Cancer and The Chinese Shar-Pei

It is important and necessary that we define some terms so we’re all talking on the same level. Cancer is a cellular tumor the natural course of which is fatal. This term has taken on a more general meaning to include the leukemias and other more diffuse types of abnormal cell growth. Neoplasia in the formation of a neoplasm which is defined as any new and abnormal tissue growth in which the growth is uncontrolled and progressive. Tumor is synonymous with neoplasm. Malignancy is the property of invasion and metastasis. Metastasis is the transfer of cancer cells from the primary focus e.g. tumor, to other parts of the body. Benign is the opposite of malignant with no tendency for spread or invasion of tumor cells into adjacent tissues and is generally favorable for recovery. From these definitions the following characteristics of cancer are revealed:

1. Cancer is characterized by rapid and uncontrolled growth of cells.
2. Cancer cells are generally abnormal cells or immature cells (undifferentiated cells).
3. Cancer has the potential for metastasis and invasion.
4. Cancer is generally fatal if left untreated and often fatal in spite of treatment.

What causes cancer? The body is composed of billions of cells each with a defined life span. These cells die and are replaced though the process of multiplication and differentiation. Differentiation is the process by which an immature cell develops into a functional mature cell. This process usually occurs in an orderly and predictable manner. Skin cells flake off the surface of the skin and are replaced by new skin cells. Intestinal cells are damaged in the gut and are replaced by new intestinal cells. These new cells demonstrate the characteristics of growth inhibition i.e. when the cells come in contact with other cells they stop growing and maturation i.e. they develop into cells of recognizable type and function. Mature cells are unable to replicate; the cells that are able to reproduce are generally very immature cells. These immature cells are often calledstem cells and can develop into any number of types of mature cells. What triggers the differentiation into a certain cell type is currently and active area of research. Ultimately, the characteristics of normal cells are encoded in the cell’s chromosomes. Chromosomes are made up of subunits of instructions called genes and genes are composed of DNA. If the DNA is damaged, the cell may become unable to replicate or it may produce abnormal cells as it replicates. Uncontrolled growth of abnormal cells is cancer and usually results in death of the organism. Damage to cellular DNA can be the result of exposure to toxic chemicals such as hydrocarbons in cigarette smoke, pesticides, asbestos, drugs, high energy radiation such as occurs in prolonged UV light exposure, exposure to ionizing radiation such as occurs with X-rays, trauma, certain viruses such as the retroviruses, and inadequate nutrition such as certain vitamin and mineral deficiencies. It can also occur as a chance event. With millions of cells being renewed on a daily basis, occasional abnormal cells are produced and can lead to cancer. This is probably the primary reason that cancer tends to develop in organs with high cell turnover such as the GI tract, the skin, the liver, the bone marrow, etc. Hormones probably play a role — it is well known that the incidence of mammary carcinoma is much higher in unspayed female dogs and the development of prostatic cancer is lower in neutered male dogs. Viruses are also important inducers of cancer. These viruses, known as oncogenic viruses, incorporate their genetic material into the chromosomes of the host. From this vantage point the viral genetic instructions trigger uncontrolled growth in the host.

The immune system plays a very important role in the prevention of cancer and is also beginning to play a vital role in the treatment of cancer. It is generally felt that the immune system plays a role in cancer surveillance — as abnormal cells develop, the immune system identifies and eliminates them before they can lead to cancer. There are cells in the immune system capable of destroying tumor cells. These include killer cells, NK cells (natural killer cells), macrophages and even some types of white blood cells. The body also reacts to tumor cells by producing antibody to the cells and the killer cells respond to antibody-coated tumor cells by destroying them. NK cells are found in the blood and can specifically react to abnormal cells. These may play a role in graft-versus-host rejection reactions. A higher incidence of various types of cancer has been observed in immunodeficient individuals and this may play a role in the apparent increased susceptibility of the Shar-Pei to certain types of cancer.

