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Soft Tissue Sarcomas

Description- Soft tissue sarcomas are a diverse group of mesenchymal tumors (cells that develop into connective tissues like blood vessels, blood and lymphatic blood vessels). They account for 15% of all skin and subcutaneous (lying under the skin) tumors in the dog. Statistics put the figures at 35 per 100,000 dogs who are at risk of contracting the disease. Most of these soft tissue sarcomas are solitary lesions. They can be classified based on certain histological similarities. Since these tumors are of mesenchymal origin, they arise from connective tissues like muscle, adipose, neurovascular, fascial, and fibrous tissue. They could be either benign or malignant in nature. Malignant lesions consist of fibrosarcoma, peripheral nerve sheath tumor, myxosarcoma, undifferentiated sarcoma, liposarcoma, histiocytic sarcoma and rhaddomyosarcoma. Although skin and subcutaneous tissues are the most common, they may develop from any anatomical site of the body. The common features of these sarcomas include:

• They usually appear as encapsulated but in reality they are not. They are undifferentiated and proliferate through and along facial planes. They are locally aggressive.
• They tend to recur after surgical extirpation.
• They tend to spread through the blood in up to 20% of cases.
• They generally don’t metastasize to regional lymph nodes.
• Tumors more than 5cm in diameter are not responsive to chemotherapy and radiation therapy.

These tumors are not easy to diagnose. They have several overlapping features among themselves and also with tumors of other histiogenesis. Soft tissue sarcomas are mostly seen among larger breeds. Reports have shown that male dogs have a higher predisposition.

Types of tumor- Based on their similar histologic features and biologic behavior, the tumors can be divided into different types. For the sake of convenience some pathologists have recommended the use of a more generic term like soft tissue sarcoma or spindle cell tumor of canine soft tissue.

Tumors of Fibrous Origin
Nodular fasciitis (fibromatosis, pseudosarcomatous fibromatosis)
Nodular fasciitis is a non-malignant lesion. It develops from the subcutaneous (continuous layer of connective tissue over the entire body between the skin and the deep structures of the body like the muscles) fascia or superficial portions of the deep fascia (connective tissue that resides throughout the body giving it support and form and connecting all the tissues and organs in dogs) in dogs. They are usually nodular, undifferentiated and locally aggressive. Infantile desmoid type fibromatosis (uncommon locally invasive tumor) is a variant of nodular fasciitis. Wide surgical extirpation of these tumors is usually curable. There is a possibility of recurrence, if the tumor has been partially resected. They generally don’t spread.

Fibrosarcoma
Most fibrosarcomas develop from the skin, subcutaneous tissue or oral cavity. They represent malignant fibroblasts. Tumors are generally well differentiated. They represent spindle shaped (thickest in the middle and tapering at both ends) tumor cells with little cytoplasm (part of a cell enclosed within the plasma membrane [it separates the inside of the cell from the outside]). Golden retrievers and Doberman pinschers of older breeds have a higher predisposition. Sometimes histologically low grade, yet biologically high grade tumors are seen in the oral cavity. They have a propensity to grow very large and infiltrate deeper structures including bone. However, metastasis is not very common in this case.  

Tumors of the Peripheral Nerves
Peripheral nerve sheath tumor
These are generally malignant lesions of nerve sheath origin. They are known as neurofibrosarcoma, malignant schwannoma and hemangiopericytoma. They can arise in any part of the body. These tumors involve the peripheral nerves of the brain and spinal cord or the nerves originating from their roots. Wide surgical extirpation of the peripheral nerve tumors is usually curative. These tumors infiltrate underlying fascia, muscle and deeper tissues. Although these tumors are malignant, the rate of metastasis is quite low. There is a very potent chance of recurrence following conservative surgery (surgery designed to preserve or to remove with minimal risk, diseased or injured organs, tissues, or limbs). They grow slowly and can vary in range from 0.5 cm to more than 10 or 12 cm in diameter. Those that are located in the axial region may cause compression of nerves. The clinical signs include muscle atrophy, paralysis and pain.

