Nasal tumours in the dog and cat

Nasal tumours are not frequent in the dog, representing around 1-2% of all neoplasms in this species._¹ They usually originate from the nasal cavity and secondarily may extend to the frontal sinuses. Primary tumours of the frontal sinuses are rarer. The incidence of nasal tumours in the cat is lower than that in the dog. 

SIGNALMENT

No gender predisposition to the development of nasal tumours has been reported in either the dog or the cat. The mean age of onset in the dog varies between 9 and 10 years of age, although forms of nasal sarcoma have been reported in younger subjects._^2-4  In the cat, the mean age at diagnosis is 8-10 years. The dog breeds which are more predisposed are the Airedale,  Labrador, Golden Retriever, Scottish Terrier, Collie, Shetland Sheepdog and Basset Hound. Furthermore, the Labrador and the Golden Retriever are prone to tumours of the nasal planum. Among cats the breed with the greatest predisposition is the Siamese.

AETIOPATHOGENESIS

The aetiopathogenesis of nasal tumours is not entirely known. The high incidence of these tumours in dolicocephalic and mesocephalic breeds, compared to the rare cases reported in brachycephalic breeds, as well as the equal distribution existing between pure breeds and mongrels, suggests that there is a correlation with environmental pollutants._^5,6 In fact, the risk of developing a nasal tumour seems directly related to the extension of the nasal cavity, to the air filtering capacity and hence to a greater exposure of the nasal turbinates to the potential carcinogenic action of environmental substances. Furthermore, nasal tumours have been reported following the local application of clotrimazole in dogs with nasal aspergillosis._⁷

In cats, chronic rhinitis seems to favour the development of nasal tumours. Feline leukaemia virus (FeLV) could favour the onset of nasal lymphomas, although these nasal malignancies have been described in both FeLV-positive and -negative cats._⁶

BIOLOGY

Eighty percent of nasal tumours are malignant and have an unfavourable prognosis: patients die of cancer in spite of undergoing treatment._^2,8 Tumours usually develop in the caudal two-thirds of the nasal cavity._^1,9 They are locally invasive, cause bone lysis and in the terminal stages of the disease tend to metastasise. The percentage of patients with metastatic disease at presentation is in fact low (1-12.5%), while around 41% of treated subjects were found to have metastatic lymph node and pulmonary lesions at post-mortem examination._^10-12 If not treated, patients with a nasal tumour  are usually euthanized within a few months, given the local progression of the tumour._⁸

TUMOUR TYPES

In the dog, two-thirds of malignant nasal tumours are carcinomas. Of these the most common form is adenocarcinoma,_¹³ followed by squamous cell carcinoma, transitional cell carcinoma and undifferentiated carcinoma._¹⁴ The epithelial neoplasms include neuroendocrine tumours._⁶ Mesenchymal neoplasms, which account for around one-third of nasal neoplasms, include chondrosarcoma, osteosarcoma, fibrosarcoma and undifferentiated sarcoma._¹⁵ More rarely it is possible to find round cell tumours such as lymphoma, mast cell tumour_¹⁶ and transmissible venereal tumour. Other possible tumours are olfactory neuroblastoma,_¹⁴ melanoma,_¹⁷haemangiosarcoma, fibrous histiocytoma, leiomyosarcoma and rhabdomyosarcoma._⁶

In the cat, the most frequent nasal tumour is lymphoma, followed by carcinoma, squamous cell carcinoma and adenocarcinoma._^18-21 Rarely, chondrosarcoma, fibrosarcoma and osteosarcoma_²² can be found. Cases have also been reported of mast cell tumour, melanoma,_²³ plasmacytoma,_²⁴ neuroblastoma_²⁵ and benign tumours such as hamartoma,_²⁶ haemangioma, chondroma and neurofibroma. Squamous cell carcinoma may affect the nasal planum of cats._²⁷