Another important point in any discussion of cancer involves the differentiation of benign tumors versus malignant ones. This determination is extremely important in order to give the veterinarian an idea of the clinical course of the cancer and the prognosis for the patient. Benign neoplasia tends to be made up of mature cells that are well organized, the tumor usually has sharply defined borders, a slow rate of growth and no metastasis or spread outside the primary tumor focus. The primary problem with benign tumors is due to the local compression of the surrounding tissues caused by the tumor growth. They can also be disfiguring and difficult to remove surgically due to their size. Malignant neoplasia generally involves immature cells with a rapid rate of cell division, the cells invade the surrounding tissue and they often metastasize to other areas of the body. These tumors are more dangerous due to their invasiveness making surgical removal much more difficult and because they spread thoughout the body affecting other body systems.

How does cancer produce disease? Cancer cachexia is seen in almost all cancer patients and is a profound state of malnutrition and wasting. This often occurs in spite of adequate nutritional intake. Alterations in metabolism are seen in cancer patients resulting in net energy gain by the tumor and net energy loss by the host. This occurs largely due to inefficient metabolism by the cancer cells. The cancer patient often has to use muscle protein as an energy source that results in muscle wasting. The presence of cancers cells within an organ can interfere with that organ’s normal function and results in organ failure. Paraneoplastic syndromes are systemic effects caused by substances produced and released from tumor cells. Many cancers are associated with ectopic hormone production. This type of hormone production is not regulated by the body’s normal feedback control mechanisms and can result in severe metabolic derangements. Cancer is one of the most common causes of hypercalcemia or increased blood calcium levels. Some cancers are associated with low blood sugar or hypoglycemia. Often cancer is accompanied by anemia or low red blood cell counts. This can occur due to blood loss, red blood cell destruction and/or cancer effect on the bone marrow. Other effects of cancer can be chronic fever, increased white blood cell count, increased globulin (immune protein) levels in the blood, decreased platelet count and neurologic abnormalities.

The primary cancer that are being seen in Shar-Pei seem to be mast cell tumors, lymphosarcoma, histiocytomas and intestinal adenocarcinomas.

Mast Cell Tumors
Mast cells are a normal cell type in subcutaneous tissue of the dog, located just beneath the skin. Mast cells are identified by the distinctive granules contained within the cytoplasm of the cell. These granules contain vasoactive substances such as histamine, heparin, serotonin and other mediators of the inflammatory response. Many substances can cause mast cells to degranulate and release the contents of the granules. IgE, an immunoglobulin involved in allergic reactions, is a primary mediator of degranulation as are various drugs, enzymes, physical trauma, etc. Shar-Pei normally have more mast cells in their skin and subcutaneous tissue than found in other breeds which may partially account for the apparent increase in mast cell tumors in the breed. Other breeds at increased risk for mast cell tumors include Boxers, Bulldogs and other breeds of Bulldog descent. They are a common tumor of the skin and usually seen in middle-aged dogs. In the Shar-Pei they seem to occur at a younger age and appear to be particularly aggressive in their behavior. Also seen in Shar-Pei is a type of mast cell tumor with a more chronic benign-type course that is controlled with corticosteroids and topical therapy. A variant of mast cell tumor called agranular spindeloid mast cell tumor is more common in Shar-Pei. This form of mast cell tumor has very few granules in the cytoplasm and can be difficult to diagnose on fine-needle aspiration.

Mast cell tumors are graded on the degree of maturation shown by the mast cells that make up the tumor. The more mature the mast cells the better the prognosis. Grade 1 denotes a well-differentiated cell population, Grade 2 has intermediately differentiated cells and Grade 3 has very immature or undifferentiated cells. This grading system is based on biopsy of the tumor and helps to predict the behavior of the tumor. Grade 3 mast cell tumors tend to spread rapidly, involve lymph nodes, are difficult to completely remove surgically and don’t respond well to chemotherapy. Mast cell tumors are often associated with gastrointestinal tract ulceration due to the release of histamine form the tumor cells. Treatment is surgical removal with follow-up chemotherapy or radiation therapy.