Tumors of Adipose Tissue
Lipoma
Lipomas are non-malignant lesions that originate from adipose tissues (body fat). The variants of lipoma include angiolipoma and angiofibrolipoma. Lipomas are relatively common in older breeds. They usually develop from subcutaneous locations. Sometimes they also originate in the thoracic cavity, spinal canal, abdominal cavity and the vulva (external genital organs of a female dog) and vagina of dogs. A majority of the lipomas don’t need to be resected surgically.

Intermuscular lipoma
They originate from the semimembranosus (muscle in the back of the thigh one of the hamstrings) or semitendinosus (muscle in the back of the thigh, the medial of the hamstrings) muscles. Intermascular lipomas generally grow slowly. They appear as a fixed mass and occasionally cause lameness.

Infiltrative lipoma
Their occurrence is rather rare. They comprise well-differentiated adipose tissues. It is very difficult to differentiate these tumors from the more common ones.They are usually benign and also don’t metastasize. However, they are locally invasive and
infiltrate neighboring muscles.Treatment consists of amputation and radiation therapy.

Liposarcoma
They are rare malignant tumors that arise from lipoblasts (embryonic fat cell). As contrary to common belief, liposarcomas are not the malignant forms of lipoma. Liposarcomas have been mostly reported in older breeds. They are usually reported in subcutaneous locations especially along the ventrum (belly) and extremities (limbs). Liposarcomas may also originate from the primary sites like the bone and the abdominal cavity. Liposarcomas are generally firm and poorly differentiated. They are locally invasive with a low metastatic potential. However, they have been reported to spread to the lungs, liver, spleen and bone.

Tumors of the Smooth Muscle
Leiomyomas leimyosarcomas
They originate from the smooth muscle cells. Although affected sites include spleen, liver, genitourinary tract, retroperitoneal space, vessel wall and sub-cutaneous tissue, the gastrointestinal tract bears the brunt. The paraneoplastic syndrome includes hypoglycemia (state produced by a lower than normal level of blood glucose), nephrogenic diabetes insipidus (a form of diabetes insipidus, characterized by high glucose levels) and secondary erthyrocytosis (also called polycythemia, it is defined by an increase in total red blood cell number, packed cell volume (PCV), and hemoglobin concentration above reference intervals). Leiomyomas are non-malignant in character, small and well circumscribed. They are also commonly found in the vagina. They protrude from there and are generally hormone dependant. Ovarihysterectomy is the treatment mostly recommended for dogs with vaginal leiomyomas.

On the other hand, leiomyosarcomas are cancerous in nature. They have a tendency to spread depending upon the site from which they have originated. Tumors arising from the liver have 100% metastatic potential. While those originating from other abdominal sites and smooth muscles have 50% and 0% metastatic potential respectively. For gastrointestinal leiomyosarcoma, the most common metastatic sites include regional lymph nodes, mesentery and liver. Others include the spleen, kidneys and peritoneum. This is a pretty common gastrointestinal tumor and mostly affects the jejunum and  cecum (it is a pouch, connecting the ileum with the ascending colon of the large intestine). But the whole gastrointestinal tract can be brought under attack from the esophagus to the rectum. Some researchers call them gastrointestinal stromal tumors. They arise from interstial cells of Cajal (type of cell found in the gastrointestinal tract) or vascular or gastrointestinal smooth (involuntary non-striated muscles)
muscle cells.

Older breeds have a higher predisposition for leiomyosarcoma, while for leiomyomas, males dogs are believed to have a higher incidence. These tumors mostly affect the stomach and the clinical signs include inappetance, weight loss, vomiting, diarrhea, polyuria, polydipsia, anemia and hypoglycemia (lower than normal level of blood glucose). Vets normally opt for surgery for dogs suffering from leiomyosarcoma. They make perforations in the intestine with localized to diffuse peritonitis (inflammation of
the peritoneum).

The outcome is good with complete surgical extirpation. But in some cases there have been reports of a recurrence following incomplete surgery of a gastric leiomyoma and cutaneous leiomyosarcomas. Dogs that went through the knife for gastrointestinal leiomyosarcoma showed a median survival time of 1, 2 and 3 years in 75, 66 and 60% of cases. In one of the cases, a dog with metastasis at the time of survival showed a median survival time of 21.7 months. Reports indicated that dogs undergoing complete surgical resection for with median survival time showed a survival time of 1, 2 and 3 year survival rates of 75 and 66% respectively. However, other reports indicated that metastasis has a direct impact on survival time. Dogs with splenic leiomyosarcoma and hepatic leiomyosarcoma have a median survival time of 8 months and 0 months respectively.

