Goetz TE. DVM , Diplomate, ACVIM; Long, M.T. DVM
Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois, Urbana 61801.
Treatment of Melanomas in Horses.
The Compendium, April 1993
The prevalence of neoplasia in horses has been estaimated to be between 1% and 3%. Melanomas are reported to make up 3.8% of the total number of neoplasms diagnosed in horses. Melanomas occur in horses of all colors, but they are seen most commonly in gray and white horses older than six years of age. Approximately 80% of gray horses older than 15 years of age are affected by melanomas. Rarely, the tumors are congenital. A sex predication for melanomas has not been determined definitely. Melanomas can occur anywhere on the body, however, they have an externam predilection for the undersurface of the tail near its root, the perineal and perianal regions, the male genitalia, the head below the entrance to the pinna, the ear margin, and the paratoid salivary gland.
Melanomas can be hard, soft, solitary, or multiple. Often they are located subcutaneously and are covered by normal haired skin, however, with time, they may become ulcerated and infected. Typically, they are dark brown to black or gray, but some are unpigmented. Diagnosis of unpigmented (amelenotic) melanomas requires microscopic examination of biopsy specimens. Historically, equine melanomas have not been staged but instead have been classified simply as benign or malignant.
Clinically, equine melanomas develop and behave in one of three distinct ways. Most commonly, there is slow growth over a number of years without metastisis. Melanomas may be benign for as long as 10 to 20 years. The next most common pattern is benign growth that suddenly assumes malignant characteristics and metastasizes. Conversely, some melanotic tumors are malignant from thei first appearance and readily metastasize. Metastisis to any region of the body is possible, but there apparently is a predilection for the serosal surface of the spleen, liver, and lungs.
In addition to the possible threat to the life of the affected horses, melanomas can be therapeutic, economic, and practical nuisances. Benign melanomas can interfere with urination, defecation, and coitus and can preclude saddle, bridle, and halter application if they develop on the horses' backs and in the bridle and halter paths.
Modalities that may be useful in the treatment of equine melanomas include environmental management, wide surgical excision, cryonecrosis, biological response modifiers, and chemotherapy. A consistently satisfactory form of treatment still does not exist.
Since 1935, the incidence of cutaneous melanomatosis in humans has increased 11-fold, perhaps as a result of the increased ultraviolet B radiation reaching the earth's surface. Subjectively, there also appears to be an increased incidence of equine melanoma in temperate North America during the warmer months of the year, when horses typically spend more time on pasture and are exposed to larger quantities of ultraviolet radiation. It seems prudent, therefore, to decrease the exposure to sunlight of horses at risk (gray horses) of developing melanomas by keeping them indoors during the day. Anatomic regions at risk of developing melanomas may benefit from the topical application of sunscreens.
Once melanomas have formed, wide surgical excision is an acceptable form of treatment in selected horses. Tumors best suited for this form of treatment are small to moderate in size (less than three centimeters in diameter), are not numerous (not greater than 15), and are located in surgically accessible anatomic regions. Frequently, surgical excision is associated with less-than-optimum results because of rapid tumor recurrence from abnormal melanoblasts in proximity to the surgical field. Occasionally, some horses develop vast undulating sheets of black tumorous tissue from the coalescence of numerous smaller solitary melanomas. In our experience, melanomas of this type are usually found on the undersurface of the tail or in the perineal or perianal regions. Although not amenable to excision, these tumors may be clinically managed with cryonecrosis.
Cryonecrosis, used asa primary entity or as an adjunct to surgical excision, can be of benefit in most horses with cutaneous melanomatosis. Cryonecrosis is often used to treat melanomas when the size of the tumor precludes removal by surgical excision and primary closure. Tumor recurrence can be reduced by excising as much of the tumor as possible before cryonecrosis. The remaining tumor bed is then cryonecronized to -20 degrees c (-4 degrees f), allowed to thaw, and cryonecronized a second time. Initial surgical excision is often not possible in horses with immense sheets of tumorous tissue. Melanomas of this kind can be treated with cryonecrosis as described. The cryosurgical unit must be capable of cryonecrosing faster than the body's ability to thaw the tissue being treated. This type of melanoma is rarely cured but can be managed by cryonecrosing the affected region as needed (once or twice a year). Cryonecrosis can usually be accomplished in standing, sedated horses, in some horses, however, general anesthesia may be required.
