Cancer Presentation

Sarah E. Sheafor, DVM, DACVIM (Oncology)
SouthPaws Veterinary Specialists and Emergency Center

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Diagnostics Methods:

• Examination.  Visual examination of a lump, along with careful palpation, can give the doctor clues as to its nature.  A comprehensive examination of the patients for other lumps and/or complications which may be associated with certain tumors is the first step in the diagnostic process.
• Fine needle biopsy and cytology.   Insertion of a fine needle into the lump allows for cells to be removed and placed on a slide for examination.  While some tumors cannot be diagnosed utilizing this method even when examined by expert cytologists, a significant number can be identified, and sometimes their degree of malignancy can be assessed.  A simple and quick stain may give a definite in some tumors.
• Solid biopsy and histopathology. The definitive diagnosis of a tumor is carried out on a solid piece of tissue removed under anesthetic, either before an attempt is made to remove the tumor, or at definitive surgery. This is sent to a laboratory for histopathological examination.  There are times when a biopsy is needed before an operation to remove the tumor can be planned, though it may often be more practical to remove the whole of the apparent tumor and send it all away for examination. Occasionally the results may suggest that surgery has not been adequate, because the tumor is more aggressive than was thought or because the edges of the tissue removed contain tumor cells.
• Special tissue stains.  There are many special stains which can be used to give extra information about the identity of cells and their behavior. Most involve highly specialized techniques and can only be done at specialist laboratories, but there is one which is relatively simple. It is called AgNOR staining and shows up bits left over in cell nuclei after division. Normal cells should be tidy and have one or perhaps two AgNORs, but fast dividing tumor cells have more. There is evidence to suggest that the number of AgNORs per nucleus is related to the degree of malignancy in certain tumors, while their significance in others is less sure.
• X-ray.  X-rays are, of course, one of the main ways to look inside a body to obtain information about disease. Many pets with cancers will have their chests X-rayed to check for the presence of secondary (metastatic) tumors in the lungs. It is important to remember that a lump smaller than about 1cm is not necessarily visible on a chest X-ray and that the cells or clumps of cells that spread to the chest are microscopic, so an X-ray can only detect well establish metastases.
• Ultranosonograpy.   Most people know about ultrasound scans for pregnancy. The imaging technique has many more uses. It allows us to see inside organs such as the liver to search for metastases as well as primary tumors which would not be detected by X-ray. Also, fluid filled organs such as the bladder will show very clear pictures on ultrasound scan.
• MRI.   MRI scans can be very useful in planning treatment of tumors.
• Exploratory Surgery. There are times when none of the above methods will give enough information and we have to resort to surgical exploration to assess a tumour. Generally this will be combined with an attempt to remove the tumor, or at least to obtain biopsy specimens.
• Staging.  Staging is the assessment of local, regional and distant spread of the tumour, and of complicating factors if any. Proper staging can give a good idea of the chance of success of surgery of other modality of treatment. It is the sum result of all the investigations described above.

Common Canine Cancers.
Hemangiosarcoma:  There are three types of hemangiosarcoma found in dogs:  internal, which can include the spleen, liver, or heart; subcutaneous or intramuscular; and cutaneous.

Internal hemangiosarcoma can be found in the spleen, liver, or heart.  Initial diagnosis of this cancer can be made by radiographs or ultrasound of the questionable areas.  For tumors that are found in the spleen or liver, most dogs will live 19 – 52 days without chemotherapy after surgical removal of the tumor.  With successful chemotherapy, we can increase the life expectancy of these dogs to 6 – 8 months.

Dogs that are diagnosed with subcutaneous or intramuscular hemangiosarcoma should have the tumor completely excised by a surgeon.  With surgery alone, the life expectancy of these patients is 6 months.  We can increase this to 1 ½ years with successful chemotherapy.

Cutaneous hemangiosarcoma is a sun-induced cancer that does not invade the subcutaneous space.  It is cured with complete surgical excision.  It is advised that chest radiographs and abdominal ultrasound are performed to determine whether this disease is a primary tumor or a manifestation of metastatic disease due to another primary tumor.

Lipomas:  Lipomas are one of the most common benign tumors found in dogs. Most older or overweight dogs have at least one lipoma. Almost every dog owner has, at one time or another, found or felt one of these common fatty tumors on their dog They almost always are located in the subcutaneous tissue. They are firm yet moveable and they are painless and not associated with infection or hair loss.

Lymphoma: Lymphoma is a systemic, malignant disease of lymphoid tissue. Because of the systemic nature of the disease, it is generally treated with a combination of therapies that can include chemotherapy and radiation. Non-Hodgkin’s lymphoma (NHL) can begin in a nodal form in a localized region, but it ultimately tends to develop into a disseminated disease form. Prognostic factors that predict the course of the disease and the treatment options are known for each individual patient.

