Successful rescue treatment using chlorambucil for presumed recurrence of sinonasal lymphoma in a cat

Abstract

Case summary

A 12-year-old male neutered domestic shorthair cat presented with a 2-week history of serous unilateral nasal discharge, swelling of the nasal bridge and sneezing. Whole-body CT revealed a mass filling the entire right nasal cavity with lysis of the cribriform plate. The cat was diagnosed with sinonasal large-cell lymphoma based on cytopathological analysis, with PCR-based lymphocyte clonality testing showing a monoclonal population with rearrangement of the immunoglobulin heavy chain gene. The cat received radiotherapy with a dose of 30 Gy in seven fractions given three times weekly, and then cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP)-based chemotherapy was initiated soon after completion of the radiotherapy schedule. Despite this treatment, CT performed 4 months after radiotherapy revealed enlargement of the lesion in the right nasal cavity consistent with presumed progression of the cat’s lymphoma. The cat then received rescue chemotherapy with chlorambucil, which markedly reduced the size of the disease burden in the nasal and frontal sinus without severe adverse effects. At the time of writing, the cat was receiving chlorambucil for 7 months without any clinical signs suggestive of tumour relapse.

Relevance and novel information

To our knowledge, this is the first case of feline sinonasal lymphoma with chlorambucil used as rescue chemotherapy. This case indicates that chemotherapy with chlorambucil may be a useful treatment option for cats with relapsing sinonasal lymphoma following radiotherapy and/or CHOP-based chemotherapy.

Case description

A 12-year-old male neutered domestic shorthair cat weighing 4.5 kg (body condition score 4/9) presented at Morita Animal Hospital with a 2-week history of serous unilateral nasal discharge, swelling of the nasal bridge and sneezing. At the initial presentation (day 1), the cat showed a non-painful subcutaneous swelling of the nasal dorsum with mild serous nasal discharge. There was no palpable lymphadenopathy or abnormal findings on routine haematology and serum biochemical analysis. The cat had negative test results (performed by another veterinarian) for feline immunodeficiency virus and feline leukaemia virus at 3 years of age, and testing for these viruses was not performed at initial presentation. On day 509, however, we tested for these viruses and the results were negative.

Contrast-enhanced whole-body CT and MRI were performed under general anaesthesia on day 2 at the referring institution (ER Bunkyo, Tokyo, Japan), which identified a mass filling the entire right nasal cavity, measuring 4.9 cm (longest diameter), with subcutaneous, orbital and right frontal sinus invasion and lysis of the cribriform plate (Figures 1 and 2). No asymmetry in the mandibular and medial retropharyngeal lymph nodes was seen. The liver, spleen and kidneys had subjectively normal appearances on CT, and abdominal ultrasound also revealed normal echogenicity of these organs. Cytology was obtained via traumatic catheterisation using a plastic cannula introduced into the nasal mass through the external nare, which revealed a population of monomorphic intermediate-to-large lymphoblasts with finely granular chromatin, anisonucleosis and occasional mitotic figures. Additionally, a monoclonal population of cells with the immunoglobulin heavy chain gene (IGH) rearrangement was identified by PCR-based lymphocyte clonality testing of the biopsied sample.^1,2 Thus, we diagnosed sinonasal large-cell lymphoma with a monoclonal population, with rearrangement of IGH and no evidence of involvement on imaging of the liver, spleen or kidneys.

Figure 1

Transverse CT of the cat at diagnosis. (a,b) The rostral aspect of the nose at (c,d) the level of the orbit and (e,f) the level of the cribriform plate at the initial presentation; (b,d,f) post intravenous iodinated contrast agent administration. The tumour lesion filled the entire the right nasal cavity with subcutaneous (arrows), orbital and frontal sinus invasion. Lysis of the cribriform plate was also seen (arrowhead)

Figure 2

MRI of the cat at diagnosis: (a) T2-weighted, (b) fluid-attenuated inversion recovery (FLAIR), (c) T1-weighted and (d) T1-weighted postcontrast images were obtained. The mass in the sinonasal cavity was hypointense-to-isointense in T1-weighted images and isointense-to-hyperintense in T2-weighted and FLAIR images. The lesion was heterogeneously enhanced in the postcontrast image

The owner elected for treatment with radiotherapy followed by chemotherapy. L-asparaginase (400 U/kg SC) was administered on day 4, and prednisolone (1 mg/kg PO q12h) was administered from day 3 and tapered over 4 weeks (1 mg/kg PO q12h for 7 days and then 1 mg/kg PO q24h for an additional 24 days). The clinical signs of nasal discharge and facial deformity of the cat were markedly improved after the initial treatment with L-asparaginase and prednisolone. From day 14, the cat received three-dimensional conformal radiotherapy delivered with 4 MV photons from a linear accelerator (Primus Mid-Energy 4 MV linear accelerator; Siemens Healthcare). At the time of the initiation of radiotherapy, the clinical signs, including nasal discharge and facial deformity, were completely resolved and the cat was asymptomatic. The radiotherapy plan was generated by a CT-based computer-generated treatment planning system (RayPlan 9A; RaySearch Laboratories) using a customised bite block. The gross tumour volume was defined as a gross tumor on contrast-enhanced CT. The clinical target volume included regions at risk for microscopic disease based on CT at diagnosis (day 2), as CT revealed a marked tumour reduction in the right nasal cavity at the time of the radiotherapy (Figure 3a,b). The planning target volume was defined by a margin of 2 mm around the clinical target volume to accommodate positioning errors and motion. Dose distribution was improved using a tissue-equivalent bolus material of 0.5 cm depth. The prescribed total dose was 30 Gy divided in seven fractions given three times weekly.

