Melanomas are the most prevalent malignant oral tumour 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 melanomas behave less or more malignant.

Oral melanomas occur especially on the gums, followed by the lips, tongue and hard palate.

Behaviour

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 tumour tissue (histopathological parameters). These tumours 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 melanomas demonstrate radiographical proof of bone involvement, metastasis occurs in 58-73% of cases to the local lymph nodes, 14-67% to the lungs and 65% to the tonsils. Therefore, early detection of this tumour type is very important.

Prevalence

Thirty to forty percent of all oral tumours in dogs are melanomas. This tumour mainly occurs in older dogs (average of 12 years) but may also be seen in younger dogs.

Breed predisposition

A higher risk to develop this type of tumour was reported for Chow Chows, dachshund, Golden retriever, poodle, Scottish Terrier. Dogs with heavily pigmented mucosae are said to be more sensitive to develop malignant melanomas.

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 melanomas contain pigment (up to 30% of melanomas do not contain melanin). If it is possible to determine whether the punctured tissue mass is a round cell tumour 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

Histologic examination of the lymph nodes is recommended. These lymph nodes can be the major lymph nodes of the head and neck or lymph nodes identified via sentinel lymph node mapping (injection of a dye that shows the lymphatic drainage pathway). For this tumour 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 melanomas, 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. CT scans or MRI scans are critical for the surgical planning of oral melanoma, especially melanomas involving the upper and lower jaw bones. Bone involvement has been reported in up to 57-92% of dogs with oral melanoma.

Surgery

Surgery is the most effective local treatment for melanomas. Small tumours (<2 cm in diameter) that are not attached to the underlying tissue layers, are well defined and grow slowly tend to be benign and easily excisable. Large, ill-defined, rapidly growing tumours (> 2 cm) with ulceration can make surgical excision challenging.

Because melanomas are so invasive and can spread quickly, wide margins need to be calculated when the tumour 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 tumour (ideally 1 layer of tissue). If only incomplete margins (space around the tumour) can be obtained, the combination of surgery with radiotherapy or additional treatments such as chemotherapy and immunotherapy should be considered - although the efficacy of chemotherapy and immunotherapy against metastases is still under investigation.

For dogs that undergo a partial removal of the upper or lower jaw, quality of life is usually very good, and most dogs resume eating within three days of surgery.

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 tumour of the oral cavity and the local lymph nodes (mandibular and retropharyngeal) are treated. Typically, a margin of 2 cm is applied around the tumour 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 once per week for 6 weeks or twice per week for 3 weeks). Response to treatment occurs fairly quickly (tumour size decreases within weeks of first treatment). A complete or partial reduction of the tumour is possible, although it is often temporary. The occurrence of 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 tumours treated with radiotherapy smaller than 5 cm3, chances of response and survival time were higher than for larger tumours. The reported most common survival time for radiotherapy range from 4.5 to 14.7 months. The prognosis improves as the tumour 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 tumours 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 tumour or intravenously. Until now, chemotherapy has not been shown to be very effective in melanomas.

Intralesional chemotherapy (directly in the tumour):

The information about these treatment options is rather anecdotal. Implants that release the chemotherapeutic agent cisplatin are placed in the tumour. With this treatment, up to 70% of treated dogs may experience temporary tumour reduction, but no cure. One can also inject cisplatin into the tumour and then apply electrodes to the tumour. 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 (see non-exhaustive list on electrochemotherapy). Overall, electrochemotherapy seems to be a reasonable option in dogs who are not surgical candidates. The response rate is similar to that of radiotherapy.

Systemic chemotherapy:

The best clinical effects against oral malignant melanomas have so far been obtained with chemotherapeutics such as carboplatin and cisplatin. However, chemotherapy has not been shown to be very effective in melanomas so far.

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 few immunotherapeutic treatments available in Europe.

Oncept®

Melanoma expresses the pigmentation enzyme tyrosinase and its expression increases as the tumour grows. Therefore, treatments that target tyrosinase will also allow targeting of melanomas. Oncept® is a therapeutic cancer vaccine that produces a foreign (human) tyrosinase. This vaccine teaches the dog's immune system to better recognize melanoma cells and attack them. A study compared 58 prospectively enrolled dogs with surgically resected stage II and III oral melanomas treated with adjuvant Oncept® to a historical control group of 53 dogs. Dogs treated with Oncept® had a significantly better outcome: the median survival time for dogs in the historical group was 324 days whereas the median survival time could not be determined in the vaccinated group as only 26% of the dogs died as a result of their disease. However, caution should be exercised when interpreting these results because, due to increasingly earlier detection and better treatment methods, dogs have a longer survival time today than in the past. This vaccine could be interesting as an additional treatment in a minimal residual disease setting (when as little cancer tissue as possible is present (e.g. after surgery)) and this approach is still under investigation.

Pet Biocell

is a German company that produces personalized cancer vaccines. To date, there are no large studies available that demonstrate this treatment option is effective.

Elias Animal Health

is an American company that produces cancer vaccines and collects white blood cells after administration of the cancer vaccine. 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, there are no trial results available for melanoma, only for bone tumours (14 dogs enrolled of which 50% of dogs survived greater than one year and 36% survived multiple years).

Oral melanomas are considered to be extremely malignant tumours because of their high invasiveness and strong tendency to metastasize. Small non-metastatic tumours can be completely cured. Surgery is sufficient for a low-grade tumour of 0.5 cm diameter on hairy skin, but a high-grade oral tumour of 5 cm diameter has a poor prognosis. The average survival time depends on the stage in which the tumour 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 tumour diameter is ≤ 2 cm and there are no local lymph nodes or metastases
• II: if the tumour diameter is between 2-4 cm and no local lymph nodes are affected or metastases
• III: if the tumour diameter is> 4 cm without affected lymph nodes or metastases; if the tumour 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 tumour.

The prognosis worsens as

• the tumour is larger (melanomas less than 2 cm (stage I) are associated with a median survival time of 511 days, while melanomas larger than 2 cm or metastatic melanomas (stage II-III) are associated with a median survival time of 164 days)
• the stage is higher (most common median survival times for dogs with oral melanoma treated with surgery is 511-874 days (stage I), 160-818 days (stage II) and 168-207 days (stage III)).
• the tumour 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.

Median 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