This cancer originates in histiocytes, a form of white blood cell found in the skin and loose connective tissue throughout the body. Their function is to engulf bacteria and other foreign debris to remove them from the body. Benign (non-malignant) growth of histiocytes is known as a histiocytoma. Benign histiocytomas are common in young dogs and typically regress spontaneously without treatment. It is recommended however that you consider having your veterinarian remove and biopsy any suspicious growth to determine its exact nature.
Malignant histiocytomas and malignant histiocytosis (spread to the bloodstream has occurred) are very uncommon in most breeds of dogs. The Bernese Mountain Dog and the Flat-Coated Retriever are notable exceptions. It should be emphasized that these two breeds do not share the precise kind of malignant histiocytoma; each of these two breeds is unique for its own subtype. Although these tumors are quite rare in other breeds, they are the most common malignancy in Flat-Coated Retrievers. Most tumors originally diagnosed as poorly-differentiated malignancies are indeed malignant histiocytomas. The histologic features of malignant histiocytomas are directly related to soft-tissue sarcomas, a collection of cancers of the connective tissues. They share several common features:
- They may arise from any anatomic site in the body.
- They tend to appear as pseudo-encapsulated fleshy tumors, but have poorly defined margins and are capable of local infiltration
- Local recurrence after conservative surgical excision is common.
- Sarcomas spread through the blood in up to 25% of cases
- They generally have a poor response to chemotherapy and radiation therapy for measurable disease.
The histological characteristics of these tumors and the fact that they appear to be breed-related (and likely family or blood-line related) resemble what is referred to as Li Fraumeni syndrome in humans. In those patients, there is a defect in one of their oncogenes that normally produces a protein that works to suppress cell division. Cancer is essentially a result of uncontrolled cell division. This malfunctioning oncogene predisposes these patients to cancers, particularly soft-tissue sarcomas, and several other malignancies, all occurring at unusually young ages.
In Flat-Coated Retrievers, besides the predominant malignant histiocytoma, these soft-tissue sarcomas also present themselves as fibrosarcomas, adenocarcinomas, lymphomas, neurofibrosarcomas, mast cell tumors, hemangiosarcomas, chondrosarcomas, osteosarcomas, carcinomas and others. Multiple cancers often occur independently in an individual dog. In Li-Fraumeni patients, the gene p53 which produces the p53 protein which normally acts to suppress cancer, has been found in a mutated form. The p53 protein has the ability to instruct the cell to stop cell division or cause death of the cell if the division is already advanced. When this protein has mutated, cell division is unrestricted and malignancies develop. Early research on p53 indicates that this mutation occurs as an inherited disorder or as a copying error of DNA or due to the effect of carcinogens. Dr. Mary McLoughlin of Ohio State University reported in her presentation to the National Specialty in June of 1994 that preliminary studies indicated 50% of malignant tumors from Flat-Coated Retrievers have tested positive for this p53 mutation. Research is currently ongoing at Ohio State University on the mutational analysis of the p53 gene in Flat-Coated Retrievers.
Malignant histiocytomas usually present themselves as soft-tissue sarcomas. The tumor will have a "fleshy" or "lumpy" feel to them. They can occur anywhere in the body including the skin, thorax, lungs, liver, spleen, kidneys, adrenal glands and brain. They may or not be encapsulated. Most adhere to deeper tissues and infiltrate into underlying fascia, muscle and other tissues.
Diagnosis must be made by microscopic examination of the tumor cells. The cell-type classification for some sarcomas may vary from pathologist to pathologist. Some poorly differentiated malignant histiocytomas have been misdiagnosed by one pathologist, only to be sent to another and correctly identified as malignant histiocytosis. It is important to know the histologic type of sarcoma, the size, the site, the grade of differentiation and the stage of the disease. A needle aspiration biopsy may be helpful in suspected cases, but usually complete surgical excision of the growth with a minimum of a 3cm margin of unaffected tissue is recommended.
A multitude of treatments has been attempted for malignant histiocytomas. They have a poor response to chemotherapy and to radiation therapy. Surgery is the mainstay of treatment with chemotherapy and radiation as adjuvant therapies. Because histiocytomas can spread microscopically from the main tumor site, it is extremely important to surgically remove the tumor and a surrounding margin of healthy tissue as completely as possible. If the pathologist reports that incomplete margins have been excised, a second surgery to remove additional tissue or radiation therapy is indicated. Malignant histiocytomas and soft-tissue sarcomas cannot be "shelled out" or "peeled out" with the expectation of permanent control.
Prognosis is generally considered to be poor. At best, chemotherapy can be considered palliative (will alleviate, but not cure). Doxorubicin-based protocols, along with vincristine and cyclophosphamide (VAC) have shown partial responses to malignant histiocytosis and complete or partial responses to other soft tissue sarcomas. At the University of Wisconsin, clinical trials are underway in treating malignant histiocytomas and other soft tissue sarcomas with a new chemotherapeutic called Doxil. This drug has yielded interesting results, prompting researchers to use it as a first drug of choice and then in combination with other chemotherapeutics.
Begley, S. The cancer killer. Newsweek. 1996, Dec.23;42-47.
Couto, G. Cancer in Flat-Coated Retrievers. Semi-annual report. Columbus, OH: The Ohio State University, 1993, Dec.
Nash, J. New ideas for controlling cancer. Time. 1994, April 24. National Institute of Health. Family cancer syndrome tied to genetic defect. Cancer facts. 1995, Dec. 17.
McLoughlin, M. Answers for cancer? Seminar given by Dr. McLoughlin, D.V.M., FCRSA National Specialty, Chicago, IL Reprinted in part from the FCRSA newsletter, February 1995, p.96.
Withrow, S., ed. Small animal oncology,2nd ed. 1996; 211-220.