CLINICAL SIGNS

The clinical evolution of nasal tumours is often slow and insidious. Subjects are usually taken to the veterinarian for a nasal discharge when the discharge has already been present for an average of 3-4 months_^2,9,28 (Fig. 1). In the initial stages of the disease the tumour is unilateral, however with progression it becomes bilateral, due to the erosion of the nasal septum, and serohaemorrhagic. Clinical signs include non-paroxysmal sneezing, epistaxis, epiphora due to obstruction of the naso-lachrymal duct, a more or less marked exophthalmos due to invasion of the orbit and neurological signs such as convulsions, sensory deficits, neurological deficits and behavioural alterations caused by involvement of the cribiform plate and infiltration of the encephalon._² The invasion of the cranial cavity is not always correlated with clinical neurological signs._¹⁵ An intranasal mass prevents the passage of air to a variable extent and breathing may become stertorous. In the advanced stages of the disease the animal may become lethargic, emaciated and dyspnoeic and facial deformities may develop. Tumours of the nasal planum and of the nasal vestibule appear as ulcerated lesions, often haemorrhagic, and also associated with nasal discharge.

Clinical signs in the cat are of variable duration, ranging between 7 days and 5 years, depending on the site of the tumour (nasal or nasopharyngeal). Nasal tumours are characterized by nasal discharge, sneezing, epiphora, epistaxis, facial deformity (Fig. 2) and dyspnoea. Nasopharyngeal involvement is characterized by stertorous breathing and voice alterations. Should a nasopharyngeal tumour be present palpation of the soft palate may reveal the presence of a mass._²⁹

DIFFERENTIAL DIAGNOSIS

Around 33% of dogs with a chronic nasal discharge have a nasal neoplasm._¹⁴ However, a nasal discharge may also be present in cats and dogs  in cases of rhinitis,_²⁰ which may be chronic, lymphoplasmacytic, mycotic (nasal aspergillosis, penicillosis, rhinosporidiosis, cryptococcosis), bacterial or viral;  rhinitis may also be caused by the presence of foreign bodies, oronasal fistulae, dental disorders, inflammatory polyps or stenosis._²⁰ In the case of epistaxis the differential diagnosis must include primary  and secondary coagulopathies (e.g. ehrlichiosis, leishmaniasis) and the hyperviscosity syndrome (multiple myeloma).

DIAGNOSIS AND STAGING

Clinical examination
The clinical examination must include visual inspection, palpation of the nose, in order to exclude the presence of facial deformities or bone lysis, and an assessment of the patency of the nasal canals, by holding a glass slide, or a piece of cotton or gauze in front of the nostrils. The oral cavity should also be inspected, followed by palpation of the soft palate to exclude the presence of neoformations, deformities of the hard palate or nasopharyngeal masses. The eye-ball should be compressed, in order to determine whether there is increased resistance to backwards movement of the eye, which indicates invasion of the retro-orbital space. Regional lymph nodes are assessed by palpation; if the lymph nodes are enlarged a fine needle biopsy is indicated to exclude metastatic involvement. Metastatic spread to regional lymph nodes is rare at presentation.

Table 1. Classification of nasal tumours according to radiographic assessment (WHO) and  computed tomography studies (modified).

Blood tests
Laboratory investigations must include blood tests, blood-chemistry assessment (including total proteins and protein fractions) and a coagulation screen (in the case of epistaxis and if biopsies are to be taken). These tests are not very informative in the presence of a tumour. In extremely rare cases nasal neoplasms may be related to paraneoplastic syndromes characterized by erythrocytosis, immune-mediated thrombocytopenia and hypercalcaemia._³⁰

Diagnostic imaging

- Radiography

Chest X-rays should be performed with right and left latero-lateral and dorso-ventral or ventro-dorsal projections, to exclude the presence of lung metastases, although these are rare at presentation.

Radiography of the nasal cavity with a ventrodorsal open-mouth projection (Fig. 3) and with a rostrocaudal projection is used to assess the frontal sinuses. X-rays can show loss of definition of the turbinates, bone lysis and/or proliferation, secondary opacity of the frontal sinus caused by accumulation of mucus due to obstruction of the naso-frontal ostium or to tumour invasion, unilateral or bilateral soft tissue-like homogeneous radio-opacity, deviation of the septum, erosion of the vomer and swelling of extranasal soft tissues.³¹ Radiographic images may also supply information useful for differentiating a neoplasm from rhinitis._^32,33 X-rays are less useful than computed tomography (CT) or nuclear magnetic resonance (NMR) imaging at providing information on the intracranial extension of the tumour._³¹ Radiology is useful as a first diagnostic approach in the case of a clinical suspicion of a nasal tumour, but CT or NMR are necessary to plan the therapy (surgery and/or radiotherapy) correctly. 

