Update on canine melanoma (Proceedings)

Please be aware that these notes are not designed to be a complete reference. It is advisable to consult with an oncologist for current treatment recommendations prior to developing a therapeutic plan for your patient.

Malignant melanoma is the most common oral tumor in the dog. It is generally an aggressive tumor type, both locally invasive and associated with a high metastatic rate. Because the behavior of this tumor is similar to malignant melanoma in humans, we can learn from the experience in human oncology and there has been great interest in studying dogs with OMM as models for the human disease. Early detection and knowledge of treatment options is important to provide the best prognosis for patients with oral malignant melanoma (OMM). This lecture will discuss the diagnosis and current treatment options for dogs with OMM.

Signalment/Presentation

Oral tumors are common in the dog (7% of all tumors). Malignant melanoma (OMM) is seen with greatest frequency (30% of all oral tumors). OMM is seen most commonly in older dogs (median 11-12 years). Overrepresented breeds include poodle, cocker spaniel, golden retriever, dachshund, and Scottish terrier.

Signs noted by owners are a mass, halitosis, ptyalism, and dysphagia. A mass or loose teeth (due to bone lysis) may be noticed first by the veterinarian, especially at dentistry. Masses of the caudal mouth/pharynx are often difficult to detect until they are very large. At the time of diagnosis they can sometimes extend into the nasal cavity or retrobulbar space. It is important for a good oral exam to be part of your physical exam and owners who brush their dog's teeth frequently find these tumors at earlier stages. OMM is much more treatable when small. The most common location for OMM are on the buccal mucosa, lips, gingiva, tongue, or hard palate. Approximately 2/3 of melanomas are pigmented. These masses are often pedunculated, ulcerated, and invasive.

Differential Diagnoses – Canine Oral Tumors

Histopathologic Types

1. Malignant melanoma (can be melanotic or amelanotic)

2. Squamous cell carcinoma

3. Fibrosarcoma

4. Epulides (acanthomatous, fibromatous, ossifying) – benign, but invasive, tumors arising from the periodontal ligament

5. Osteosarcoma

6. Odontogenic tumors/ameloblastoma – benign tumors arising from dental laminar epithelium

7. Plasma cell tumor

8. Other round cell tumors (mast cell tumor, lymphoma, TVT)

9. Papilloma – benign, papovavirus-induced, regresses 4-8 weeks

10. Multilobular osteochondrosarcoma

11. Chondrosarcoma

12. Hemangiosarcoma

Non-neoplastic Differential Diagnoses

1. Gingival hyperplasia

2. Tooth root abscess/osteomyelitis

3. Eosinophilic granuloma complex

Diagnosis and Staging

Oral masses are generally difficult to aspirate and touch preparations are not likely to be helpful because the masses are often covered with oral mucosa or ulcerated/inflammed. For most oral masses, incisional biopsy is necessaryto obtain the diagnosis for treatment planning. If the mass is very small, excisional biopsy may be appropriate. If removing loose teeth or treating a tooth root abscess at dentistry, biopsy the involved tissue.

I. Minimum Database Before Biopsy

1. Physical examination with good oral exam and regional lymph node palpation. Palpate palate, check nostrils for airflow, and retropulse eyes to examine for nasal and retrobulbar extension if tumor location is suggestive. Draw location and size of mass on mouth diagram or photograph it. Sedation may be necessary to for thorough examination of oral masses.

2. CBC, Profile, Urinalysis – usually no specific abnormalities referable to oral mass, but important for evaluation of overall health.

3. Aspirate local lymph node – allows biopsy/excision of lymph node at time of biopsy of oral mass if indicated.

II. Tumor Localization for Treatment Planning and Evaluation for Metastasis

**If index of suspicion that this is a malignant tumor (old dog, large oral mass, adherent to bone, enlarged mandibular lymph nodes, etc), do this before biopsy**

1. Evaluation of primary tumor (usually done under same anesthetic episode as biopsy)

a. High detail skull radiographs to look for lysis – need intraoral view, not as helpful as CT scan or MRI

b. CT scan – better for visualization of extent of tumor, bone windows allow evaluation of bone invasion

c. MRI – also can provide excellent visualization of tumor but less available at this time

2. Evaluation of regional lymph nodes

OMM usually spreads first to regional lymph nodes

a. Aspirate ipsilateral mandibular lymph node even if normal in size (in one study, 40% of normal sized nodes had metastasis and 49% of enlarged nodes did not have metastasis)

b. Aspirate both mandibular lymph nodes for tumors at midline area

c. Aspirate retropharyngeal node if enlarged (you will not feel this unless it is enlarged)

d. Examine tonsils when under anesthesia

e. Consider lymph node biopsy if cytology is suggestive of metastasis, but not definitive. Remove nodes at time of oral tumor resection if metastasis present.

3. Evaluation for distant metastasis

It is common for OMM to spread to the lungs

a. Three-view thoracic radiographs

b. Consider abdominal radiographs and ultrasound in older dogs (to look for other diseases) and for dogs with OMM or round cell tumors

c. If distant metastasis is present, will pursue palliative options for local disease.

