Dr Ana Nemec
Ana Nemec, DVM, PhD, Dipl. AVDC, Dipl. EVDC; Ana Rejec, DVM, PhD, Resident, Veterinary dentistry
Animal Hospital Postojna, Cesta v Staro vas 20, 6230 Postojna, Slovenia
Case history and clinical signs
Figure 1: Amelanotic malignant melanoma affecting right rostral maxilla in a 4-year-old female German shepherd at presentation.
A 4-year-old 30-kg female spayed German shepherd was presented due to rapidly growing rostral maxillary mass. At presentation, the proliferative mass, located around right maxillary third incisor and canine tooth was ulcerated and bleeding (Fig. 1). The patient was otherwise healthy with physical exam findings, CBC and biochemistry all within normal limits. Staging options were discussed and the client elected computed tomography (CT) of the head and neck as well as chest CT together with biopsy of the lesion and an abdominal ultrasound.
Imaging and histopathology findings
Figure 2: A CT image taken at the level of maxillary canine teeth at presentation. Note an invasive lesion occupying majority of the right nasal cavity and crossing the midline
Pre- and post-contrast CT images revealed an invasive lesion, located primarily around the maxillary canine tooth and extending from the right maxillary second incisor tooth to the mesial root of the right maxillary second premolar tooth, occupying majority of the right nasal cavity and crossing the midline (Fig. 2). CT of the neck and chest revealed no metastatic disease to the regional lymph nodes and lungs, and abdominal ultrasound was also within normal limits.
Histopathology of the lesion revealed spindle-cell neoplasm, with differential diagnoses being fibrosarcoma or spindle-cell amelanotic melanoma, and further immunohistochemistry using Melan A and PNL-2 antibodies was performed and was suggestive of amelanotic melanoma.
A stage III (with no detectable metastasis based on the diagnostics performed) amelanotic melanoma was diagnosed.
Treatment and follow-up
Figure 3: With the dog under general anaesthesia in dorsal recumbency an incision is planned to remove the tumor with narrow margins (“debulking surgery”).
Figure 4: Once the right rostral maxilla and left incisive bone are en-block removed together with the tumor, hemostasis is achieved by ligation of major palatine arteries. Note macroscopically-visible tumor remnants in the right nasal cavity.
Figure 5: Immediate post-operative photograph of the 4 years old dog with OMM.
Due to an extensive involvement of the nasal cavity, wide resection was impossible to achieve without significantly impairing the cosmetic appearance and function of the animal, and the client elected palliative-intent extended unilateral rostral maxillectomy to reduce tumor burden (Figs. 3-5), followed by a course of adjuvant hypo-fractionated radiotherapy of the surgical area (6 x 6 Gy twice weekly) 3 weeks after the surgery (Figs. 6-9).
Figure 6: Three weeks post surgery the mucosal flaps have healed and any remaining sutures are removed to minimize irritation and inflammation before radiation therapy is initiated
Figures 7: Radiotherapy is performed 3 weeks after surgical resection of amelanotic malignant melanoma with the dog under general anesthesia. Note a lead plate positioned in the mouth to prevent irradiation (exit dose) of the healthy mandibles. A bolus is used on the maxilla to achieve optimal dose distribution in the irradiation field.
Figure 8: Radiation therapy technologist adjusting the patient and equipment to correctly apply the radiation treatment plan.
Figure 9: Acute side affects of radiotherapy (radiomucosititis) 2 weeks after completion of radiotherapy, which diminished with supportive antibiotic, local antiseptic and anti-inflammatory treatment.
Melanoma vaccine treatment (4-dose, biweekly protocol, then boosters in 6-month intervals) was added to the treatment protocol as an immunotherapy approach to multimodal treatment approach. At all re-checks, the patient was clinically healthy and the most recent re-check head and neck and chest CT revealed no metastases 5 years after the diagnosis (Fig. 10).
Figure 10: 5-year follow up – no clinical nor CT evidence of local tumor recurrence
Malignant melanoma (OMM) is the most common nonodontogenic oral tumour in dogs. Clinical signs may vary greatly; the tumour is not necessarily pigmented (black). Histopathological diagnostics may be complicated as a tumour may present as amelanotic variant and/or as epithelioid-cell OMM, spindle-cell OMM or mixed-cell OMM. Therefore, immunohistochemistry is often needed to determine the diagnosis. OMM is locally invasive, with 50% of tumours being associated with surrounding bone invasion. Metastases are also common: in 74% of cases, OMM metastasise in regional lymph nodes and in up to 92% of cases in the lungs.
Hence, before any treatment is attempted, a patient with an OMM needs to be properly staged. To evaluate local disease, tumor location is noted and the lesion measured. Diagnostic imaging of the local lesion should include pre- and post-contrast CT of the head, as skull radiographs and/or intraoral dental radiographs will underestimate the extent of the lesion and especially invasion of maxillary tumor into adjacent structures. Magnetic resonance imaging (MRI) can also be considered and PET/CT is becoming available in veterinary medicine as well.