Tumors of Skeletal Muscle
Rhabdomyosarcoma
These tumors are generally malignant in nature and they arise from myoblasts (the type of cells found in the muscles) primitive mesenchymal cells (multipotent cells that have the power to divide into different cell types). They normally originate from the skeletal muscle of the tongue, larynx, myocardium (muscular middle layer of the heart) and urinary bladder. They are highly proliferative and have a fairly good metastatic potential. The sites of metastasis include the lungs, liver, spleen, kidneys and adrenal glands.

They can be histologically classified into embryonal, botryoid (having numerous protuberances resembling a bunch of grapes), alveolar and pleomorphic (having many forms).

Embryonal rhabdomyosarcoma originates in the head and neck region like the tongue, oral cavity and larynx. Older dogs have a higher incidence. Botryoid rhabdomyosarcoma originates in the urinary bladder. Breeds like Saint Bernard have a higher predisposition.

Dogs treated with radiation therapy, chemotherapy and surgical extirpation have yielded positive results.

Tumors of Vascular and Lymphatic Tissue
Lymphangiosarcoma
These are uncommon lesions originating from lymphatic endothelial cells (thin layer of cells lining the interior surface of blood vessels). They are normally soft, cystic and edematous (excessive accumulation of fluid in tissue spaces or body cavity) that are found in the sub-cutis (deeper part of the dermis). The clinical signs include extensive edema and drainage of lymph through the skin or a cystic mass. Lymphangiosarcoma have a fairly high metastatic potential. A dog which underwent surgery, had a local recurrence. He was treated with a chemotherapy protocol of doxorubicin. There was no report of any recurrence 9 months following remission.

Hemangioma
They originate from the vascular endothelial origin (single pavement layer of cells which line the luminal surface of the cardiovascular system). Hemangiomas are non-malignant lesions originating from the skin, liver, spleen, kidneys, bone, tongue and heart. Ultraviolet radiation affects short-haired dogs with poorly pigmented skin. Although these are non-malignant lesions they can cause severe anemia.

Hemangiosarcoma
Hemangiosarcomas are highly malignant in nature. Visceral organs (internal organ of an animal in particular like the internal organ of a thorax or abdomen) like the spleen, right atrial appendage (small conical muscular pouch attached to the right atrium of the heart), liver, skin, pericardium, lung, kidneys, oral cavity, muscle, bone, oral cavity, genitourinary tract (organ system of the reproductive organs and urinary system),  peritoneum and retro peritoneum (space in the abdominal cavity behind the peritoneum) are the common sites from hemangiosarcomas originate. Cutaneous hemangiosarcoma occurs in poorly pigmented, light-haired dogs on the ventral abdomen and preputial (exocrine glands located in front of the genitals of mammals) region of dogs. Wide surgical excision is the treatment of choice for dogs with hemangiosarcoma.

At the initial stage dogs with cutaneous or dermal hemangiosarcoma that underwent complete surgical extirpation showed a survival rate of 78% and a median survival time of 780 days. Metastasis was reported in distant dermal sites but in dogs with a median survival time of 780 days. But dogs suffering from stage II cutaneous hemangiosarcoma, have a metastatic rate of 60% and a median survival time of 172 to 307 days. Around 23% of them undergo complete surgical excision owing to the large size of the tumors.

Tumors of Synovial Tissue
Synovial cell Sarcoma
It is a tumor of malignant nature originating from the synoviocytes (cells of the synovial memebrane) of the joint capsule (sac like fibrous tissue that envelops a synovial joint) and tendon sheath (sheet of membrane around a tendon). Synoviocytes are basically of two types- phagocytic (phagocytes are white blood cells that protect the body by ingesting harmful foreign particles like bacteria and dead cells) and pinocytic (a mechanism by which cells ingest extracellular fluid and its contents; it involves the formation of sheaths by the cell membrane, which close and break off to form fluid-filled vacuoles). Due to the high metastatic nature of synovial cell sarcoma, they normally attain devastating proportions in the first or second stages only. So it’s chance of moving on to the next stage is nullified. Hence they have been classified as monophasic and biphasic. However, this classification has been taken from human oncology and not from small animal medicine.

