Feline anaplastic oligodendroglioma: long-term remission through radiation therapy and chemotherapy

Abstract

A 10-year-old spayed female Abyssinian cat was presented with cluster limbic focal seizures with secondary generalisation. From magnetic resonance imaging (MRI) findings, the cat was diagnosed clinically as having a glioma in the left piriform lobe, and hypofractionated radiation therapy (RT) was performed using a linear accelerator. Although the tumour size had reduced significantly at 4 months after RT, recurrence was observed at 11 months after RT. Additional RT was performed and was effective; however, recurrence was observed at 11 months after the additional RT. Chemotherapy was started using nimustine (ACNU; 30 mg/m², every 6 weeks). Tumour regression was confirmed by follow-up MRIs from 2 to 5 months after starting chemotherapy. Four years and 2 months after the first presentation the cat died as a result of tumour lysis syndrome following treatment of a high-grade lymphoma. Histopathological diagnosis of the brain tumour confirmed anaplastic oligodendroglioma.

Case Report

Gliomas, such as oligodendrogliomas and astrocytomas, are frequent central nervous system tumours secondary to meningiomas in dogs, ¹ and several reports have documented the results and prognoses of dogs with glioma treated with megavoltage radiation therapy (RT) and/or chemotherapy (nitrosoureas).^2–4 In contrast to canine gliomas, those in cats are rare, ⁵ and no study has described the long-term outcome in cats. Here, we report long-term remission of a cat with glioma (anaplastic oligodendroglioma) that was treated with RT followed by chemotherapy.

A 10-year-old spayed female Abyssinian cat was presented with repetitive and cluster seizures consisting of limbic focal seizures (salivation, facial twitching and chewing) with secondarily generalisation (day 0). Although the neurological examination was normal and seizures were controlled by phenobarbital (PB) (2.5 mg/kg, PO, q12h: Phenobal; Daiichi-Sankyo), magnetic resonance imaging (MRI) (AIRIS 0.4 Tesla; Hitachi) was performed to evaluate the differential diagnoses. MRI revealed a focal parenchymal swelling with mild hyperintensity on T2-weighted images (T2WI) and hypo- to isointensity on T1-weighted images (T1WI) without contrast enhancement on gadodiamide (Omniscan; Daiichi-Sankyo) T1WI (Gd-T1WI) in the left piriform area. From these MRI findings, the lesion was thought to be a low-grade glioma or epileptic brain damage. To discriminate these pathologies, a second MRI was performed after 1 month. On the second MRI (day 25) (Visart 1.5 Tesla; Toshiba), the lesion was slightly enlarged with the same signal intensities, and the cat was diagnosed clinically as having a glioma (Figure 1a, b).

Figure 1

Time-course changes of magnetic resonance imaging (MRI) findings. All images show a transverse plane at the level of the piriform area. (a), (c), (e), (g), (i) and (k) are T2-weighted images (T2WIs) and (b), (d), (f), (h), (j) and (l) are gadodiamide T1-weighted images (Gd-T1WIs). (a)–(h) were obtained by a 1.5-Tesla MRI system and (i)–(l) were obtained by 3.0 Tesla. (a, b) The second MRI (day 25). A focal parenchymal swelling showed mild hyperintensity on T2WI and no contrast enhancement on Gd-T1WI in the left piriform area. (c, d) Four months after radiation therapy (RT) (day 220). The size and signal intensities of the lesion were reduced significantly on T2WI. (e, f) Sixteen months after RT (day 578). A mild hyperintensity on T2WI and heterogeneous and/or ring enhancement on Gd-T1WI was recognised within the lesion (arrow). The lesion had reverted to characteristics prior to RT and showed regrowth. (g, h) Two months after additional RT (day 669). Although the lesion remained as hyperintense on T2WI, ring-enhancement disappeared on Gd-T1WI. (i, j) Eleven months after additional RT (day 948). The lesion showed regrowth. (k, l) Two months after initiating nimustine (ACNU) (day 1021). The lesion was reduced significantly except for mild hyperintensity on T2WI in the piriform area. A partial loss of tissue in the parahippocampal gyrus in the left was also observed (arrow heads)