4. TNM Staging of Oral Tumors

Primary Tumor

Tis: Tumor in situ

T1: <2cm

T2: 2-4 cm

T3: Tumor >4cm

a: No bone invasion

b: None invasion

WHO Stage

Stage I – T < 2 cm

Stage II – T ≥ 2 cm & < 4 cm

Stage III – T ≥ 4 cm or LN +

Stage IV - Distant metastasis

Regional Lymph Nodes

N0: No mets

N1: Movable ipsilateral nodes

N2: Movable contralateral nodes

N3: Fixed nodes

a: Met not confirmed

b: Met confirmed

Distant Metastasis

M0: No mets

M1: Distant mets

III. Histopathologic Examination

1. Incisional biopsy (diagnostic intent)

a. Take a large piece – often oral tumors have large necrotic areas

b. Use a blade or punch biopsy instrument

c. Do not use laser or cautery to biopsy - these disturb cell morphology

d. Have cautery available for after biopsy - the mouth is well-vascularized

e. Plan biopsy tract to be resectable with tumor. Biopsy toward the junction of tumor and normal tissue, but avoid contamination of normal tissue with tumor.

2. Excisional biopsy (curative intent)

**This should be reserved only for very small tumors**

a. Clearly document location of tumor in record (photograph or draw clearly)

b. Submit all tissue resected and provide orientation for histopathologist

3. Information to look for on your histopathology report

a. Diagnosis

b. If undifferentiated tumor (might be read out as anaplastic sarcoma), request special stains

Melan A is specific but not as sensitive for poorly differentiated tumors

S100 is more sensitive, but less specific as it stains tissue of neural crest origin

c. Margins (if excisional biopsy) – ideally would like 1 cm margins around tumor on histopathologic exam

d. Mitotic index/grade – indicator of proliferative activity and possibly metastatic potential

e. Vascular/lymphatic invasion – if present, tumor has started to metastasize

Behavior of Canine Oral Malignant Melanoma

OMM is a locally invasive tumor and frequently invades underlying bone. This is also a highly metastatic tumor and metastasis has been reported to be the most common cause of death. 85-95% of dogs will develop lymph node metastasis and 14-67% will develop distant metastasis, typically to the lungs but other sites are possible. The metastatic rate may be lower for OMM of lip and tongue.

Treatment

I. Surgery

Surgical resection of OMM at an early stage, when the tumor is small, is the treatment offering the best prognosis. Unfortunately, the majority of these tumors are not small at the time of presentation. The procedure performed must be appropriate for the tumor type, size, and location. If locally invasive, mandibulectomy, maxillectomy, or orbitectomy may be necessary. Generally, these procedures are well tolerated when performed properly. **Patients should be thoroughly screened for metastasis and other life-threatening conditions before performing aggressive surgical procedures.** Advanced imaging (CT scan or MRI) is recommended for surgical planning for most oral tumors. Margins of concern should be marked. If tumor excision is incomplete or if surgery is not possible, radiation therapy is recommended for local control.

II. Radiation Therapy

External beam radiation therapy is effective for improving local control of incompletely excised OMM. In addition, RT is effective for shrinking/slowing the growth of non-resectable OMM and palliating pain associated with bone lysis. Local lymph nodes are generally treated at the same time whether lymph node metastasis is detected or not. Response to radiation therapy is largely related to stage of disease. Smaller tumors respond better and are controlled for longer periods of time. Malignant melanocytes have increased ability to repair radiation-induced damage and require a higher dose per fraction so they are sometimes treated with special protocols with higher doses given less frequently. 80-90% of OMMs will shrink with radiation therapy. If a tumor is extremely advanced or if a dog has distant metastasis, a palliative radiation protocol might be considered to improve patient comfort and slow tumor growth. CT scan or MRI is required for planning radiation therapy. It is possible that improved local tumor control will decrease or delay metastasis, but radiation therapy does not treat distant metastasis.

Acute side effects associated with radiation therapy in this area include oral mucositis, glossitis, alopecia, erythema, desquamation, and, if an eye is in the treatment field, keratitis, conjunctivitis, and possibly corneal ulcer. Severity depends on treatment protocol. These effects generally heal by about 1 month following therapy except for eyes in the RT field, which are left with decreased tear production. Serious late side effects are rare, particularly with the prognosis associate with OMM, but could include necrosis of bone, gingiva, and skin. Leukotrichia and changes in skin/mucosa texture are expected, but do not affect patient quality of life.

III. Chemotherapy

Because OMM has as high metastatic rate, the use of chemotherapy is logical for treatment of systemic spread of the tumor. In addition, if effective, chemotherapy may help with local tumor control. Chemotherapy should be considered for all dogs with this tumor, especially if lymph node involvement is detected. Currently there are few studies describing chemotherapy for OMM in dogs. Carboplatin appears to be the most active agent, with a response rate of 28% in the setting of gross tumor and may be associated with improved survival times in dogs with OMM treated with RT (results of studies have been contradictory).

Recently, abnormal cyclooxygenase-2 (COX-2) expression has been demonstrated in some OMM, suggesting a possible role for non-steroidal anti-inflammatory drugs in treating these tumors.