The diagnosis of synovial cell sarcoma is riddled with controversies. So, with the help of immunohistochemistry, doctors differentiate synovial cell sarcoma from other joint tumors, although occurrence of the latter is very limited. But some investigators have raised objection to this, saying that the histological grading of synovial cell sarcoma provides insight into the outcome of the disease. Synovial cell sarcoma mostly spreads to the lungs and the regional lymph nodes.

These tumors are highly proliferative have a fairly good metastatic potential. Reports suggest that the due to the aggressive nature of the disease in approximately 32% of cases, the dogs were presented with metastasis at the time of diagnosis.

Middle aged breeds are mostly affected. No sex predilection has been noted so far. Flat coated dogs like Golden retrievers are over represented. It affects the larger joints, elbow, stifle (joint of the hind leg) and shoulder but any joint can be affected.

The most common clinical symptom is lameness. Vets mostly resort to limb amputation in this case. But chances of recurrence following amputation are quite high. This is known as ‘stump recurrence’. In order to avoid local recurrence, the vets should perform the amputation at a very high level. The scope of chemotherapy has not been properly investigated in dogs. But some reports have pointed to the success of doxorubicin based chemotherapy protocols in non-metastatic synovial cell sarcoma.

The outcome depends upon certain factors like the grade, the rate of metastasis and the extent of treatment. According to reports dogs diagnosed with lymph node and lung metastasis showed a median survival time of 6 months. But dogs not diagnosed with metastasis at the time of detection, showed a median survival time of 36 months or greater. Dogs that undergo amputation show a median survival time of 850 days. While dogs with grade III synovial cell sarcoma, survive only 7 months.

Tumors of uncertain histiogenesis
Myxosarcoma
Myxosarcomas are “low grade” soft tissue sarcomas originating from the connective tissues of the body. They are locally infiltrative. But they are less likely to metastasize. If there is no evidence of metastasis, the vets resort to complete surgical removal. Or sometimes for better results they also combine surgery with radiation therapy. It is normally very difficult to get rid of a large tumor on a limb with surgery by itself short of an amputation.

Malignant mesenchymoma
It is an uncommon soft tissue sarcoma. Mesenchymoma normally affects the lungs, thoracic wall, liver, spleen, kidney, digits and soft tissues. They grow very slowly and attain mammoth proportions. Splenic mesenchymomas have a better outcome than other forms of splenic sarcomas and they showed a median survival time of 12 months in 50% of cases.

Symptoms- They present themselves as a soft mass originating from anywhere in the body. In some cases where the tumors grow rapidly, intratumoral hemorrhage and necrosis (premature death of cells) are noticed. However, hypoglycemia is very commonly seen in dogs with smooth muscle tumors. For tumors which arise in the abdomen and the gastrointestinal tract, vomiting, diarrhea and melena (black feces associated with gastrointestinal hemorrhage) are quite common. Symptoms like weight loss and anorexia are pretty common. Since leiomyosarcomas arise from the gastrointestinal tract, spleen and urogenital tract, they result in intestinal obstruction and perforation that eventually leads to peritonitis (defined as inflammation of the peritoneum). Rhabdomyosarcomas that occur in young dogs mostly arise from the bladder. The clinical signs include hematuria (blood in the urine), dysuria (urge to urinate frequently) and hypertropic osteopathy (bone disease secondary to disease in the lungs). The clinical signs for peripheral nerve sheath lesions may include lameness, muscle atrophy (decrease in the mass of muscle) and paralysis. Since these lesions are located axially, it is not possible to diagnose them in the initial stages. Therefore clinical signs are not distinct unless they have grown very large.

Diagnostic techniques- Firstly it is very important to know which type of tumor the dog is suffering from as well as its histologic grade before undertaking any work-up. But for any type of tumor the routine examinations include hematologic and serum biochemical blood tests, three-dimensional radiographs and regional imaging. Blood tests are generally found to be within the normal reference range, but abnormalities like anemia, thrombocytopenia (presence of relatively few platelets in blood) are seen in dogs with histiocytic sarcoma and hemangiosarcoma.