- Computed tomography and nuclear magnetic resonance imaging

CT and NMR are the investigations of choice in the case of a nasal tumour, with CT being particularly useful because of the high number of clinical practices that now have the equipment to do such an examination. Both techniques allow staging of the tumour, can be used to guide a biopsy and help to plan any radiotherapy. They are more sensitive than X-rays at assessing the exact extension of the tumour (unilateral versus bilateral) and the involvement of adjacent structures, such as the cranial cavity, frontal sinuses, orbits, cribriform plate and hard palate._^31,34-39 Extension of the tumour into the skull bone, caudal recess, maxillary recess, nasopharynx, cranial cavity and adjacent bones can also be determined._¹⁵ In the assessment of nasal tumours without intracranial involvement the two techniques are equivalent in terms of the information they can provide._⁴⁰ CT is superior to NMR for the assessment of lysis of the turbinates and cribriform plate and erosion of the nasal septum or of the bony structures adjacent to the nose (Fig. 4). NMR is superior for detecting small amounts of fluid within the nasal cavity, thereby differentiating a tumour from an accumulation of secretions or necrotic tissue._⁴⁰

In the cat the presence of osteolysis of the paranasal structures, destruction of the turbinates, lysis of the nasal septum, presence of a space-occupying mass and extension to the orbit and to the soft tissues of the face raise the suspicion of a neoplastic lesion; these are not, however, pathognomonic findings as they can also occur in the case of severe rhinitis. A nasal biopsy is, therefore, necessary. Also in the cat, CT and NMR appear to be better than radiography at localising lesions and determining their extension._³⁸

Biopsies

The definitive diagnosis is based on cytology and/or histology of a biopsy sample. The use of swabs to prepare smears for cytology is not indicated, as in 95% of cases these smears are not diagnostic because of the contaminant material which is always present in the nasal cavity. Likewise, direct nasal lavage (through the nares) or retrograde lavage (from the nasopharynx) is generally not useful for harvesting diagnostic material because of contaminants. A biopsy can be taken under endoscopic guidance (rhinoscopy) using a brush_⁴¹ or a specific type of biopsy forceps. Neoplasms which tend to exfoliate may be biopsied with the brushing technique, but biopsy material collected with this technique is often not diagnostic in the case of mesenchymal neoplasms._⁴² Rhinoscopy is not only helpful for the biopsy, but it also allows the lesions to be seen, facilitating the diagnosis (of masses, mycotic colonies, foreign body). Rhinoscopy should be performed both directly, through the nostrils, and with a retrograde approach, through the choanae_¹⁴ (Figs. 5 and e b). Biopsies can also be taken blindly, but the likelihood of having a non-diagnostic result is greater. In order to collect a reasonable amount of tissue using the blind technique, a core biopsy can be taken by introducing a sufficiently rigid cannula (e.g., nasal cannula, urinary catheter, rigid plastic cannulae used to protect tru-cut needles) into the nasal cavity of interest._^43,44(Figs. 6a and b). The cannula is connected to a 10-12 cc syringe. It is essential to measure the exact length of the cannula, which should not be greater than the length between the nostril and medial canthus of the eye, in order to avoid risking an injury to the cribriform plate of the ethmoid bone at insertion. The procedure must be done with the subject under general anaesthesia, preferably with the animal intubated. The cannula is inserted into the nose and then made to penetrate the lesion; aspiration is achieved by pushing and pulling the syringe plunger. The bleeding which follows is abundant but temporary. In the presence of facial deformity a transcutaneous, fine needle biopsy may be performed. This is a minimally invasive technique, but the specimen collected is often contaminated by blood and by secondary infections and may be non-diagnostic. If the above-mentioned biopsy techniques do not lead to a diagnosis being made or do not obtain a sufficient amount of tissue, exploratory surgery (dorsal or ventral rhinotomy)should be performed.

