While most melanomas in gray horses are benign, histologic changes during tumor development (e.g., expanding into surrounding muscle) can cause them to become malignant.
Photo: Alexandra Beckstett, The Horse Managing Editor
The luster and shine of a horse's coat speaks volumes about his inner health. But problems might lurk beneath the skin in the form of tumors or other lumps. As you groom your horse, take extra care to notice any suspicious changes, as some skin lesions can pose troubling health consequences. The most common equine skin tumors to watch for are melanoma, squamous cell carcinoma (SCC), and sarcoids.
Horses' tumor susceptibility, especially for melanoma or SCC, correlates with the degree or lack of skin pigmentation. Researchers claim in studies that 75-80% of gray horses over the age of 15 eventually develop melanoma. However, the equine form of this skin tumor is not usually malignant or as rapidly progressing as that which occurs in humans or dogs. In 2008 Leif Andersson, PhD, and his colleagues in the Department of Animal Breeding and Genetics at the Swedish University of Agricultural Sciences examined the association between melanoma and gray coat color in horses. Andersson reports that gray horses carry "a unique (genetic) mutation, inherited from generation to generation, that predisposes to melanoma development."
While most melanomas in gray horses are benign, histologic changes during tumor development (e.g., expanding into surrounding muscle) can cause them to become malignant. In humans, for example, a genetic predisposition such as fair skin coupled with exposure to sunlight's ultraviolet (UV) rays can be a melanoma-causing combination.
"Gray horses are protected from damaging effects of UV light by the hair coat and black skin pigmentation," Andersson continues. "The difference in malignancy between gray horse and human melanoma occurs because of underlying mutations that occur in different genes. Our data documents that the specific mutation that causes graying also predisposes a horse to melanoma."
Melanoma development also depends on the type of gray--there is a distinction between a pure gray or white horse and one sporting a "speckled" or "flea-bitten" coat. Horses that inherit two copies of the gray mutation (homozygous)--one from each parent--sport the pure white (pink skin) or gray coat (black skin) color, whereas horses carrying a single copy of the gray mutation (heterozygous) might be speckled gray. "Homozygous gray horses turn gray more quickly and tend to develop more melanoma but do not show speckling," Andersson explains. "Most speckled grays are heterozygous for the mutation and have less melanoma incidence. This molecular understanding of the cause of gray horse melanoma opens up an opportunity to develop an efficient therapy (for treating this condition)."
Melanoma tumors with an actively necrotic (dead tissue) center can rupture and "bleed" black, tarry material--these can become aggressive and disseminate elsewhere in the body (metastasize), including the central nervous system. Veterinarians usually can identify internal melanomas using diagnostic procedures such as abdominal ultrasound or endoscopic exam of guttural pouches (air-filled cavities in the horse's skull, behind the ears).
The best melanoma management advice has been to leave them alone unless they ulcerate, interfere with tack placement, or metastasize internally. But more recently veterinarians have been targeting and eliminating these tumors.
Veterinarians often turn to pharmaceutical and surgical methods. Christina Hewes, DVM, Dipl. ACVS, of the Morrie Waud Equine Center in Delavan, Wisc., for instance, has used the drug cisplatin extensively as a chemotherapeutic approach to equine tumors. "Cisplatin binds to DNA in tumor tissue to cause cross linking (bonds between the proteins that keep cells from dividing), which prevents cell growth and causes apoptosis (programmed cell death)," says Hewes. "It targets rapidly dividing cells, like tumor cells. Local administration causes minimal side effects because skin and subcutaneous (beneath the skin) cells divide more slowly than tumor cells." She notes that cisplatin beads release drug continuously for 30 days, allowing the horse's body to absorb them slowly.
"Melanomas can be removed successfully with debulking (cutting away) only, but if the entire tumor cannot be removed, implanting with cisplatin (beads or sponges) helps to kill residual cells," she says. Residual cells that are left following traditional excision methods can potentially regrow, sometimes with increased intensity and invasion into surrounding tissue. Thus, Hewes prefers surgical removal via laser excision, explaining, "Laser removal vaporizes cells 0.2 mm deeper than the visible incision line. Although this is a small distance, often it is enough to kill residual tumor cells."
A commercial melanoma vaccine (developed for dogs by Merial) is available only through veterinary oncologists, or a veterinarian can prepare an autologous vaccine from a horse's own melanoma tissue (the excised tumor is chopped into bits, frozen, and stored, and then thawed pieces are injected beneath the mane). While vaccine treatment is expensive and not entirely curative, users of either vaccine have reported fairly good success in shrinking melanomas. Researchers also report that the oral anti-ulcer medication cimetidine might slow melanoma growth.
Nongray mature horses that develop melanoma usually have a poor prognosis leading to death due to systemic spread, according to Hewes. In contrast, young horses of any color have an excellent prognosis following tumor removal.
