Primary nasal tumors represent approximately 1 to 2% of all cancers that occur in dogs (11). Nearly two-thirds of all intranasal tumors are carcinomas, with adenocarcinoma being the most common, although transitional carcinoma, undifferentiated carcinoma, and squamous cell carcinoma are also reported (12). Canine nasal carcinomas are characterized by progressive local invasion, high rate of recurrence, and low rate of metastasis at diagnosis (10). Therefore, their treatment is focused on local therapy. The focus of treatment is on local therapy.

Surgeries such as dorsal, ventral, and rostrolateral nasal approaches have been well described (20). However, the median survival time (MST) of dogs after surgeries is similar to that of dogs without treatment, although surgical excision is efficient in improving the quality of life (10). Definitive radiation therapy (DRT) has been considered as the standard treatment for canine nasal tumors over the past 40 years (9). DRT is the treatment with fractions administered daily over a period of 3 to 4 weeks whereas stereotactic radiation therapy (SRT) is the treatment for tumors with 1 to 5 large dose radiation fractions. SRT is a treatment option that can reduce the risk of anesthesia in patients due to the smaller number of required treatment sessions. SRT has been proven to be effective in minimizing acute side effects for nearby organs at risk (OAR) (5). This is due to the rapid fall off of dose in SRT, which allows for precision targeting of the tumor while sparing the surrounding normal tissue (5).

Tumor response also has a significant impact on survival time (4,19). While tumor response can be determined based on the improvement of clinical signs, confirming it through a CT scan may be more accurate. Follow-up CT scans can be performed at 1-3 months or 3-6 months after RT, and the CT images can be compared with RT planning CT to evaluate clinical response via image-based response (5,14,19). The timing of evaluation is important, as performing a CT scan at the time of relapse after the maximum point of tumor response may result in a misdiagnosis of decreasing tumor size. However, there are currently insufficient studies on standardized CT follow-up after SRT.

The aim of this study was to describe outcomes of canine nasal carcinomas with cribriform plate lysis after treatment with SRT and to determine of appropriate CT recheck timing after SRT through CT series scans of nasal carcinoma.

Case 1

A nine-year-old, 6.5 kg, spayed female schnauzer dog was referred with a complaint of discharge and epistaxis with 6 months of duration not responding to conservative therapy. The owner reported recent facial deformity.

Physical examination revealed exophthalmos of the left eye and deformity of the left nasal plane. A complete blood count (CBC) showed leukocytosis (20.8 × 10³/μL, reference range: 6-12). Serum chemistry showed an elevated serum level of alkaline phosphatase (264 U/L, reference range: 47-254).

CT (GE lightspeed 16-mulislice helical CT; GE healthcare, little Chalfont, UK) scan was performed for diagnosis and RT planning using a tube voltage of 120 kVp, a current of 200 mA, and a slice thickness of 1.25 mm. The patient was premedicated with glycopyrrolate (Mobinulinj.^®, Myungmoon pharm, Korea; 0.01 mg/kg, SC). Then, anesthesia was induced with propofol (Provive inj.^®, Myungmoon pharm, Korea; 6 mg/kg IV) and maintained with isoflurane (Ifran^®, Hana pharm, Korea) via endotracheal intubation. The patient was positioned in sternal recumbency with a T vacuum-lock bag (Vac-Lok, Civco Medical, Orange City, IA, USA). Teeth were placed in preformed bite block that was inserted into an acrylic indexed frame. An acrylic face mask (Thermoplastic mask, Civco Medical, Orange City, IA, USA) was also placed. The bite block and acrylic face mask were made from an aquaplast sheet with thermoplasticity at high temperatures. The patient received 900 mgL/kg of iohexol (Omnipaque 300^®, GE Healthcare, Ireland) at a dose 3 mL/kg for contrast enhancement. CT scan identified a mass in the entire bilateral nasal cavity with soft tissue attenuation and mild homogeneous contrast enhancement. The mass had caused left nasal, left maxillary, pterygoid bone, hard palate, and cribriform plate lysis. It extended to the left frontal sinus, nasopharyngeal, left orbital, and intracranial regions (Fig. 1). There was no evidence of metastatic disease in regional lymph nodes or other areas. Biopsy of the nasal mass was performed using biopsy gun (Bard-Magnum Biopsy Instrument, Covington, GA, USA) under anesthesia. Histological examination resulted in a diagnosis of a nasal carcinoma. Based on histopathology and CT imaging, the tumor was diagnosed as a T3N0M0 nasal carcinoma at stage 4 (WHO criteria (16) and modified Adams CT staging system (1).