Since 1985, clinical experience has shown that cimetidine can be beneficial in the management of melanomas in some horses. Cimetidine has been recognized as a biological response modifier that is effective in the treatment of various human and animal tumors, including malignant melanomas. Some patients with neoplastic disorders may have suppresor T cells that alter the body's own antitumor defense mechanism. Histamine activates suppressor T cells via H2 histamine receptors. Cimetidine apparently blocks the activation of these cells, thereby augmenting cell-medicated and humoral immune responses.
Cimeditine provides the greatest therapeudic benefit in equine patients with melanomas that are actively increasing in size and number. Its effect on melanomas that have not changed in size or appearance for many years is minimal. Cimetidine is administered orally at a dosage of 2.5 mg/kg three times daily. If the drug cannot be administered in this fashion, the total daily dose (7.5 mg/kg/day) can be divided into one or two daily doses, however horses treated every eight hours have responded (subjectively) best. If there is no change in the size or number of melanomas after three months of treatment, therapy should be discontinued. If there is a continual decrease in size and number of melanomas, therapy should continue until two to three weeks after a positive response is no longer apparent. The progression of the disease may be halted for months to years after the cessation of treatment, even if there was no clinically observable response to treatment.
Presently, there is no way to decide whether an individual horse will respond to treatment. A good response to treatment is typically characterized by a decrease of approximately 50% in the size and number of melanomas and no further progression of disease for several years. Changes in the number or size of melanomas during therapy typically become clinically discernible after two to seven weeks of treatment. In some horses, melanomas may again become active after months to years of disease quiescence. These horses often have a favorable response to cimetidine.
Cimetidine can also be used to decrease the chance of melanoma recurrence following cryonecrosis, surgical excision, or chemotherapy or to decrease the size and number of melanomas before surgical intervention. To date, no toxic effects of treatment with cimetidine have been reported in horses. Banning the expense and inconvenience of prolonged administration, cimetidine is a useful alternative in the clinical treatment of horses with melanomas. The usefulness of newer, more potent H2 antagonists is not known at this time.
Historically, systematic chemotherapy has been of minimal benefit in treating horses with melanomas. Recent investigations with cisplatin, however, suggest that intralesional chemotherapy of solitary cutaneous melanomas may be beneficial. Before intralesional injection of cisplatin, the melanoma should be surgically debulked, leaving only the base of the tumor. Preinjection debulking decreases the quantity of drug used, thereby decreasing cost and potential local toxicity. Small melanomas (i.e., one to two centimeters in diameter) can be treated intralesionally without initial debulking.
Melanomas are usually treated with cisplatin at a dose of 1mg/cm of tumor at two-week intervals for a total of four treatments. At this dosage, it may be difficult to inject the calculated quantity of cisplatin into the tumor without some of the drug leaking from injection sites. Tumors should be injected with a 22- to 25- gauge needle. The tract formed by the needle should be filled with cisplatin as the needle is withdrawn from the tumor. Injection tracts should be within five to eight millimeters of each other because the ability of the tissue to diffuse cisplatin is limited. Post injection swelling can be minimized by administering systematic antimicrobial (potentiated sulfonamides or penicillin) and antiinflammatory (phenylbutazone) drugs the day of and for four days following chemotherapy.
Cisplatin should be prepared immediately before treatment using a sesame oil carrier to prolong its effect. The reconstituted drug is stable at room temperature for 15 hours.
With local intralesional therapy, a tissue concentration that is significantly higher than that obtained following systemic (intravenous) therapy can be acheived with essentially no signs of toxicity. This form of treatment has been used on pregnant broodmares and breeding stallions without ill effect.
Tumor resistance to cisplatin has not been described. Less-than-ideal therapeutic outcomes are most likely the result of inadequate tissue deposition of the drug secondary to less-than-optimum injection technique. Recurring melanomas usually become apparent by approximately eight months after treatment at the periphery of treated lesions. Recurrent tumors do not develop resistance to cisplatin and can be treated a second time using the protocol used during the initial treatment.
Even with the many treatment modalities presently available for equine melanomas, the disease may still be difficult to manage clinically. Often, a successful therapeutic outcome mandates the use of combination therapy that takes into account the age of the horse, the time of the year, the number, size, and progression of the lesions, and the financial limitations of the owner.