IV. Immunotherapy

Enhancing the immune system's response to cancer has been a strategy for treating cancer for many years. This type of therapy may be particularly useful for treating OMM. A conditionally licensed xenogeneic DNA vaccine for OMM was released in 2007. This vaccine consists of plasmid DNA coding human tyrosinase (a protein expressed by melanocytes). The plasmids are taken up by muscle and produce human tyrosinase. Because this is a foreign protein, the dog's immune system is stimulated and because canine tyrosinase is similar to human tyrosinase, antibodies will also react with canine tyrosinase and stimulate the dog's immune system against the tyrosinase in the melanocytes of the OMM. With adequate local control, long term survival (>1 year) has been described. This vaccine is administered with a needless air propulsion device every other week for 4 doses and then boostered every 6 months. Preliminary studies suggest that the vaccine is safe. Possible toxicities include pain at the injection site, fever, and depigmentation of ears and feet. Currently the vaccine is licensed for administration by veterinary oncologists to dogs with Treatment of dogs with stage II or stage III melanoma with locoregional disease control. This means that the tumor and affected lymph nodes must be completely excised or treated with radiation therapy. Locoregional control is important because it takes weeks for the immune response to be stimulated.

V. Symptomatic Therapies

Antibiotic therapy is recommended for dogs with oral tumors due to the likelihood of secondary infections. Clindamycin or clavamox are appropriate agents because of anaerobes in mouth. Anti-inflammatory doses of prednisone or a NSAID may be helpful for inflammation (do not give together because of potential for gi ulceration). If painful, the addition of tramadol or codeine may help to keep comfortable for a period of time. Soft food may be easier to eat. Rarely in dogs, an enteral feeding tube may be needed for support.

Prognosis

Melanoma generally carries a poor prognosis mainly due to its high metastatic rate, but some dogs die of recurrence and some dogs with small OMM can be cured with surgery. With no treatment, the average survival for dogs with OMM is 2-3 months.

PROGNOSIS WITH SURGERY: Overall, The Median Survival Time After Surgery Is Reported To Be 6-8 Months With A 25% 1 Year Survival Rate. 0-48% Recurred In Multiple Studies. It Is Important To Note That Some Dogs With Small OMM Can Enjoy Long Term Control With Appropriate Surgery. In One Study, The Median Survival Time For Dogs Treated With Surgery Was 511 Days If The Tumor Was <2cm Versus Only 164 Days If >2 Cm Or Lymph Node Metastasis. (Macewen Et Al. 1986) Even For Small Tumors, It Is Important To Consider Completeness Of Excision, Aggressiveness On Histopathology, Vascular/Lymphatic Invasion, And Mitotic Index To Determine Whether Further Therapy Is Indicated.

PROGNOSIS WITH RADIATION THERAPY (RT): Radiation Therapy Is Effective In Shrinking OMM, However, Similar To Surgery, The Median Survival Time In Multiple Studies Has Been 7-10 Months, With Patients Dying Of Metastasis And/Or Local Recurrence. Progression Free Rates Are About 35% At 1 Year And 20% At 2 Years. Prognosis With RT Is Also Related To Tumor Size. In One Study, The Combination Of Low Dose Carboplatin With RT Resulted In A Median Survival Time Of 1 Year (Freeman Et Al. 2003); However Another Study Did Not Confirm This Finding. (Murphy Et Al. 2005)

PROGNOSIS WITH VACCINE: In A Preliminary Study For 33 Dogs With Stage II/III OMM And Locoregional Control Treated With The Xenogeneic DNA Vaccine, The Median Survival Time Was 569 Days. Considering All Dogs (Stage II-IV), The Median Survival Time Was 389 Days. (Bergman Et Al. 2006)

BOTTOM LINE REGARDING TREATMENT: It Is Ideal To Treat When OMM Is Very Small. Completely Excised Small Tumors That Are Not Anaplastic, Having No Vascular/Lymphatic Invasion, No Lymph Node Metastasis, And Lower Mitotic Indices May Be Controlled Long-Term. The Best Treatment For All Other OMM Is A Combination Of Local And Systemic Therapy.

PROGNOSTIC INDICATORS

1. Larger size (>2 cm) is associated with a poorer prognosis.

2. Bone lysis is associated with worse prognosis.

3. Rostral location is associated with a better prognosis with surgery. This is likely due to earlier detection and better surgical options. This does not seem to be a prognostic indicator in dogs treated with RT. OMM of the tongue is associated with a lower metastatic rate (maybe about 50%) and longer survival times.

4. An alternate staging system (Hahn) including size, mitotic index, and presence of metastasis, was prognostic but is not routinely employed. We do, however, consider these factors.

5. In the skin, melanomas with a mitotic index <3/10 HPF are associated with benign behavior and those with a mitotic index > 3/10 HPF are associated with more malignant behavior. We do not have a cut off for OMM, but do consider mitotic index.

6. A recent study (Spangler et al. 2006) showed that mitotic index (MI), nuclear atypia, and tumor score (MI + nuclear atypia score + inflammation + necrosis + size/volume factor) were prognostic for melanocytic neoplasms.