferred in the setting of microscopic residual disease, this form of therapy focuses on disrupting the vascular environment so that dormant tumor cells do not gain the blood supply needed to grow (antiangiogenesis). Metronomic chemotherapy has also been shown to have immunomodulatory effects that help the body detect and eradicate tumor cells. A study evaluating the use of metronomic Cytoxan and piroxicam as adjuvant to incompletely excised grade II STS in dogs showed that the addition of this therapy significantly increased the disease-free interval (DFI), or time before which the tumor recurred11. Specifically, the median DFI for dogs receiving metronomic had to be estimated because not enough dogs in this group had tumor recurrence, and the predicted median DFI was well over a year (410 days). Conversely, the median DFI was just 211 days for dogs that did not receive metronomic therapy following incompletely tumor excision. Interestingly, all dogs not receiving metronomic had tumor recurrence. Side effects associated with low dose chemotherapy are minimal and reversible, therefore it serves as a nice option for owners that want to pursue something that may have benefit and is not too intense on the patient.
August was started on metronomic therapy and a monitoring regimen of periodic physical examinations, blood work, and thoracic radiographs was instituted. She continues to tolerate therapy and thrive clinically, with no evidence of tumor recurrence at the 9-month mark. A total of one year of metronomic therapy is planned; thereafter simple monitoring will be continued. This case serves as an excellent example of how sometimes the most aggressive approach may not always be necessary or indicated for a particular patient, and that newer approaches such as those that combine more conservative surgery with metronomic therapy can serve as reasonable and potentially successful substitutes for more invasive interventions in older patients or those with concurrent diseases.
Christine Mullin, VMD, Diplomate ACVIM (Oncology)
Hope Veterinary Specialists, Malvern
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