Lymphosarcoma
This type of cancer involves abnormal lymphocytes. Recall that lymphocytes are types of white blood cells involved in the immune response. They are located thoughtout the body including the spleen and liver, but are primarily found in the numerous lymph nodes. Lymphosarcoma is one of the most common types of cancer found in the dog. There are four classifications: multicentric, mediastinal, gastrointestinal and cutaneous. Multicenttic lymphoma is the most common form and is characterized by a peripheral lymphadenopathy or lymph node enlargement. This may be associated with wight loss and a decrease in appetite and activity. I have probably seen more gastrointestinal lymphoma in the Shar-Pei which presents as signs of liver disease such as jaundice (yellow mucous membranes) or gastrointestinal involvement presenting as maldigestion/malabsorption problems with chronic vomiting, diarrhea and wight loss. Hypercalcemia or high serum calcium levels are often associated with this type of cancer and can precipitate kidney problems. This association of hypercalcemia with lymphoma is an example of a paraneoplastic syndrome and this reminds us that cancer can effect the body in other ways than a primary tumor effect. One of the most common clinical signs associated with hypercalcemia is increased water consumption and urination.

Lymphoma is one of the types of cancer that often responds well to chemotherapy. Of course, response depends on the type of lymphoma, the stage, and the dog’s physical state. The best response is seen in cases where just the peripheral lymph nodes are involved. Gastrointestinal forms, mediastinal forms and cutaneous forms respond poorly to chemotherapy.

Histiocytomas
These are fairly common tumors which generally occur in young dogs, but can be seen in dogs of any age. They arise form the monocyte-macrophage cells in the skin. Shar-Pei seem to have a predilection for these tumors. They occur as solitary, fast growing, nonpainful, raised masses often found on the extremities and the head. They are benign tumors that may regress spontaneously. The main concern is they can be confused with other malignant tumors. Surgical removal is curative, although other ones may develop elsewhere.

Intestinal Adenocarcinoma
Shar-Pei seem to be prone to various types of gastrointestinal cancers the most common of which is the intestinal adenocarcinoma. Often the only symptom is acute death due to perforation of the tumor and resultant peritonitis. It is very likely that one reason intestinal caner seems to be relatively common in the breed is related to the high incidence of inflammatory bowel disease in the Shar-Pei.

Diagnosis of cancer in dogs involves laboratory testing, radiographs, and exploratory surgery with the intent of obtaining biopsies. It is most important to establish a specific diagnosis as early as possible so treatment can be started early. The main problem in dogs is getting the early diagnosis. Maintaining a high index of suspicion is helpful and a willingness to pursue diagnostics and the accompanying expense is extremely important. Symptoms may be very non-specific such as “he’s just not himself”. Loss of appetite and wight loss are often early indicators of cancer, but are in no way specific symptoms. Skin masses should be biopsied early — the “wait and see” attitude can be deadly.

Treatment of cancer in the dog is similar to treatment in humans. Surgery, chemotherapy and radiation therapy are useful in different types of cancer. Dogs seem to tolerate chemotherapy better than people so don’t be too quick to rule out trying chemo. Cancer therapy is now a specialty in veterinary medicine so the owner of a dog with cancer should be wiling to consult with an expert (oncologist). As important as the treatment of cancer is, the monitoring of treatment side-effects and monitoring for recurrence or spread of the cancer is equally important. This usually entails follow-up blood monitoring for such things as low white blood cell count, evidence of bone marrow suppression and watching platelet numbers. Periodic radiographs may be necessary to monitor for spread of the cancer to the lungs or other organs. Treatment of cancer is expensive and the owner must be willing to diligently pursue treatment and even that doesn’t guarantee success.