Fine needle aspirates are taken for evaluation of the tumor but it's efficacy remains under scrutiny. It is not regarded as a fool-proof method of differentiating reactive fibrous tissues (dense tissue found in various parts of the body with very few living cells) from soft tissue sarcomas.

Imaging studies are essential because without them doctors would not be able to plan out the exact course of treatment. Three-dimensional imaging techniques like computed tomography and magnetic resonance imaging are important for determining the stage of the disease. Other imaging modalities like survey radiographs, ultrasonography, angiography (helps in visualizing the inside or lumen of blood vessels or other organs of the body) and nuclear scintography.  

For staging the metastatic disease, doctors resort to thoracic radiographs, abdominal ultrasnography, advanced imaging, fine needle aspirates or biopsy of regional lymph nodes. Three dimensional radiographs are important because they help to find out whether the disease has metastasized to the lungs or not. In typical soft tissue sarcomas, lymph node metastasis is not common. So, fine needle aspirates or regional biopsy of lymph nodes should be taken only if they are found to be abnormally swollen.

Abdominal imaging helps to detect intra-abdominal metastasis if there is any.

Treatment- Surgery is the treatment of choice since these tumors are quite aggressive. This is the best way of controlling the tumor locally. The surgical margins should be wide and the tumor completely resected. But in case the tumor has not been extirpated fully, a second surgery can be performed. The scar of the surgery is considered highly neoplastic. So, the whole surgical wound is subjected to irradiation.

Radiation therapy can be used in combination with surgery. Marginal surgical resection together with radiation therapy offers a good alternative for limb amputation in extremity soft tissue sarcoma. For best possible results, radiation therapy is normally started 7 days post operatively to minimize complications that may arise from radiation. Full-course fractionated protocols like 3.0 to 4.2 Gy on a Monday-Friday or Monday-Wednesday-Friday schedule totaling to 42 to 63 Gy are recommended. It might give rise to complications like moist desquamation (thinning of the skin) but is hardly visible.

The outcome is very satisfying with a median survival time of 700-798 days. Reports suggested local tumor recurrence in 5%-30% dogs by 1 year and 16-60% dogs in the long term. It has been observed that the median survival time for dogs treated for non-oral soft tissue sarcomas is 2270 days.

In the earlier instances we saw how radiation can act as an attractive means of treatment when combined with incomplete surgical resection. But radiation can also be used alone for pain alleviation. Radiation can be used alone with a recommended dose of more than 50 Gy. Reports showed that with this dose, tumor control was achieved for one year in 50% of dogs. But it slid to 33% after 2 years. However, we don’t know much about the viability of its usage as the sole form of treatment.

In some cases, irradiation combined with hyperthermia (condition of excessive heat created artificially using drugs) achieved local control of tumors and the median survival time was found to be 750 days. But if the tumors grow very large in size, hyperthermia cannot be used. Moreover local hyperthermia doubles the chances of metastasis.

Preoperative radiation therapy is becoming more frequent in veterinary medicine because of certain factors like smaller field of radiation, the inactivation of a large number of peripheral tumor cells and the reduction of the tumor size.

Although efficacy of chemotherapeutic protocols on dogs with soft tissue sarcomas remains to be explored, doxorubicin-based protocols either alone or in combination with cyclophosphamide have yielded the most promising results. However, the effectiveness of doxorubicin alone or in combination with either vincristine, or cycloposphamide has been found to be almost similar.

Prognosis- The outcome for soft tissue sarcomas is usually good. The median survival for dogs with surgery varies from 1416 days following surgery to 2270 days with surgery and radiation therapy. But ultimately 33% dogs succumb to tumor related causes.

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Reference

Withrow and MacEwen’s Small Animal Clinical Oncology- Stephen J. Withrow, DVM, DACVIM (Oncology), Director, Animal Cancer Center Stuart Chair In Oncology, University Distinguished Professor, Colorado State University Fort Collins, Colorado; David M. Vail, DVM, DACVIM (Oncology), Professor of Oncology, Director of Clinical Research, School of Veterinary Medicine University of Wisconsin-Madison Madison, Wisconsin