Figure 3

Transverse CT of the level of the (a,c,e,g) maxillary third premolar and (b,d,f,h) frontal sinus. (a,b) At the initiation of radiotherapy (RT), the tumour in the right nasal cavity was markedly reduced following treatment with L-asparaginase and prednisolone. (c,d) Four months after RT, a lesion enlargement in the right nasal cavity, which was suspected to be a recurrent lesion of the nasal tumour, was observed despite receiving RT followed by cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP)-based chemotherapy. (e,f) One month and (g,h) 4 months after rescue chemotherapy with chlorambucil, the presumed recurrent lesion gradually reduced in size in the right nasal and frontal sinus

From day 33, the cat was placed on cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP)-based chemotherapy, as previously reported. ³ Subsequent doses of vincristine were reduced by 20% due to adverse effects following the first dose (grade 3 anorexia and grade 3 vomiting). ⁴ Follow-up CT performed 3 months after completion of radiation therapy as planned (day 116) revealed enlargement of the lesion in the right nasal cavity vs the time of radiotherapy planning, which was suspected to be a recurrent sinonasal lymphoma (Figure 3c,d), although there had been no clinical signs suggestive of tumour relapse between the time of initiation of radiotherapy and the first follow-up CT. The CHOP-based chemotherapy was discontinued, while rescue chemotherapy with chlorambucil (1 mg PO q24h) was initiated from day 120. Follow-up CT performed 31 days after the initiation of treatment with chlorambucil (day 151) demonstrated a 55% volume reduction in the presumed recurrent lesion of the tumour (Figure 3e,f), and the general condition of the cat was good, without nasal discharge. Although chemotherapy with chlorambucil was continued, the dosage of chlorambucil was reduced by 33% on day 180 because of its adverse effects (grade 4 elevation in alanine transaminase [ALT; 237 U/l; reference interval 22–84] and grade 1 neutropenia). To be precise, it was administered in a 3-day cycle at a dose of 0.5 mg PO on days 1 and 2, and 1 mg PO on day 3. CT on day 109 post-treatment with chlorambucil (day 229) revealed an 80% volume reduction in the presumed recurrent lesion of the tumour vs the tumour volume on day 116 (Figure 3g,h), and no evidence on imaging of disease relapse in the organs, including the brain, mandibular and medial retropharyngeal lymph nodes, liver, kidneys and spleen. Moreover, ALT improved (99 U/l), and the cat was otherwise clinically well but for mild gastrointestinal signs (diarrhoea and/or vomiting). At the time of writing (day 323), the cat continued to receive treatment with the same dosage of chlorambucil and had no clinical signs suggestive of tumour relapse. We will continue to treat with chlorambucil unless a long-term complete response is seen on follow-up CT.

Discussion

Chemotherapy is the primary treatment for most feline lymphomas, as they typically develop systemic progression. However, feline sinonasal lymphoma is often diagnosed as stage 1 (tumour localised to the nasal cavity and/or nasopharynx), and radiotherapy is used as a treatment modality, with median survival following radiotherapy ranging from 155 to 955 days.^5–9 However, the median survival time of cats with sinonasal lymphoma treated with chemotherapy alone is short, ranging from 98 days to 154 days.^6,9–11 Although the usefulness of combining radiotherapy with chemotherapy is controversial, a previous study of 17 cats with sinonasal lymphoma revealed that the cats achieved long-term overall survival (955 days) after receiving combined radiotherapy and CHOP-based chemotherapy. ⁵ Additionally, one-third of cats with sinonasal lymphoma treated with radiotherapy alone developed systemic progression soon after treatment in a recent study, thereby suggesting that some cases considered to have stage 1 disease might have had microscopic disease outside the nasal cavity at diagnosis. ⁸ Therefore, chemotherapy, either with cyclophosphamide, vincristine and prednisolone, or a CHOP-based protocol, with or without radiotherapy, is often used for cats with sinonasal lymphoma.^3,5,10–12 However, an optimal rescue chemotherapy protocol for relapsed sinonasal lymphoma following radiotherapy and/or chemotherapy remains to be established in cats. Although the use of several chemotherapeutic agents such as lomustine, mechlorethamine, methotrexate, cytarabine, actinomycin D and melphalan has been reported for relapsed feline lymphoma in various sites (including the nasal cavity), response rates were typically poor with median progression-free survival ranging from 14 to 61 days.^13–16

Chlorambucil is most commonly used to treat low-grade gastrointestinal lymphoma in cats and is well tolerated.^17–20 Adverse effects associated with chlorambucil are generally mild relative to those of the aforementioned rescue protocols. A recent case report with naive feline nasopharyngeal large B-cell lymphoma noted a long-term clinical benefit following treatment with chlorambucil alone. ²¹ In this case, the cat did not experience adverse effects associated with chlorambucil, or clinical signs consistent with local relapsing lymphoma for 754 days. In our case, the cat responded to rescue chemotherapy with chlorambucil for 7 months with mild gastrointestinal symptoms, ALT elevation and neutropenia.

Conclusions

To our knowledge, this is the first case to report successful rescue treatment with chlorambucil of a presumed recurrent high-grade sinonasal lymphoma in a cat. Chemotherapy with chlorambucil may be a useful treatment option for relapsed feline sinonasal lymphoma following radiotherapy and/or CHOP-based chemotherapy, although further studies are needed in larger populations to confirm this finding.