Owing to the difficulty of surgical resection and the owner’s request, megavoltage RT using a linear accelerator (PRIMUS; Siemens) was started on day 53. The lesion was treated with a hypofractionated protocol that was 6 Gy per fraction from four directions once a week for 6 weeks (total 36 Gy). The third MRI was performed at 4 months after RT (day 220), and the size and signal intensities of the lesion were reduced significantly (Figure 1c, d).

The fourth MRI was performed at 11 months after RT (day 417), and the lesion had reverted to the size and signal intensities observed prior to RT, which was considered recurrence. However, as the cat did not show any clinical signs, the owner did not wish to treat the animal at this time. On the fifth MRI (day 578), in addition to findings from the fourth MRI, heterogeneous and/or ring enhancement on Gd-T1WI was recognised within the lesion (Figure 1e, f). These findings were thought to associate with recurrence and/or malignant transformation of the glioma. The owner chose additional RT, and the lesion was treated using a decreased dose (6 Gy once a week for 2 weeks, total 12 Gy) of RT (day 601). Although the lesion remained as mildly hyperintense on T2WI on the sixth MRI (2 months after additional RT, day 669), the enhanced lesion had almost disappeared (Figure 1g, h).

On day 700, the cat again experienced cluster seizures, and was treated with 1 mg/kg q12h of diazepam (DZP) (Horizon; Astellas) and 1 mg/kg q24h of prednisolone (Predonine; Shionogi). After treating the cluster seizures, seizures were controlled by 2.0 mg/kg q12h of PB and 0.5 mg/kg q12h of DZP. However, regrowth of the tumour was observed on the seventh MRI (Signa HDxt 3.0 Tesla; GE) (11 months after additional RT, day 948) (Figure 1i, j). Because the lesion had already been treated with RT for a second time, the owner chose chemotherapy.

Chemotherapy with nimustine (ACNU) (Nidran; Daiichi-Sankyo) was started at 30 mg/m² intravenously every 6 weeks (on day 966). During chemotherapy, mild and transient leukopenia was observed (pretreatment average, 13,300/μl; 1 week post-ACNU average, 6200/μl) that recovered within 2 weeks of each administration. An eighth MRI was performed at 2 months after initiating ACNU (day 1021). The lesion was reduced significantly, except for mild hyperintensity on T2WI in the piriform area (Figure 1k, l).

On day 1267, the cat experienced anaphylactic shock immediately after the seventh administration of ACNU, and was treated promptly and routinely. The cat recovered without clinical signs except for mild and transient pulmonary oedema. As the lesion regrew with ring enhancement, as observed on the ninth MRI (5 months after cutoff of ACNU, day 1413), chemotherapy was changed from ACNU to lomustine (CCNU, 30 to 50 mg/m², PO, every 6 weeks) (Ceenu; Miracalus) and restarted.

At day 1475, the cat showed anorexia, enlarged mesenteric lymph nodes and chylothorax by ultrasound, and leukocytosis and normocytic normochromic anaemia by complete blood count. Fine-needle aspiration of the mesenteric lymph nodes revealed high-grade lymphoma. Although chemotherapy for lymphoma (400 μ/kg of L-asparaginase and 0.5 mg/m² of vincristine) was started, the cat became worse and died on day 1534 (approximately 4 years and 2 months). Sixteen hours after death, post-mortem MRI and autopsy were performed. On the post-mortem MRI, the intracranial lesion showing hypo- to isointensity on T1WI and hyperintensity on T2WI suggested tumour recurrence (Figure 2). From characteristic histopathological and immunohistochemical findings, the lesion was diagnosed as an anaplastic oligodendroglioma according to the World Health Organization classification (Figure 3).^6,7 Lesions in the intraperitoneal and superficial cervical lymph nodes had lysed macroscopically and were immunohistochemically diagnosed as B-cell lymphoma. Tumour lysis syndrome occurred as a result of treatment with chemotherapy for lymphoma, and was diagnosed as the direct cause of death.