Mast Cell Tumors:  Mast cell tumors (MCT) in dogs are classified into three grades:  I, II, and III.  Both I and II are considered low grade and grade III is considered a high grade process.  Grades are determined by biopsies taken of the tumor during surgical removal. 

Low grade mast cell tumors generally have a less than 15% chance of metastasis.  Aggressive local therapy is the treatment of choice for these tumors.  A local cure can be achieved when a surgeon removes the tumor with “clean” surgical margins.  There is a 95% cure rate if radiation is used in the area after surgical removal if the surgical margins are not clean.  Chemotherapy is only indicated if there is a MCT in an anatomically difficult area for surgery or radiation therapy, if the pet has had previous multiple MCTs, or if there are negative prognostic factors (location, metastasis, rapid growth). 

High grade MCTs have a 90% chance of metastasis with the average survival time being 3 - 4 months without successful treatment.  This type of MCT  metastasizes to the lymph nodes, liver, spleen, and bone marrow. 

Oral Cancers:  Squamous cell carcinoma (SCC) is the second most common oral malignancy, representing 20–30% of oral cancers, in dogs.

Osteosarcoma:  Osteosarcoma is the most common primary bone tumor in dogs. It most commonly occurs in the long bones of middle-aged, large and giant breed dogs. The distal radius is the most frequent location for osteosarcoma. Dogs present with signs of lameness and swelling. A presumptive diagnosis is often made based on signalment, physical examination, and radiographic findings of a osteolytic, osteoproliferative or mixed bone lesion. Differential diagnoses for these lesions include other primary bone tumors (chondrosarcoma, fibrosarcoma, hemangiosarcoma), lymphoma or multiple myeloma of bone, tumors metastatic to bone (carcinomas), systemic mycoses, and bacterial osteomyelitis. Osteosarcoma can be definitively diagnosed via bone biopsy. Thoracic radiographs are an important part of the diagnostic workup, as 5%-10% of dogs will have visible metastatic lesions at the time of initial presentation. Routine screening of blood and urine are also essential to evaluate the overall health of the patient, and to determine the best therapeutic options.

Soft Tissue Sarcoma:  Soft tissue sarcomas are a diverse group of malignant tumors that originate from mesenchymal tissue. Common tumors within this group include liposarcomas, hemangiopericytomas, leiomyosarcomas, and neurofibromas. Despite commonalities, the biological behavior of each member of this group is distinct. Soft tissue sarcomas are considered to be locally invasive with distant metastasis developing in regional lymph nodes, lung, and liver. If possible, the first-line treatment is surgical removal followed by adjuvant treatment. Local recurrence can be a primary concern following surgical removal.

Soft tissue sarcomas in dogs include a diverse group of cancers that are loosely associated. Their biological behavior, response to therapy, and molecular alterations can vary widely. Common veterinary soft tissue sarcomas include fibrosarcomas, peripheral nerve sheath tumors, liposarcomas, and malignant fibrous histiocytomas. Sarcomas have occasionally been associated with previous radiation treatment, trauma, foreign bodies (such as orthopedic implants), and parasites (Spirocerca lupi).

Grade I (well-differentiated) tumors are considered low grade and have an approximate metastatic rate of 10%, grade II (intermediate grade) tumors have an approximate metastatic rate of 20%, and grade III (poorly differentiated) tumors have an approximate metastatic rate of 30-50%.

Treatment of most soft tissue sarcomas is determined by tumor location, clinical stage, histologic type, tumor grade, and the completeness of surgery. An aggressive first surgery is considered to be the first line of defense for these types of tumors. Local recurrence is common with conservative surgery. Radiation therapy is considered for tumors with incomplete margins. This has yielded a 95% one-year control rate for well-differentiated (grade I) tumors. Chemotherapy using doxorubicin-based protocols or mitoxantrone generally provides less than a 20% overall response rate.

Common Types of Feline Cancer:

Lymphoma:  Intestinal lymphoma is now the most common form of lymphoma in the cat.  The average patient is an elderly cat with a history of vomiting, diarrhea, weight loss, appetite loss or any combination thereof. Patients are generally older cats (median ages ranging from 9-13 years depending on the study) with a tendency for male cats to be more predisposed to development of the condition than female cats.

Diagnosis of intestinal lymphoma is best made by biopsy and if a mass is present, it can be surgically removed at the time biopsies are taken. Alternatively, the mass can be aspirated (cells removed via syringe) and the cells analyzed in the lab. This may not be as definitive as biopsy but is often adequate; surgery, of course, enables the removal of the growth (if there is one) and relieves the obstruction.