Evaluation of regional lymph nodes may be challenging. Although palpation of the mandibular lymph nodes should be routinely performed, it needs to be realized, that 40% of palpably normal lymph nodes contain metastases. Fine needle aspiration of the regional lymph nodes may be helpful, but reaching the main draining center of the head – retropharyngeal lymph nodes – requires ultrasound-guided approach. Also, it has recently been described, that consensus between cytology and histopathology for staging of lymph nodes in patients with melanocytic neoplasms is poor, and negative result does not rule out metastases. Evaluation of size and contrast-enhancement pattern on post-contrast CT images can be very helpful in evaluating regional lymph nodes for metastases, and PET/CT is also very promising. Excisional biopsy of the lymph nodes is debatable, as complete staging requires removal of all lymph nodes of the head and neck. Excisional biopsy of the sentinel lymph node – technique which is well developed in human medicine – is the goal and determination of the sentinel node will hopefully become easier with advanced imaging techniques.
Staging is completed with evaluation of distant organs for possible metastatic disease, where chest CT is much more sensitive to diagnose pulmonary metastases compared to thoracic radiographs. Full body CT may be recommended, if involvement of abdominal organs is suspected, which is rare in cases of canine OMM, and abdominal ultrasound is usually performed.
Once the stage of the OMM is determined, the treatment approach(es) and prognosis can be discussed with the client. It is worth mentioning here, that scientific data on treatment outcomes for specific stage OMM, especially when several treatment approaches are combined, are scarce. Hence, proper communication with the client is extremely important to present as much as possible information and keep realistic expectations. Generally, prognosis for animals, especially if the tumour arises from dentate areas, is guarded due to early and common metastases. Dogs with small OMM (smaller than 2 cm in diameter, stage I) located rostrally and those without metastases, have the best prognosis. With radical tumour resection (tumour with associated 1 cm of healthy tissues as determined by CT) median survival time was reported to be 723 days and related to tumor stage. It has also been reported, that even incomplete tumour resection (dirty margins) increases survival time. When complete resection cannot be achieved (as was expected in the presented case), or the client declines surgical treatment, or when surgery has resulted in incomplete removal of the tumor, or when regional metastases are present, other treatment options exist, although some studies questioned the benefits of adjuvant therapies. When recommending an adjuvant treatment, most commonly suggested is radiation therapy, which can also be the sole treatment for OMM (local and regional disease). The outcome of radiation therapy depends, as with surgery, on the stage of the tumor as well as on the radiation protocol; most commonly hypo-fractionated radiation protocols are recommended and, when used as a sole treatment of OMM, can result in median survival times a bit shorter than those achieved with surgical treatment. Acute side effects, such as radiomucositis are common, expected and usually resolve with supportive treatment, while late life-threatening side effects, such as osteoradionecrosis or secondary tumors, are rare, but need to be discussed with the client in advance, especially when long-term survival of irradiated patients is expected.
OMM is considered poorly responsive to chemotherapy, but is a highly immunogenic tumor. Although the exact immune mechanisms are not completely understood and are likely individually-specific, several immunotherapy and/or gene-electrotransfer therapy approaches have been suggested for canine OMM patients. Most (clinical) research has been performed on a canine melanoma vaccine (xenogeneic plasmid DNA with a cDNA insert encoding human tyrosinase), which has been shown to be safe, but data on its’ efficacy are conflicting. Although it remains unclear, what (if any) role melanoma vaccine and other treatments played in the prevention of metastatic disease in the case described in this report, it is important to realize, that the outcome of canine OMM treatment may not neccessary be poor. In addition, new multimodal approaches are being developed to treat canine OMM and are changing this disease with historically poor outocme into a chronic disease, at least in selected cases.
Clinical study at Animal Hospital Postojna
At Animal Hospital Postojna we recently began a study titled “Evaluation of immune system response to hypo-fractionated radiotherapy in canine non-operable oral, cutaneous or digital melanoma’ together with the Oncovet Clinical Research Centre in France. The study aims to evaluate immune system response to hypo-fractionated radiotherapy in canine non-operable oral, cutaneous, or digital melanoma and to assess the ability of this therapy to improve the response to immunotherapy in combined treatment. With the client’s agreement, we include dogs (males and females) with malignant melanoma when the tumour cannot be surgically removed, either due to its localisation preventing the recommended wide excision, or the client’s refusal to approve such a procedure. In that case, hypo-fractionated radiotherapy remains the preferred treatment. If you or anyone you know are interested in participating in the study and would like to know more about the study protocol and obligations, risks and potential constraints as well as benefits that we offer if you decide to participate, please, contact us at firstname.lastname@example.org