Nasal Neoplasia in the Dog and Cat
Margaret C. McEntee, DVM, DACVIM (oncology),
DACVR (radiation oncology)
Nasal and paranasal sinus tumors represent approximately 60-80% of all canine respiratory tract tumors, but only 1-2% of all tumors and are less frequently observed in cats. Nasal tumors occur most commonly in the nasal cavity with secondary extension into the frontal and other paranasal sinuses. The majority of nasal tumors are malignant. Nasal tumors are primarily locally invasive and infrequently metastasize. The rate of metastasis at presentation in dogs and cats has ranged from 0-12.5%. There is no consistent sex predilection in either the canine or feline. Age at presentation in the dog ranges from 2-16 years, with a median of 10. Dogs with nasal sarcomas may present at an earlier age. The mean age of cats with nasal tumors is 8-10 years, with a range of 1-19 years.
Epidemiology and risk factors
Dolichocephalic and mesaticephalic dogs have a higher risk while brachycephalic dogs have a lower risk of developing sinonasal cancer. Brachycephalic breeds with the associated malformations and nasal stenosis are typically open mouth breathers with resultant decreased exposure of the nasal turbinates to potential environmental carcinogens. Risk of nasal cancer appears to correlate with the amount of surface area in the nasal passages and the efficiency of the filtering capability. Mixed breed dogs have an equivalent risk of developing nasal cancer as purebred dogs suggesting a possible environmental influence. Exposure to environmental tobacco smoke, indoor kerosene or coal combustion and use of flea spray have all been associated with an increased risk of sinonasal cancer in dogs.
Breeds considered to be at increased risk include Airedale terriers, basset hounds, old English sheepdogs, Scottish terriers, collies, Shetland sheepdogs, and German shorthair pointers. Labrador retrievers and golden retrievers appear to be over-represented in the group of dogs that present with nasal planum tumors.
Transmissible venereal tumor (TVT) has been reported to occur in the nasal cavity although it is more commonly found on the external genitalia. TVT is transmitted by contact with mucous membranes and occurs more readily if there are breaks in the integrity of a mucosal surface.
In cats there is some indication that chronic rhinitis/sinusitis may be an initiating factor for the subsequent development of nasal neoplasia. Nasal lymphoma has been reported in FeLV positive as well as FeLV negative cats.
In dogs the duration of symptoms prior to diagnosis ranges from 2 weeks to 2.5 years with an average duration of 3-4 months. The most common clinical signs are decreased airflow through the affected nasal passage, epistaxis and sneezing. Other signs include reverse sneezing, stertorous breathing, serous, mucoid or mucopurulent nasal discharge, dyspnea, lethargy, weight loss, and facial deformity or swelling. On oral examination there may be obvious deviation of the hard palate or a defect may be palpable. Tumors on the nasal planum or in the nasal vestibule can be readily visualized and are typically localized to the rostral aspect of the nose. The most common clinical signs at presentation in dogs with nasal planum tumors include ulceration, bleeding and sneezing. Ocular signs include ocular discharge, exophthalmia, blindness, and it may be possible to detect decreased retropulsion of the eye(s). Central nervous system signs include seizures, behavior changes, obtundation, and neurologic deficits. Neurologic signs frequently occur only in the advanced disease state, but a subset of dogs and cats present initially for neurologic signs.
In cats the duration of clinical signs prior to presentation has ranged from 7 days to 5 years. There is variability in clinical signs based on whether there is a nasal or nasopharyngeal tumor present. Cats with nasal disease commonly have a history of nasal discharge and sneezing, whereas cats with nasopharyngeal disease more often have stertorous respiration, and change in phonation. Digital palpation of the soft palate may reveal a mass effect in cats with nasopharyngeal tumors. Other clinical signs include epiphora, epistaxis, and facial deformity.
Approximately 33% of all dogs with chronic nasal disease have nasal neoplasia. The differential diagnoses for chronic nasal disease include: aspergillosis, lymphoplasmacytic rhinitis, bacterial rhinitis, foreign body (e.g., plant awn), oronasal fistulae, dental disease, inflammatory polyp, and Pneumonyssus caninum (nasal mite), penicilliosis, rhinosporidiosis, and pythiosis. In patients with epistaxis other differentials include primary coagulopathies, secondary coagulopathies (e.g, canine ehrlichiosis) and hyperviscosity syndrome (e.g., multiple myeloma). In cats differential diagnoses include nasopharyngeal/inflammatory polyps, bacterial or viral rhinitis, lymphoplasmacytic rhinitis, and cryptococcosis.