TREATMENT

Surgery
Surgery alone is ineffective and the survival of animals treated in this way (mean survival of 4-6 months) is comparable to that of untreated subjects (3 months)._^2,12,45 Surgery may be done as a debulking procedure, prior to orthovoltage radiotherapy, to favour the penetration of radiation._^13,46 There are contrasting opinions on the use of surgery in combination with megavoltage radiotherapy. According to some authors the combination of surgery and radiotherapy does not seem to improve survival compared to that achieved by radiotherapy alone._^3,12,46-48 However, Adams and colleagues_⁴⁹ reported an increased survival in subjects undergoing adjuvant surgery (median survival of 47.7 months) compared to that in animals treated with radiotherapy alone (median survival of 19.7 months). In dogs undergoing surgery the incidence of complications (chronic rhinitis, osteomyelitis/osteonecrosis) is, however, higher. The surgical approach to the nose may be a ventral or a dorsal rhinotomy. Surgery, alone or in combination with radiotherapy, is indicated in the dog in the management of squamous cell carcinoma of the rostral part of the nasal cavity (nasal planum, nasal vestibule)._⁵⁰ For the treatment of nasal planum carcinomas in the cat refer to the dedicated section.

In cats with nasal adenocarcinoma or undifferentiated carcinoma, surgery has been used alone, with a mean survival of 2.5 weeks._⁵¹ Surgery has also been used as a debulking procedure, before radiotherapy (orthovoltage, cobalt 60), with minimal side effects; in reality, given the limited depth of nasal cavities in the cat, debulking surgery to favour the penetration of radiation could be avoided._⁵²

Radiotherapy
Radiotherapy is currently the treatment of choice for nasal tumours in the dog and cat. Notwithstanding the poor long-term prognosis, radiotherapy is capable of extending survival in treated subjects and may temporarily resolve or improve symptoms generated by the tumour. In fact, many subjects (39-100%) are reported to have complete remission of symptoms following radiotherapy._^28,46,53,54 In some cases symptoms persist but are attenuated. Radiotherapy may be used as a “therapeutic” approach, at high doses (40-54 Gy), divided into many fractions (10-18), but this is associated with a higher incidence of adverse events, which may be severe. It can also be used with a palliative intent (hypofractionated), with the goal of attenuating symptoms (pain, occlusion of upper airways, bleeding), minimising the adverse events of irradiation. Acute adverse reactions usually appear during the 2_^nd-3_^rd week of treatment, reaching maximum intensity 2 weeks after the end of therapy, and usually resolve about 4 weeks after the end of the treatment. Adverse reactions include mucositis, skin erythema and scaling, conjunctivitis and blepharitis. They are usually managed with the administration of steroidal and non-steroidal anti-inflammatory drugs, opiates, antibiotics, mouth washes and artificial tears.

The incidence of long-term complications is variable and depends on the intensity of the protocol used. Long-term complications include irreversible changes to the eyes (keratoconjunctivitis sicca, keratitis, vascularisation of the cornea, retinal haemorrhage or degeneration and cataract with possible blindness), skin (hyperpigmentation and regrowth of fur of another colour, fibrosis), osteonecrosis of the bone, cerebral necrosis and degeneration of the optic nerve._⁶ Given the high incidence of local relapses following radiotherapy, the possibility of repeating irradiation to the tumour regrowth has been evaluated. New remissions can be obtained, although they are usually of a lesser degree than the remissions obtained with the first radiotherapy; the side effects, however, are of similar intensity to those following the first treatment._⁴ A limited number of dogs have been treated with brachytherapy based on _¹⁹²iridium seeds implanted into the nose after surgical removal of the tumour._⁵⁵ The results were inferior to those obtained with external beam radiotherapy (orthovoltage or megavoltage) and the number of animals treated was limited.

Radiotherapy is used for the treatment of  nasal lymphoma in the cat, as the only treatment modality_⁵⁶ or in combination with chemotherapy._^56,57 A median survival time of 955 days was reported following the combined therapy, with survival rates at 1 and 2 years of 63% and 57%, respectively._⁵⁷ However, no significant differences were shown between animals treated with radiotherapy alone or with radiotherapy combined with chemotherapy._⁵⁶ A survival time of 382 days (63% of subjects alive at 1 year) was reported following treatment of non-lymphoproliferative neoplasms (adenocarcinoma) with megavoltage radiotherapy alone (4-8 Gy per fraction, 4-6 fractions)._⁵⁸