Figure 1. Computed tomographic (CT) images of the nasal cavity of a 9-year-old, spayed female dog with nasal carcinoma. CT images for contouring and planning before radiation therapy (RT) showed a mass in the entire bilateral nasal cavity (asterisk). The mass had caused left nasal, left maxillary, pterygoid bone, hard palate, and cribriform plate (white arrow) lysis. It had extended to the frontal sinus, nasopharyngeal, left orbital, and intracranial region (A-E). A follow-up CT image at 1 month after RT showed a 73% reduction of the tumor volume in entire nasal cavity (F-J). A follow-up CT image at 3 months after RT showed increased tumor size in the cranial part of the nasal cavity. However, the tumor volume in the caudal part decreased (K-O). Enlarged bilateral retropharyngeal lymph nodes were identified (black arrow).

Pre- and post-contrast images were imported into an external beam planning system (Monaco, Elekta AB, Stockholm, Sweden) for contouring and planning. The gross tumor volume (GTV) was contoured contrast-enhancing mass and any fluid in the extended other region as well as the nasal cavity. Additional clinical target volume (CTV) and planning target volume (PTV) expansion were not used because the entire bilateral nasal cavity was GTV and closed risk organ (left eye). Organ at risk (OAR) included optic nerve, optic chiasm, brain, spinal cord, lenses, and eyes (Table 1). Dose constraints were based on modifications of the American Association of Physicists in Medicine Task Group 101 (3) and previous studies (4,5,13). Inverse treatment planning was performed using the Monte Carlo simulation with a 0.2 cm calculation grid size for dose calculations. A single isocenter was used. Resulting volumetric modulated arc therapy (VMAT) plan was delivered using a 4-MV photon linear accelerator (Elekta Synergy, Elekta AB, Stockholm, Sweden). Quality assurance (QA) was performed after verification of dose distribution using a MapCHECK device (Sun Nuclear Corporation, Melbourne, Florida). Measurement was analyzed using a minimum of 95% gamma analysis 3%/3 mm on relative dose. The patient received 5 fractions of 7 Gy for a total dose of 35 Gy over a 5-day period. Clinical signs such as discharge and epistaxis showed improvement within 5 days after starting the SRT.

Table 1 . Mean radiation dose details for organs at risk for canine nasal carcinomas with cribriform plate lysis.

	Case 1	Case 2	Case 3
Brain	6.88 (0.56-34.99)*	13.12 (2.8-36.1)	12.2 (1.8-31.2)
Optic chiasm	11.54 (6.50-18.13)	17.78 (13.49-21.15)	29.8 (27.54 - 31.15)
Optic nerve	12.59 (4.56-22.83)	20.70 (7.40-30.45)	25.02 (11.75-30.45)
Lt. eye	10.83 (5.87-25.96)	6.76 (4-16.36)	19.29 (6.45-32.42)
Lt. lens	7.25 (6.13-11.63)	5.2 (4.09-7.9)	15.16 (7.83-26.63)
Rt. eye	7.63 (3.88-18.46)	8.81 (4.68-9.26)	7.17 (3.2-21.22)
Rt. lens	6.56 (4.66-9.29)	6.56 (4.68-9.26)	5.12 (3.67-7.76)
Skin	6.12 (0.02-38.17)	7.41 (0.047-38.57)	3.426 (0-32.42)

*Mean dose (minimum dose-maximum dose). Radiation dose unit is Gy..