Initial evaluation should include complete blood work (hemogram, biochemical profile, urinalysis), regional lymph node aspiration cytology, three view thoracic radiographs, nasal biopsy, and imaging of the nasal cavity (radiographs, CT, and/or MRI). A coagulation profile may be indicated to rule out an underlying coagulopathy. Blood work results are typically unremarkable. There have been isolated reports of paraneoplastic syndromes associated with nasal tumors including erythrocytosis, hypercalcemia and immune-mediated thrombocytopenia.
Three view thoracic radiographs are recommended to rule out pulmonary metastasis, although thoracic studies are typically negative at the time of initial presentation. In studies reporting necropsy findings 3-30% of dogs had evidence of pulmonary metastasis.
Techniques used to obtain cytologic or tissue samples from the nasal cavity include nasal flush, traumatic core biopsy, blind pinch biopsy, and rhinoscopy-assisted biopsy. Cytology can be diagnostic but biopsy and routine histopathology are recommended to obtain a definitive diagnosis prior to the initiation of therapy. It is important to inform clients that biopsies obtained by blind procedures may result in non-diagnostic samples. It may be necessary to perform a dorsal or ventral rhinotomy to obtain sufficient material for histopathology and a definitive diagnosis of neoplasia.
Radiographic examination of the nasal cavity includes up to six different views. The two most useful views are the dorsoventral intraoral view of the nasal cavity and the rostrocaudal view of the frontal sinuses. Studies have been done to compare the radiographic signs in dogs with rhinitis versus nasal tumors. Rhinitis is associated with a higher incidence of focal or multifocal lesions, localized soft tissue opacities, lucent foci, and a lack of frontal sinus involvement. Nasal neoplasia is associated with soft tissue opacities and loss of turbinate detail affecting the entire ipsilateral nasal cavity, signs of bony invasion, and soft tissue/fluid opacities within the ipsilateral frontal sinus. Routine radiography is a useful initial screening tool however complete staging of nasal disease requires CT and/or MR imaging. In older dogs and when there is a high index of suspicion nasal neoplasia then typically a CT scan is done as the initial imaging modality.
On both radiographic and CT examination of the nasal cavity a portion of the observed soft tissue opacification may be mucus, blood and/or necrotic debris. The identification of a mass effect and/or associated turbinate or bone destruction lends support to soft tissue opacification being tumor. Obstruction of the nasofrontal opening can result in mucus accumulation in the frontal sinus. Without a biopsy from the frontal sinus region and/or evidence of a mass lesion or bone destruction definitive evidence of frontal sinus involvement is often lacking.
TABLE 1 : Two Systems for Staging Nasal Tumors.
† World Health Organization Staging System
‡ Modified Staging System developed by Théon.
CT imaging is important both for staging (see Table 1) and treatment planning. For radiation treatment planning CT has been shown to be critical for identification of the full extent of disease. CT images can be directly down loaded into the radiation treatment planning computer. Dorsal plane CT imaging may provide a more accurate assessment of the integrity of the cribriform plate in comparison to the standard transverse CT images.
The most common epithelial tumors in dogs are adenocarcinomas, undifferentiated carcinomas and squamous cell carcinoma. Other epithelial tumors include transitional carcinoma, neuroendocrine tumors, and esthesioneuroblastoma. Osteosarcoma and chondrosarcoma are the most common mesenchymal tumors. Other mesenchymal tumors include fibrosarcoma, undifferentiated sarcoma, hemangiosarcoma, liposarcoma, leiomyosarcoma, myxosarcoma, rhabdomyosarcoma, malignant fibrous histiocytoma, and malignant nerve sheath tumor. Round cell tumors reported to involve the nasal cavity include transmissible venereal tumor, lymphoma, mast cell tumor, and histiocytoma. Other nasal tumors include malignant melanoma, and paranasal meningioma. Tumors of the nasal planum are far less common than nasal cavity tumors. The most common tumor of the nasal planum is squamous cell carcinoma. Other tumors that have been reported at this site include cutaneous lymphoma, fibrosarcoma, hemangioma, melanoma, mast cell tumor, and fibroma.
