Melanoma's are the most prevalent malignant oral tumor tumors in dogs, but they also appear on the haired skin, sole of the feet, nailbed and eye, the gastro-intestinal system and transitions between mucosae and the skin (such as the lip and anus). Depending on the location melanoma's behave less or more malignant.

Oral melanoma’s occur especially on the gums, followed by the lips, tongue and hard palate.

Behavior

The behavior of oral melanoma is extremely diverse and depends on many factors. The main factors influencing oral melanoma behavior are the location within the mouth, the size and certain characteristics of the tumor tissue (histopathological parameters). These tumors spread towards the head and neck and can invade the surrounding bone tissue. The metastasize quickly towards the surrounding lymph nodes, liver, lungs, kidneys, meninges etc. Up to 57% of dogs with melanoma’s demonstrate radiographical proof of bone metastases, 58-7%” to the local lymph nodes, 14-67% to the lungs and 65% to the tonsils. Therefore, early detection of this tumor types is very important.

Prevalence

Thirty to forty percent of all oral tumors in dogs are melanoma’s. This tumor mainly occurs in older dogs (average of 12 years).

Breed predisposition

A higher risk to develop this type of tumor was reported for dachshund, Golden retriever, poodle, Scottish Terrier. Dogs with heavily pigmented mucosae are said to be more sensitive to develop malignant melanoma’s.

Symptoms

Swellings can occur on the gums, lips and/or palate. These swellings can be solid and brown-black, but in one third of cases the tissue mass can be flesh-colored. Ulceration or necrosis are uncommon. Dogs can express the following symptoms: swelling in or around the mouth, weight loss, bad breath, frequent drooling, difficulties eating (dropping food from the mouth), blood loss originating from the mouth or loose teeth.

Generally, a thorough physical examination is performed, possibly followed by a blood or urine test.

The mass itself

The diagnosis can sometimes be difficult because not all melanoma’s contain pigment (up to 30% of melanoma’s do not contain melanin). If it is possible to determine whether the punctured tissue mass is a round cell tumor and contains pigment, this usually is enough to diagnose the tissue mass as a melanoma. If this is not the case, a biopsy should be taken for further examination. Via immunophenotyping (via PNL2/tyrosinase/Melan A/S100-staining) typical proteins for pigment cells can be colored. If these proteins can be found on locations where they normally do not occur, it is likely that the mass of which the biopsy was taken consists of cancerous pigment cells.

Estimating metastases

The local lymph nodes should be punctured or biopsied. For this tumor type, the size of the local lymph nodes does not accurately indicate whether they contain metastases. Most dogs with metastases have enlarged lymph nodes, but in 30-40% of cases, dogs with an oral melanoma have normal-sized lymph nodes and yet containing cancerous cells.

Because of the diverse behavior of melanoma’s, it can be indicated to take X-rays of the bones and lungs, as well as ultrasound of the abdomen to detect metastases on other locations than lymph nodes.

Surgery

Surgery is the most effective local treatment for melanomas. Small tumors (<2 cm in diameter) that are not attached to the underlying tissue layers, are well defined and grow slowly and are generally benign, allowing the dog to heal completely through surgery. Large, ill-defined, rapidly growing tumors (> 2 cm) with ulceration are difficult to remove completely by surgery.

Because melanomas are so invasive and can spread quickly, wide margins need to be calculated when the tumor is removed. With melanomas that occur on the gums, it is possible that this involves the removal of part of the upper or lower jaw. With melanomas in the cheeks, lips or tongue, bone removal is often not necessary. In general, a margin of 1 to 3 cm should be calculated depending on the degree of the tumor (ideally 1 layer of tissue). If only incomplete margins (space around the tumor) can be obtained, the combination of surgery with radiotherapy or additional treatments such as chemotherapy and immunotherapy is recommended.

Radiotherapy

Melanomas are considered relatively insensitive to radiation therapy (although much depends on the radiation therapy protocol). However, radiation therapy is considered an effective therapy for the local control of oral melanoma with minimal side effects in dogs. Usually, the tumor of the oral cavity and the local lymph nodes (mandibular and retropharyngeal) are treated. Typically, a margin of 2 cm is applied around the tumor or the surgical incision site.

Curative radiotherapy (with healing intent):

Malignant melanomas generally respond well to dose fractionation (with a total of 6 fractions either 1x / week for 6 weeks or 2x / week for 3 weeks). Response to treatment occurs fairly quickly (tumor size decreases within weeks of first treatment). Relapse: Depends on the protocol used. When cancer cells are still microscopically present, 26% of the treated dogs relapse. When macroscopic cancer tissue is still present, 45% of the treated dogs relapse. In tumors smaller than 5 cm3, the chance of a cure via radiotherapy is more likely. A complete or partial reduction of the tumor usually occurs after radiation, although it is often temporary. Average survival time: 5.3-11.9 months. De prognose verbetert naarmate de tumor meer vooraan in de mond gelegen is, er geen radiografisch bewijs is van botaantasting en geen microscopisch detecteerbare kankercellen aanwezig zijn. The prognosis improves as the tumor is located more at the front of the mouth, there is no radiographic evidence of bone damage and no microscopically detectable cancer cells are present. The side effects of radiotherapy depend on various factors such as the total dose used, the dose / fraction and the volume of tissue in the irradiation field. Rapidly occurring side effects can include swelling of the mucous membranes, as well as mild inflammation with possible pain, bleeding, ulceration and tissue death of the gums, tongue and cheek mucosa. At the level of the skin, the skin may feel dry and a skin thickening and baldness may occur in that place. These side effects usually recover within 1-2 weeks of treatment. Side effects can also occur at a later time: in 1/10 dogs a certain amount of bone tissue death has been observed in the long term and tumors can also paradoxically develop through radiation.