During the 10-day period following RT, the dog experienced only grade 1 alopecia and dry dermal desquamation, which were treated with conservative measures (7). A follow-up CT scan was performed at one month after SRT, showing a 73% reduction of the tumor volume in the entire nasal cavity (Fig. 1). There were no metastasis to lymph nodes or distant areas. Three months after SRT, the patient showed discharge and epistaxis. Follow-up CT scan confirmed that the tumor size in the cranial part of nasal cavity increased. However, the tumor volume in the caudal part decreased (Fig. 1). Enlarged mandibular and retropharyngeal lymph nodes and lung metastasis were identified. Clinical signs including epistaxis and lethargy became worsen. The patient died at 110 days after SRT.

Case 2

An 11-year-old, 31.3 kg castrated male Samoyed dog presented with chronic discharge and epistaxis for five months. Epistaxis and discharge were initially reduced with antibiotic therapy. However, a relapse occurred when therapy was withdrawn, after which time the epistaxis and discharge became progressively more severe.

Physical examination revealed reverse sneezing, dyspnea, and epistaxis from the left nostril. No facial deformity was observed. A CBC showed non-specific finding. Serum chemistry showed an elevated alkaline phosphatase (296 U/L, reference range: 23-212). Hypertension, coagulopathy, and thrombocytopenia were ruled out based on physical examination and blood test.

A mass in the entire left nasal passage that extended to the region of the right nasal passage was identified on CT scan for diagnosis. The mass showed soft tissue attenuation and homogeneous mildly contrast enhancement. The mass had caused lysis of the turbinate, sphenoethmoidal palate, hard palate bone, periorbital bone, and cribriform plate, and had invaded the intracranial region (Fig. 2). Enlarged left mandibular and retropharyngeal lymph nodes were identified, which were considered metastasis. There was no evidence of distant metastasis. Histological examination resulted in a diagnosis of a nasal carcinoma with metastatic carcinoma of mandibular and retropharyngeal lymph nodes. Based on histopathology and CT imaging, the tumor was diagnosed as a T3N1M0 nasal carcinoma at stage 4.

Figure 2. CT images of the nasal cavity of an 11-year-old, castrated male dog with nasal carcinoma. CT images before RT showed a mass in the entire bilateral nasal cavity (asterisk). The mass had caused sphenoethmoidal plate, hard palate bone, periorbital bone, and cribriform plate (white arrow) lysis that resulted in invading of intracranial region (A-D). A follow-up CT image at 1 month after RT showed a 75.6% reduction of the tumor volume in the entire nasal cavity (E-H). A follow-up CT image at 3 months after RT confirmed an increase of tumor size in the left nasal passage that extended to the intracranial region (black arrow) (I-L).

The CT simulation, RT planning, and SRT were performed according to previously described procedures. The GTV included the entire nasal cavity and frontal sinus. The patient received five fractions of 7 Gy for a total dose of 35 Gy over a period of five days.

Acute toxicity due to RT was not observed within one month following RT (7). A follow-up CT scan was performed at 40 days after SRT, showing a 75.6% reduction of the tumor volume in entire nasal cavity without any evidence of a metastasis (Fig. 2). At 150 days after SRT, the patient showed discharge and mild epistaxis. The follow-up CT scan confirmed an increase of tumor size in the left nasal passage and extension of the tumor to the intracranial region without any evidence of a metastatic disease (Fig. 2). At 190 days after SRT, the patient was presented due to severe epistaxis, dyspnea, and pale mucus. A CBC revealed a decrease in hematocrit levels (14%, reference range: 37-55). The patient received a blood transfusion, but the patient died.

Case 3

A 9-year-old, 6 kg castrated male mixed dog was presented to the referring veterinarian for dyspnea, epistaxis, and anorexia. The patient had been exhibiting a discharge with sneezing for 8 months. Clinical signs were initially improved with conservative therapy. However, a relapse occurred and became more severe recently.

Physical examination revealed upper airway stertor, open mouth breathing, and deformity of the right nasal plane with exophthalmos of the right eye. Oral examination revealed no change of the gum, teeth, or the palate. A CBC showed leukocytosis (20.2 × 10³/μL, reference range: 6-12). Serum chemistry showed an elevated serum level of alkaline phosphatase (672 U/L, reference range: 47-254).