Soft Tissue Sarcomas:   An injection-site sarcoma is a tumor thought to be induced by an injection – most often a vaccination. Post-vaccinal sarcomas are very rare but may occur in cats as a consequence of an overzealous inflammatory or immune system reaction to the vaccine.

A sarcoma is a malignant tumor composed of cells derived from connective tissue. These tumors often develop quickly and can spread (metastasize) to distant locations in the body. These tumors often are not responsive to treatment and result in serious illness and ultimately death of the animal. Recurrence of such tumors is common after surgical removal.

Injection-site sarcomas were first recognized in the late 1980’s when some changes occurred in the vaccine manufacturing process. At that time, manufacturers changed from production of modified live virus vaccines to killed virus products as directed by the United States Department of Agriculture (USDA). This change in manufacturing process resulted in the inclusion of aluminum into vaccines. It is this aluminum component of the vaccines that is suspected to be associated with development of post-vaccinal sarcomas. The feline leukemia virus and rabies vaccines are most frequently suspected in pets that develop post-vaccinal sarcomas.

The actual incidence of injection-site sarcomas is not known with certainty. Some investigators estimate that post-vaccinal sarcomas occur in as many as 1 of every 1,000 to as few as 1 in every 10,000 cats vaccinated. Injection-site sarcomas are recognized only in cats.

Despite the localized appearance of these tumors, microscopic branches of the tumor extend like fingers into the surrounding healthy tissue. During surgery to remove the tumor, these microscopic branches can remain and contribute to re-growth of the tumor. According to one study, as many as 62 percent of post-vaccinal sarcomas recur within 6 months after surgical removal.

There are several types of injection-site sarcomas:

• Fibrosarcoma – a malignant tumor arising from cells called fibroblasts in connective tissue. This is the most common type.
• Histiocytoma – a malignant tumor arising from tissue cells called histiocytes
• Osteosarcoma – a malignant tumor arising from bone
• Chondrosarcoma – a malignant tumor arising from cartilage
• Rhabdomyosarcoma – a malignant tumor arising from muscle
• Myxosarcoma – a malignant tumor arising from loose connective tissue
• Liposarcoma – a malignant tumor arising from fat

Mammary Carcinomas:  Mammary gland tumors are a type of cancer that arise from breast tissues. These tumors are similar to breast cancer in women, and they can be lethal in cats. Approximately 50 percent of these tumors are malignant, which means they can spread, and 50 percent are benign and do not spread.

The cause of mammary tumors is not well understood. Hormones such as estrogen and progesterone play an elusive role in the development and progression of these tumors. They occur in both intact (non-neutered) and spayed cats and it is the most common cancer of female cats, with two cases per thousand cats at risk, constituting over 50 percent of all cancers. Mammary gland tumors occur most commonly in females; they are rare in males.

The average age that cats develop these tumors is 10 to 12 years. Any breed of cat may develop these tumors, but breeds that appear to be at increased risk are Siamese.

Timing of ovario-hysterectomy, which is removal of the ovaries and uterus and commonly called neutering or spaying, significantly impacts development of mammary gland tumors in cats. Cats spayed prior to their first estrus cycle (heat cycle) have less than a one percent risk, those spayed between the first and second estrus have an 8 percent risk, whereas those spayed after their second estrus cycle develop these tumors as commonly as cats that are not spayed.

Body weight may influence the development and progression of these tumors.

Types of Cancer Treatment

Novel Treatment Forms

Our understanding of the biology of metastasis has expanded in recent years and is now shedding light on novel treatment strategies for patients with gross metastases and those with a high risk of metastatic recurrence.
The Biology of Metastases.

In order for a cancer cell to successfully metastasize it must leave the site of the primary tumor, pass through the tumor basement membrane, and then through or between endothelial cells to enter the circulation (extravasation). While in the circulation tumor cells must be able to resist anoikis (programmed cell death associated with loss of cellular contact), evade immune recognition and physical stress, and eventually arrest at distant organs. At that distant site the cell must leave the circulation and survive in the hostile microenvironment of the foreign tissue site. This distant site may be the eventual target organ for metastasis or may be a temporary site. In either case the cancer cell is thought to lie dormant for a protracted period of time before moving to its final location. Following dormancy, the cells receive signals to proliferate, create new blood vessels (angiogenesis) or co-opt existing blood vessels and then successfully grow into a measurable metastatic tumor. It is likely that further progression is associated with the repetition of this process resulting in metastases from metastases.

New Treatments Based on an Improved Understanding of Biology

Through an improved understanding of the biology of cancer metastasis, novel treatment approaches are now commercially available, and others are in clinical trials. No matter how promising these treatments may be, it is predictable that cancer cells will be able to overcome each individual therapy. As such, it will be important to define how these novel treatments may best be used in combination with conventional chemotherapy agents and with other novel treatment agents.