Palliative radiotherapy:

This is a form of radiotherapy that is not intended to cure, but to slow down the disease. This form of treatment is mainly used in metastatic or advanced oral malignant melanoma.

Chemotherapy

Chemotherapy may be appropriate in dogs with malignant melanoma because of the high risk of metastasis (up to 75%). This chemotherapy can be administered directly into the tumor or intravenously. Until now, chemotherapy has not been shown to be very effective in melanomas.

Intralesional chemotherapy (directly in the tumor):

The information about these treatment options is rather anecdotal. Implants that release the chemotherapeutic agent cisplatin are placed in the tumor. With this treatment, up to 70% of treated dogs may experience temporary tumor reduction, but no cure. One can also inject cisplatin into the tumor and then apply electrodes to the tumor. These provide a small shock that temporarily causes pores in the cancer cells. Through these pores, the chemotherapeutic agent penetrates into the cancer cells which die. The latter treatment is not yet standard treatment in veterinary medicine and cannot be offered on a regular basis due to the need for a special device called an electroporator.

Systemic chemotherapy:

The best clinical effects against oral malignant melanomas have so far been obtained with chemotherapeutics such as carboplatin and cisplatin.

Immunotherapy

Immunotherapy is a promising additional treatment for dogs with oral malignant melanomas. Until recently, the most popular supportive / adjunct treatment was chemotherapy. However, melanomas are not very sensitive to chemotherapy, which means that immunotherapy is gradually becoming more and more prominent as an alternative method to stop the division of cancer cells. At the moment, there are not many immunotherapeutic treatments in circulation in Belgium or the Netherlands.

Oncept®

is a therapeutic cancer vaccine that produces a protein (tyrosinase), which is a protein specific for melanocytes (pigment cells). This vaccine teaches the dog's body to better recognize and keep the cancer cells in check. This treatment is especially indicated for the treatment of dogs with stage II or III oral melanoma and in whom (after treatment) tumor growth could be stopped. The results of this vaccine were compared with data obtained in the past for dogs with this tumor type. This comparison showed that the survival time doubled after the administration of the cancer vaccine. For example, stage I-III melanomas that were locally controlled had an average survival time of 1075 days, while stage I-III melanomas that were not locally controlled had an average survival time of 553 days. However, caution should be exercised when interpreting these results because, due to increasingly early detection, better treatment methods and methods dogs have a longer survival today than in the past. This vaccine would be especially interesting as an additional treatment when as little cancer tissue as possible is present (eg after surgery).

Pet Biocell

is a German company that makes cancer vaccines. To date, there are not enough large studies available to show that this treatment works.

Elias Animal Health

is an American company that makes cancer vaccines and collects white blood cells after administration. When the white blood cells that specifically recognize the cancer cells are cultured in large numbers, they are returned to the dog to more efficiently kill the cancer cells. For the time being, only results for a bone tumor are known.

Oral melanomas are considered to be extremely malignant tumors because of their high invasiveness and strong tendency to metastasize. Small non-metastatic tumors can be completely cured. Surgery is sufficient for a low-grade tumor of 0.5 cm diameter on hairy skin, but a high-grade oral tumor of 5 cm diameter has a poor prognosis. The average survival time depends on the stage in which the tumor is located. For stage I-II, a survival time of 20 months can be expected, while for stage III-IV this is only 6 months.

Stages

• I: if the tumor diameter is ≤ 2 cm and there are no local lymph nodes or metastases
• II: if the tumor diameter is between 2-4 cm and no local lymph nodes are affected or metastases
• III: if the tumor diameter is> 4 cm without affected lymph nodes or metastases; if the tumor diameter is between 2-4 cm and there are affected lymph nodes, but no metastases
• IV: as soon as metastases are present

The prognosis is reserved to poor since metastases occur in 95% of the cases. The occurrence of metastases depends on the location, size and stage of the tumor.

The prognosis worsens as

• the tumor is larger (melanomas less than 2 cm (stage I) are associated with a survival time of 511 days, while melanomas larger than 2 cm or metastatic melanomas (stage II-III) are associated with a survival time of 164 days)
• the stage is higher
• the tumor is located in the mouth
• and at local relapse

Histology

Via histopathological examination, it is possible to find out how quickly the cancer cells divide (mitotic index). Melanomas with a mitotic index of 3 or less are associated with a better prognosis than those above 3.

Tumor location

Tumors on the lower jaw have a better prognosis than those on the upper jaw when treated with injection of chemo into the tumor (intralesional cisplatin)..

Average survival time includes:

• 65 days without treatment
• 240-318 days with surgery (median survival 17-18 months for stage I, 5-6 months for stage II and 3 months for stage III)
• 240-363 days with radiotherapy
• 1120 days with surgery and chemotherapy