The most common tumors in cats are lymphoma and carcinoma (adenocarcinoma and undifferentiated carcinoma). Other nasal and/or nasopharyngeal tumors that have been reported include fibrosarcoma, anaplastic or undifferentiated sarcoma, squamous cell carcinoma, rhabdomyosarcoma, osteosarcoma, melanoma, esthesioneuroblastoma, chondrosarcoma, chondroma, adenoma, and hemangioma.
Surgery alone is ineffective in the treatment of nasal cavity tumors resulting in survival times comparable to that observed in untreated dogs. The mean survival time for 41 dogs undergoing surgery alone was 4 months with a range of <1 month to 11.5 months. Surgery alone or in combination with radiation therapy is important in the management of squamous cell carcinoma of the rostral nasal cavity (nasal planum, nasal vestibule) in the dog as radiation therapy alone to date has been shown to be ineffective.
External beam radiation sources that have been used to irradiate nasal tumors include orthovoltage, and megavoltage (Cobalt 60 or linear accelerator). Radiation alone or after cytoreductive surgery has been the standard of care for treating nasal tumors. Cytoreductive surgery is recommended prior to orthovoltage radiation due to depth-dose characteristics and the difficulty in delivering dose at depth in dogs with nasal tumors. Surgery has not resulted in improved survival in dogs treated with megavoltage radiation and in this setting is not recommended. Surgery may play a role in the treatment of nasal tumors after radiation therapy but this awaits additional investigation.
The reported median survival times for dogs treated with orthovoltage radiation is 23 months and 16.5 months. The 1- and 2-year survival rates were 54% and 43% in the report by Evans et. al., and were equivalent to the previously reported survival rates. The mean and median survival with cobalt irradiation for 27 dogs was 20.7 and 12.8 months, with a 1-year survival rate of 59% and 2-year survival rate of 22%. Comparable results were obtained in a study of 77 dogs treated with cobalt 60 teletherapy with a mean survival of 21.7 months and median survival of 12.6 months, 1-year survival rate of 60.3%, and 2-year survival rate of 25.1%. Radiation therapy has been shown to be efficacious in the treatment of transmissible venereal tumors. In one study 7/8 dogs obtained a cure with a single 10 Gy dose.
In early reports of irradiation of nasal tumors a single dorsal port was used based on external landmarks (medial ocular canthi bilaterally, caudal extent of the frontal sinuses, and the nasal planum). With CT imaging it was determined that in 28 of 31 dogs these external landmarks would have underestimated the tumor extent and resulted in a geographic miss. Failure in dogs with nasal tumors after irradiation is usually due to local recurrence as opposed to metastasis. The mid to caudal nasal cavity has been identified as the most common site of recurrence. Thrall, et. al., evaluated the efficacy of a boost technique to deliver additional dose to the expected site of recurrence, but due to significant acute reactions and poor survival (median survival = 177 days) the described protocol was not recommended.
Surgery alone in four cats with nasal adenocarcinoma or undifferentiated carcinoma resulted in a mean survival time of 2.5 weeks. In one report the interval between surgery and euthanasia ranged from 2-8 months. There are fewer reports on irradiation of feline nasal tumors. Cytoreductive surgery prior to irradiation has been used prior to orthovoltage and cobalt 60 irradiation with minimal side effects. However, due to the depth of the nasal cavity in cats radiation alone may be effective with orthovoltage as well as megavoltage radiation therapy. The median and mean overall survival time (n = 16 cats) in one study was 11.5 and 14.8 months respectively, with a 1- and 2-year overall survival rate of 44.3% and 16.7%. Evans, et. al. reported a mean and median survival (n = 9 cats) of 27.9 and 20.8 months with a 66.7% 1-year, 44% 2-year, and 33% 3-year survival rate. Rhinotomy was performed in 6 of the 9 cats prior to orthovoltage irradiation. Straw, et. al. reported a mean survival of 19 months and median survival of 13 months for 6 cats treated with megavoltage radiation alone.