Extravasation/Invasion

Dissolving the extracellular matrix is essential for cancer cells as they initiate the metastatic process within the primary tumor site and when cells leave the circulation at distant metastatic sites. This process of invasion is mediated by a series of enzymes including matrix metalloproteinases (MMP). Many commonly used veterinary drugs inhibit MMP activity (i.e., doxycycline); however, agents specifically designed to antagonize these enzymes have been developed and evaluated in both human and veterinary cancer patients. Most clinical trials, in human patients, using MMP inhibitors have not been successful. A failure to define optimally effective doses and treatment schedules, as well as unexpected toxicities related to these MMP inhibitors may in part explain their failures as drugs. Interestingly, at doses well below those used in human clinical trials, modest improvements in outcome were seen in selected dogs with lymphoma entered to a randomized, placebo blinded trial with a selective MMP inhibitor in combination with conventional chemotherapy. The improvement was most evident in older dogs and dogs with the highest pre-treatment MMP levels (Personal communication G. Ogilvie).

Evade Immune Surveillance

The belief that the immune system may play a role in the treatment of cancer has been held for over 100 years. Coley, a surgeon in the early 1900s, observed the spontaneous regression of bulky tumors in women following bacterial sepsis. His belief that the fever associated with sepsis was responsible for regression of the tumors lead him to administer mixtures of bacteria to patients in the hopes of re-creating fever and resultant tumor regression. These bacterial mixtures, referred to as Coley's toxins, were the first documented attempts at cancer immunotherapy. Since the days of Coley, considerable progress in our understanding of the immune response (and lack of immune response) against cancer has emerged. This understanding may be summarized in the following generalizations:

This understanding has lead to several promising strategies that use the immune system to first detect and then destroy cancer cells. Approaches to immunotherapy include the following:

The ability of cancer cells to survive in distant "foreign" tissues immediately after arrest or while cancer cells are in a dormant state is a hallmark of successful metastasis. For most metastatic cancers, this ability to survive is in part regulated by internal genetic cues, but also by signals received from the microenvironment (growth factors). A number of small molecules that inhibit signal transduction from growth factor receptors have been developed as cancer agents. Many of these agents may have a role in treating metastases through the disruption of critical survival signals provided by these growth factor receptors. In work from London et al, a small molecule inhibitor (SU11654) of the split tyrosine kinase receptor family was found to be active in a number of canine cancers, including mast cell tumors, metastatic sarcoma, and mammary carcinoma.

The split tyrosine kinase receptors that are inhibited by SU11654 have a diversity of biological effects. As such, their inhibition may not be limited to preventing survival and may be the result of the inhibition of many steps in the metastatic cascade. As a class, small molecular inhibitors of tyrosine kinase receptors represent one of the most promising types of novel therapies for cancer and cancer metastases. Clinical trials using these agents are underway at several veterinary referral centers and veterinary teaching hospitals across the United States.  For information on clinical trials, visit www.perseusfoundation.org.

Angiogenesis

Angiogenesis describes the generation or recruitment of new blood vessels. It appears that new blood vessel development is essential for tumor cells to grow and metastasize. The new blood vessels may be created by the tumor or may be recruited from the surrounding normal tissues. If new blood vessel formation or recruitment can be inhibited, a tumor cannot progress and may cause established tumors to regress. Therapies that are directed against blood vessels and not tumor cells are likely to be active against a wide spectrum of cancers. Biological differences between tumor associated endothelial cells and normal endothelial cells have become apparent. This has lead to several novel therapeutic agents that either prevent new blood vessel formation or survival (antiangiogenic agents), or specifically target existing tumor-associated blood vessels (vascular targeting agents). Recent studies using antiangiogenic peptides of thrombospondin-I (TSP-I) have demonstrated surprising objective regressions of metastatic cancers in dogs with a variety of histologies and have significantly extended remission duration in dogs with lymphoma when combined with chemotherapy (demonstrated in a randomized controlled trial). Trials with TSP-I peptides in dogs are underway at several sites across the United States.

Progress that has been made in our understanding of the basic biology of cancer has uncovered several opportunities for the treatment of cancer. The improved knowledge of cancer biology has allowed differences between cancer cells and normal cells to be identified and has uncovered important interactions that occur between cancer cells and the host. The cancer treatment strategies discussed above specifically target cancer, and as such are less likely to result in the toxicities that are associated with conventional cancer therapy. Effective and non-toxic cancer therapy is therefore the goal. In the very near future, we can expect these novel treatments to be used in conjunction with conventional cancer treatment modalities (surgery, radiation therapy, and chemotherapy) in the management of our veterinary cancer patients.