Squamous Cell Carcinoma
Certain horse breeds, such as Paints and Appaloosas, often lack pigmentation at the mucocutaneous junctions, which are where skin meets mucous membranes. These areas--the mouth, within the eye, the vulva, penis, prepuce, and anus--are most susceptible to developing squamous cell carcinoma (SCC). Those located on the vulva, prepuce, and related areas are far more difficult to resolve than those on the horse's cornea.
Elizabeth Carr, DVM, PhD, Dipl. ACVIM, ACVECC, associate professor at Michigan State University's College of Veterinary Medicine, discusses the puzzling locations of SCCs in horses. "The eyes, muzzle, prepuce, and vulva, with only a fine hair covering, receive sunlight exposure to a greater degree than does the hair-covered back of a horse," she says. "Often, these are light-colored areas lacking UV-¬protective melanin pigment. In one study 69% of ophthalmic (pertaining to the eye) SCC developed on nonpigmented, pink skin."
Carr continues, "UV light penetrates skin cells to damage DNA, which results in abnormal cellular growth patterns. Depending on injury type, it may become a precancerous cell or fully transform into a malignant, cancerous cell." The precancerous stage is generally treatable; once cancer cells become malignant, they have the potential to invade surrounding tissue and become more difficult to target.
Typically, cutaneous (skin) SCC only invades locally but might spread to local lymph nodes. "If untreated, lymph nodes develop masses that could invade into deeper tissues, but it's unusual to see skin SCC metastasize to internal organs," Carr remarks. "SCC in the horse has low metastatic potential, with primarily regional invasion (instead)." If the lesion occurs in or near the eye, for example, it might wreak significant damage in ocular tissues. Carr comments that SCC also can originate internally, such as in the stomach.
For cutaneous SCC treatment to be successful, veterinarians must recognize it early. "Surgical excision is a great choice," notes Carr. "However, it's not always possible to completely remove all malignant cells. In those cases I combine therapies by adding intralesional chemotherapy treatment to surgery." For small areas that might contain residual cancer cells, Carr might treat topically with chemotherapeutic 5-fluorouracil (5-FU) or imiquimod (an immune-boosting drug); otherwise, she relies on cisplatin or other chemotherapeutic agents. Not all SCC requires the big guns, though. "Cryotherapy (freezing with liquid nitrogen) is very useful to treat small tumors or tumor margins following excision," she adds.
Fernando Malalana, DVM, GPCert (EqP), MRCVS, of the University of Liverpool Equine Hospital, uses the chemotherapeutic drug mitomycin C (MMC) for equine periocular (around the eye) SCC based on success he's seen reported in human ophthalmology. Malalana recommends four rounds of weekly MMC treatments--topical treatment along with instilling an MMC-solution into the conjunctival sac (conjunctiva is the thin vascular membrane that arises at the edge of the cornea and extends over the white part of the eye and folds back, forming this sac before covering the third eyelid and lining the eyelid) every six hours for seven days--for regression of small tumors. For larger tumors he reports that MMC stops growth or reduces tumor size to enable better surgical resolution. "With the exception of conjunctival lesions, which didn't seem to respond to treatment, 25% (of SCC tumors) reoccurred if MMC was used solely or following surgical excision," he notes.
Elizabeth Giuliano, DVM, MS, Dipl. ACVO, associate professor of ophthalmology at the University of Missouri's College of Veterinary Medicine, recently proposed another approach to treating periocular SCC: photodynamic therapy (PDT). "PDT utilizes a photosensitizing agent and light in the presence of oxygen to produce a localized phototoxic effect," she explains. "This two-stage process first delivers the photosensitizer to the patient, usually by intravenous injection; then, the target tumor is laser irradiated." The therapy kills tumor cells through photochemistry (chemical reactions that proceed with the absorption of light by atoms or molecules), which damages cellular structures, causes tissue inflammation, and reduces blood supply and oxygen availability to tumor cells.
Radiation therapy is yet another effective SCC management tool; however, it is not without its downsides: expense and logistics. The veterinarian inserts "seeds" or beads containing radioactive material into the cancerous tissue, where they damage the DNA of local cancer cells as well as that of normal tissue. "Until radioactive beads are removed, the horse is hazardous and must be housed in a facility licensed for radiation therapy," explains Carr. "In addition, a veterinarian needs special licensing to implant radioactive beads. These concerns make radiation therapy an uncommon, although effective choice."
While most SCC cases are cutaneous and treatable, Carr notes that SCC of the stomach carries a very poor prognosis because it's difficult to resolve surgically. "The biggest issue regarding internal SCC lesions is that they are generally undiagnosed until they've become quite large and invasive," she says. "At this point there is little that can be done."