CT scan identified a mass in the entire right nasal cavity that extended to the left nasal cavity with soft tissue attenuation and homogeneous mildly contrast enhancement. The mass had caused nasal bone, maxillary bone, pterygoid bone, hard palate, and cribriform plate lysis. It had extended to the nasopharyngeal, right orbital, and intracranial regions (Fig. 3). Enlarged right mandibular and retropharyngeal lymph nodes were identified, which were considered metastasis. Base on histopathology and CT imaging, the tumor was diagnosed as a T3N1M0 nasal carcinoma at stage 4.

Figure 3. CT images of the nasal cavity of a 9-year-old, castrated male dog with nasal carcinoma. CT images before RT showed a mass in the entire right nasal cavity (asterisk). The mass had caused nasal bone, maxillary bone, pterygoid bone, hard palate, and cribriform plate (white arrow) lysis. It had extended to nasopharyngeal, right orbital, and intracranial regions. Metastasis of right mandibular and retropharyngeal lymph nodes (white arrowhead) was identified (A-D). A follow-up CT image at 1 month after RT showed a 79% reduction of the tumor volume in the entire nasal cavity (E-H). A follow-up CT image at 3 months after RT confirmed an increase of tumor size in the right nasal passage with enlarged contralateral retropharyngeal lymph nodes (black arrowhead) (I-L). Follow-up CT images at 5 months after RT showed that the tumor was enlarged with extended intracranial region. The tumor size was confirmed to be similar to that before RT (M-P).

RT planning and SRT were performed as previously described. The patient received three fractions of 10 Gy for a total dose of 30 Gy over a period of three days. Chemotherapy was considered an adjuvant treatment option, but the owner declined.

Acute toxicity within 7 days following RT was limited to grade 3 mucous ulceration of oral cavity that was self-limiting by conservative treatment (7). One month after SRT, the patient showed improvement of clinical signs such as dyspnea, discharge, and epistaxis. A follow-up CT scan was performed, showing a 79% reduction of the tumor volume in the entire nasal cavity (Fig. 3). Three months after SRT, the patient showed no clinical signs. A follow-up CT confirmed an increase of the tumor size in the right nasal passage with enlarged contralateral retropharyngeal lymph nodes (Fig. 3). Enlarged mandibular and retropharyngeal lymph nodes with lung metastasis were identified. Five months after SRT, relapse of clinical signs occurred. On the CT scan, the tumor was enlarged with extended intracranial region. The tumor size was confirmed to be similar to that before RT. There were evidences of metastatic disease in bilateral mandibular and retropharyngeal lymph nodes and the lung. Dyspnea and anorexia became worsen and seizure began to occur. The owner elected euthanasia at 210 days after RT.

In the present study, the MST of dogs treated for stage 4 nasal carcinoma with SRT was 110, 190, and 210 days, respectively. Previous studies have evaluated SRT for treating nasal tumor and confirmed a MST of 388, 399, or 586 days (5,6,13) with a carcinoma-specific MST of 332 days (6). The reason why the MST in our study was shorter than that in previous studies might be because previous studies included sarcomas and low CT stage nasal tumors (5,6,13). Other studies have confirmed that MST for dogs with nasal sarcoma treated with DRT is longer than that for dogs with nasal carcinoma (1,18). Especially, squamous cell, anaplastic, and undifferentiated carcinomas have significantly worse disease-free survival (4.4 months) than sarcomas (10.6 months) (1). MST for dogs with stage 4 carcinoma treated with RT is shorter (6.7 months) than that for dogs with carcinoma at stage 1-3 (23.4 months) (1,12,13). Aggressive treatment with surgery or chemotherapy combined with RT should be considered for patients diagnosed with carcinoma and lysis of cribriform plate. However, further studies are needed.

At initial diagnosis, 0% to 12% of dogs with nasal carcinomas have metastasis to regional lymph nodes or lungs (2,18). However, the proportion of dogs with metastatic disease at the time of death has been reported to be 46% (17). Metastasis negatively affects survival time (8). In the second and third cases, metastasis at lymph nodes was identified at initial diagnosis and metastasis to contralateral lymph nodes was confirmed at the time of death. The reason why metastasis was confirmed in 2 out of 3 dogs might be due to delayed diagnosis. Delayed treatment due to a late diagnosis is also considered a cause of short survival time. Thus, early diagnosis is important for a good treatment prognosis.