Chemotherapy
There is limited information on the use of chemotherapy alone for nasal tumours in the dog. In 11 subjects with nasal adenocarcinoma cisplatin was used as a single agent; symptoms improved in all patients, but the mean survival was 20 weeks, similar to that obtained with surgery alone or without any treatment._⁵⁹ Chemotherapy may be used in cats with nasal lymphoma with protocols combining vincristine, cyclophosphamide and prednisone (COP) or vincristine, cyclophosphamide, doxorubicin and prednisone (CHOP). A median survival of 140 days has been reported: subjects which achieved a complete remission (72.7%) survived longer (median survival 749 days)._¹⁷ In a group of patients treated with COP the complete remission rate was 75%, with a median survival of 358 days and 75% of subjects alive at 1 year._⁶⁰ For nasal lymphomas in the cat, radiotherapy is the treatment of choice; remissions are often complete and the survival of patients treated with radiotherapy is longer than that of patients treated with chemotherapy alone; however, a percentage of cats may exhibit late systemic involvement._⁵⁷ As it is not possible to identify these subjects a priori, the ideal treatment for nasal lymphoma should be a combination of local radiotherapy and systemic chemotherapy.

Chemotherapy has been used in dogs as a radiosensitising treatment to potentiate the effect of radiotherapy, but with discordant results. Excellent results were achieved in dogs with intranasal neoplasms treated with a combination of megavoltage radiotherapy (with a linear accelerator) and slow-release cisplatin; the median survival was 474 days._⁶¹ In contrast, in a study carried out by Nadeau,_⁶² no statistically significant differences in survival were observed between subjects treated with radiotherapy with or without the addition of cisplatin.

Finally, chemotherapy has been used as the sole treatment with the goal of alleviating clinical symptoms and slowing the progression of the disease. The protocol used consisted of alternating doxorubicin and carboplatin, every 3 weeks, combined with daily administration of piroxicam._⁶³ This non-steroidal anti-inflammatory drug was used because many intranasal tumours (carcinomas in particular) express COX-2 receptors._^64,65

Photodynamic therapy
Photodynamic therapy has been used in endonasal tumours with good results in terms of remission of symptoms and prolongation of survival._^66,67 This therapy has also been used for the treatment of nasal planum tumours in the cat, with short-term complete or partial remissions._⁶⁸

PROGNOSIS

The prognosis is usually poor because, despite therapy, treated subjects die of disease progression. Various prognostic factors have been identified which can have an impact on the survival of subjects affected by nasal neoplasms. The data from different authors are, however, often contrasting, probably because of the limited number of patients taken into consideration. Clinical staging based on the WHO classification system does not seem to influence survival,_{^{2,10-12,47,58,69}} whereas clinical staging based on radiographic_^9,11 or CT_^53,70 findings does seem to be useful in terms of prognosis. The more advanced stages, with bone involvement and extranasal spread of the tumour, are characterized by a worse prognosis. Furthermore, prognosis is negatively influenced by the presence of epistaxis,_² of metastases present at the time of diagnosis,_^12,71 age over 10 years old,_⁷¹ lysis of the cribriform plate in the case of feline lymphoma_⁵⁷ and facial deformity;_⁴⁶ this last factor is, however, controversial: according to Buchholz and collaborators_⁵³ it is not a negative prognostic factor.

Longer survival times are associated with the use of radiotherapy,_¹² the presence of a complete resolution of symptoms following radiotherapy_^28,46 and the use of treatment based on a combination of radiotherapy and neoadjuvant surgery_⁴⁹or of radiotherapy and chemotherapy with slow-release cisplatin._⁶¹ The role played by the histotype is also controversial. Many authors agree that survival is not influenced by the type of tumour;_{^{3,48,49,58,71,72}} while others consider that patients affected by carcinomas, especially if squamous cell or undifferentiated, have a worse prognosis._^11,47 Dogs with a chondrosarcoma apparently have a better prognosis than those with adenocarcinoma or squamous cell carcinoma._¹³ Finally, involvement of the central nervous system does not seem to be associated with a poorer prognosis._⁷²

In the cat, negative prognostic factors are the presence of anaemia and evidence of invasion of the cribriform plate at presentation;_^56,57 positive prognostic factors include a complete remission of the disease following treatment_^18,56,60 and the use of total doses of radiotherapy greater than 32 Gy._⁵⁶

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