Prevention and early recognition are key to successful SCC outcomes. For instance, says Carr, "Fly masks on horses with pink-skinned faces or (areas around their) eyes decrease sun exposure. Routine veterinary exam of external genitalia, particularly of pink-skinned (nonpigmented) colored breeds, achieves early recognition, which is a life-saving measure. The biggest factor in success with SCC is the follow-through. If a tumor is removed yet its margins retain residual cancer cells, it needs additional treatment or it'll simply grow back."
"Cutaneous tumors represent more than 50% of total tumors in horses; sarcoids represent more than 50% of those," reports Youssef Tamzali, DVM, PhD, Dipl. ECEIM, of Ecole Vétérinaire de Toulouse, in France. Certain horses, such as particular families of Arabian horses, might be genetically predisposed to sarcoid tumors. Many believe bovine papillomaviruses (BPV) type 1 and type 2 to be the causative agent of equine sarcoid tumors, although this is not definitive.
Sarcoids tend to be only locally ¬invasive, appearing in several forms: nodular; ¬verrucous (cauliflowerlike); fibroblastic (resembling granulation tissue); or mixed. Veterinarians recommend leaving a flat, "quiet" nongrowing sarcoid alone until it shows activity (e.g., increasing size or irritation), and they suggest always assessing nonhealing traumatic wounds for sarcoids.
Researchers have found that if a surgeon removes sarcoids from a horse without any further treatment, the horse has a high risk of recurrence (more than 50%). Thus, for treating active sarcoids many veterinarians rely on chemotherapy using implantation of cisplatin beads.
A procedure to amplify this therapy, says Tamzali, is electrochemotherapy, or ECT. "This uses electrical field pulses to induce increased cell membrane permeability to antitumor drugs, such as cisplatin," he explains. While Tamzali also uses this method to treat SCC and melanoma, the ECT unit is not yet available in the United States, but can be purchased from Europe. He notes that his research into ECT and other techniques such as electroimmunogenotherapy is ongoing.
Depending on a sarcoid's location (such as near the eyes or ears, on the lower legs, or over or near a joint or bony protrusion), it might be difficult to eliminate completely, but both Hewes and Tamzali stress that preliminary surgical debulking decreases the number of tumor cells to be killed by chemotherapy, reducing the number of treatments needed. "Debulking a tumor also activates remaining tumor cells--rapid growth makes them more sensitive to cisplatin," says Hewes.
Flat sarcoids grow more slowly than other forms, so cisplatin doesn't target their DNA effectively. "Flat sarcoids respond better to topical agents such as 5-fluorouracil," Hewes suggests. The 5-FU, however, will likely cause inflammation, redness, pain, swelling, and associated discomfort.
Topical treatment is another tactic veterinarians use to stimulate a horse's immune response to resolve sarcoids. Imiquimod cream, with its strong antiviral and ¬antitumor properties, has an 80% success rate in reducing all sarcoids' size by at least 75% (Nogueira SA et al., Vet Dermatol. 2006). Other topical paste products include an herbal compound of bloodroot and zinc chloride. Zinc chloride inflames the tumor while bloodroot alkaloids alter tumor cells so they appear antigenic (foreign) to the horse's immune system. This elicits the horse's rejection of small, flat sarcoids.
BCG (bacillus Calmette-Guerin) injections following debulking of nodular sarcoid tumors have been known to shrink tumors located remotely from injection sites; however, these might cause severe reactions. Some veterinarians will administer an autologous sarcoid vaccine when a horse has not responded to other treatments, but this approach has yielded variable results.
Freezing with liquid nitrogen or heating with radiotherapy hyperfrequency are other variably successful approaches to destroy superficial sarcoids.
Researchers continue to examine effective ways to treat sarcoid tumors. For instance, Nasir is investigating a novel treatment for viral sarcoids: gene silencing, or siRNA. "Gene silencing introduces small RNA (the genetic material ribonucleic acid) molecules into cells to 'shut down' specific gene expression and inhibit activity of the target gene so that virus is unable to replicate itself," she says. "We anticipate that siRNA sarcoid treatment will involve topical application and/or injection directly into the tumor."
In many cases Hewes suggests that equine tumors of any type should only be treated if they are actively growing, causing a problem, or in an inconvenient location. "A dedicated and vigilant owner is important to monitoring treatment progress and identifying possible regrowth of the tumor," she says. "An owner-veterinarian relationship is instrumental in achieving success for tumor resolution."
About the Author
Nancy S. Loving, DVM, owns Loving Equine Clinic in Boulder, Colorado, and has a special interest in managing the care of sport horses. Her book, All Horse Systems Go, is a comprehensive veterinary care and conditioning resource in full color that covers all facets of horse care. She has also authored the books Go the Distance as a resource for endurance horse owners, Conformation and Performance, and First Aid for Horse and Rider in addition to many veterinary articles for both horse owner and professional audiences.
POLL: University Equine Hospitals