Tumor response is associated with improved survival time undergoing radiation therapy for nasal tumors (4,19). Tumor response can be determined based on improvement of clinical signs, histopathology, and follow-up CT scans (4,19). Although improvement of clinical signs could be the result of tumor response, it is also possible that radiation therapy mitigated local inflammation, which could have contributed to the improvement of clinical signs (4). In our cases, improvements in clinical signs related to discharge and dyspnea were confirmed immediately after RT, which may have been attributed to improved nasal patency resulting from radiation mitigation of inflammation. Therefore, correct tumor response evaluation using follow-up CT is important for assessing prognosis. The timing of follow-up CT evaluation is also important. If a CT scan is performed at the time of relapse after the maximum point of tumor response following RT, it may be misdiagnosed as a still decreasing tumor. Previous studies evaluated CT-based response assessments within 3 months or between 3 and 6 months after RT (5,14,19), although the exact evaluation time has not been established yet. In this study, CT scans were performed at 1 month, 3 months, and 5 months after SRT. In cases 2 and 3, the sizes of tumors were smallest at 1 month after SRT, and increased sizes of tumors were confirmed at 3 or 5 months. In case 1, the size of the tumor decreased at 3 months after SRT. Therefore, CT recheck at 1 month and between 3 to 6 months after completing SRT is considered for accurately evaluating prognosis and confirming the timing of recurrence in patients with nasal carcinoma. However, since the CT scan results were only confirmed in three dogs, further studies with a larger sample size of patients are needed.

According to a study that performed CT recheck within 3 months after DRT in dogs with nasal tumors, volume reduction of the mean nasal tumor size showed 55% for both sarcomas and carcinomas (14). The volume of carcinoma was significantly reduced compared to that of sarcoma after DRT (14). The sarcoma showed a volume reduction of 21% and the carcinoma showed a volume reduction of 67% (14). In our cases, tumors identified showed volume reductions of 73%, 75.6%, and 79%, respectively. The reduction in tumor size after RT was more in the present study than that in the previous study. It might be because CT scan was performed at 1 month after RT in the present study.

Side effects associated with RT can be divided into early side effects (less than 3 months after RT) and late side effects (more than 3 months after RT) (4,5,15,19). Early side effects include inflammation at commonly affected areas such as the oral mucosa, ocular, and skin. Early side effects also include ocular ulceration, conjunctivitis, desquamation, erythema, and mucositis (15). Late side effects include lens change, uveitis, keratoconjunctivitis sicca, and leukotrichia (15). In the first and third cases, early radiation toxicities appeared as alopecia, dry dermal desquamation, and mucositis within 10 days after RT that were self-limiting by conservative treatments. No radiation toxicity was identified in the second case. No patient experienced any late radiation toxicity.

This study has some limitations. First, all patients were diagnosed with nasal carcinoma through histological examination. However, no subtype was identified. Since squamous cell, anaplastic, and undifferentiated carcinomas have poorer prognosis than adenocarcinoma, histologic subtype is important for accurate prognosis evaluation (1). SRT is commonly used in dogs with nasal tumors that receive 24-30 Gy in three daily treatments of 8-10 Gy (5,6). In this study, only the third case received 30 Gy of radiation in three daily fractions of 10 Gy. The other two patients were treated with 35 Gy of radiation in five daily fractions of 7 Gy because the tumor volume was large. Side effects of surrounding normal tissues such as the brain, eye, and oral mucosal could occur. Thus, it is necessary to study the difference in protocol through a retrospective study based on a large number of patients.

This study confirmed that SRT could treat canine nasal carcinomas with cribriform plate lysis without causing serious radiation toxicities. Follow-up CT examination is considered at one month and between 3 to 6 months after completing SRT to accurately evaluate the prognosis and confirm the timing of recurrence in patients with nasal carcinoma.

The authors have no conflicting interests.