There is limited information on the response of nasal tumors to chemotherapy alone. Documentation of response to single agent cisplatin lends support to the application of chemotherapy in combination therapy protocols. Cisplatin alone in 11 dogs with nasal adenocarcinoma resulted in clinical improvement in all dogs with two complete responses and one partial response for an overall response rate of 27%. The median survival time however was only 20 weeks, which is comparable to no treatment or surgery alone. Chemotherapy alone may be effective in the management of select nasal tumors such as TVT. Nasal lymphoma in cats has been treated with chemotherapy alone. Two of three cats achieved a complete remission for 5 and 10 months with a combination of cyclophosphamide, vincristine and prednisone. Cats with nasal lymphoma can have long-term control with local irradiation alone although a subset fail due to systemic disease. Feline leukemia virus positive cats may have a greater likelihood of failure due to systemic involvement. It is difficult to identify cats with nasal lymphoma at risk for systemic failure and as appropriate the most aggressive treatment should include a combination of local radiation and systemic chemotherapy.
The median survival time for 13 dogs treated with a combination of external beam radiation therapy (6 MV linear accelerator; daily Monday through Friday; 3.3 Gy/fraction; median total dose of 49.5 Gy) and slow release cisplatin was 580 days. An open-cell polylactic acid polymer (referred to as a sponge like material) impregnated with cisplatin was implanted intramuscularly at a distant site. Cisplatin in this setting is used as a radiation sensitizer with a low level of cisplatin measurable in the serum for up to three weeks, so essentially for the duration of radiation therapy. The use of a combination of fluorouracil and cyclophosphamide, mitoxantrone, or carboplatin in conjunction with cobalt 60 radiation therapy has not resulted in an improvement in survival over radiation alone.
Outcome and prognosis
The majority of studies have shown that the extent of local disease based on the World Heath Organization staging system (see Table 1) in dogs and cats does not have prognostic significance. Théon, et. al., developed a modified staging system (see Table 1) that was shown to have prognostic significance for survival. Dogs with stage 2 disease had a poorer prognosis than dogs with stage 1 disease. In other words, dogs with nasal disease that extends outside of the nasal cavity based on this one report had a poorer prognosis.
Tumor histology has been shown to have prognostic significance with sarcomas (primarily chondrosarcomas) having a better prognosis than carcinomas. Additionally, dogs with nasal squamous cell carcinoma and undifferentiated carcinomas have been shown to have significantly shorter survival times than dogs with adenocarcinoma or sarcoma.
The acute side effects of radiation therapy typically are manifested during the latter part of therapy and continue for a number of weeks after the end of treatment. Acute effects include oral mucositis, halitosis, rhinitis, and moist desquamation of the skin. The use of oral antibiotics and corticosteroids can help to alleviate the acute side effects. It is important to inform owners that signs of nasal cavity disease often persist after a course of radiation therapy. A combination of damage to the nasal turbinates from tumor growth, surgery and/or biopsy procedures, and radiation therapy result in persistent changes in the turbinates and resultant nasal discharge and/or rhinitis. Ophthalmic complications after radiation therapy can be significant. Radiation side effects include conjunctivitis, keratoconjunctivitis sicca, corneal damage, and cataracts. When feasible one or both eyes are shielded from the primary radiation beam. Three of 14 cats in one study had serious ocular complications from radiation with evidence of superficial corneal ulceration or keratitis. In one report three of 10 cats developed cataracts approximately one year after radiation therapy. Other acute and chronic radiation side effects in cats irradiated for nasal tumors appear to be minimal.
Metastasis based on compilation of data from 15 academic institutions indicated that the most common site of metastasis is to the lymph nodes, brain and lung. The highest rate of metastasis was reported in a study where 27 of 58 dogs irradiated for nasal tumors underwent necropsy examination and metastases were found in 41% with the lung and regional lymph nodes the most common sites. Although uncommon, metastasis to bone has been reported in dogs with nasal adenocarcinoma and carcinoma. Other sites of metastasis include liver, adrenal glands and testicle.
Eight of 28 cats with nasal tumors were necropsied and three had evidence of metastasis. Two cats had metastasis to the retropharyngeal lymph nodes and lung. One young cat with a nasal fibrosarcoma had venous thrombi and metastasis to the lung, heart and kidney.