Figure 2

Post-mortem magnetic resonance imaging. Hyperintensity on T2-weighted imaging suggests tumour recurrence in the piriform area

Figure 3

Gross (a) and histopathological (b, c) findings. The left piriform area contains a poorly demarcated expansile mass (arrows) (a, formalin-fixed, scale bar = 10 mm). Histologically, tumour cells have round and hyperchromatic nuclei and clear-to-lightly stained cytoplasm (perinuclear halo) with a distinct cell membrane (b, haematoxylin and eosin, scale bar = 250 µm). Immunohistochemically, these tumour cells are positive for Olig2 (c, Anti-Olig2, scale bar = 250 µm), negative for glia fibrillary acidic protein and β-III tubulin. Based on these findings, the lesion was diagnosed as an anaplastic oligodendroglioma

The incidence of gliomas in cats is reported as 7.5% of intracranial neoplasias and is uncommon. ⁵ Previous reports indicate that gliomas are often located within the deeper structures of the cerebrum, including the limbic area, especially the piriform lobe, amygdala and temporal lobe.^1,5,8,9 Recently, seizure types associated with the limbic system in cats were reported.^10–15 Pakozdy et al ¹⁴ and Vanhaesebrouck et al ¹⁵ reported that seizure types with orofacial involvement (eg, salivation, chewing) and motor arrest may be associated with limbic seizures (complex partial seizures). Seizure types in the present case were very similar and suggest the possible involvement of the original site of glioma.

Gliomas occur frequently in areas difficult for surgical mass resection. In contrast to cats, radio- and chemotherapy is often performed in humans and dogs for cases with where surgical resection would be difficult.^{2–4,16–20} In a recent study of irradiation alone in 46 dogs with brain tumours of various types and uncertain histology, the median survival time was 699 days. ²¹ We reported long-term survival (910 days) in a dog with anaplastic oligodendroglioma, ² and the RT protocol used in the present case was similar to that of the canine case. The RT and additional RT were effective for our case, and the cat was seizure-free accompanied by significant tumour regression on follow-up MRI and under PB therapy.

This relatively fast regrowth within a year suggests a malignant transformation of the glioma or the malignant nature of the glioma, rather than the RT protocol, because the lesion showed contrast enhancement at 16 months after RT. Although a malignant transformation of glioma in humans is well known, this phenomenon is unreported in cats. Contrast enhancement in gliomas correlates with histological malignance in humans and dogs, and has been used to establish grade classification of tumours.^1,8,9 By contrast, various contrast enhancements that are observed in gliomas of cats do not compare with grade classification. ⁹ In our case, the cat was diagnosed histopathologically as having an anaplastic oligodendroglioma, and showed contrast enhancement on MRI for high-grade oligodendroglioma, as has also been reported in dogs.

Radiotherapy combined with chemotherapy is performed frequently in humans. The first substances known to exert effects against malignant gliomas were the nitrosoureas, which cross the blood–brain barrier easily owing to their high liposolubility. As oral administration and dose adjustment is difficult in cats, intravenous ACNU may be useful in this species. In humans, radiotherapy combined with ACNU for the treatment of malignant gliomas reduced the tumour size significantly, and showed better improvement of neurological signs and performance status of patients when compared with radiotherapy alone. ¹⁶ Another study in humans showed that tumours of oligodendroglial origin show a higher chemosensitivity than other malignant gliomas.^17–20 Unfortunately, the cat showed anaphylactic shock after the administration of the seventh ACNU treatment. This may be related to the drug solvent rather than the ACNU itself because subsequent CCNUs were tolerable. Oligodendrogliomas in cats, as well as those in humans and dogs, may have high sensitivity to nitrosourea chemotherapy.

Conclusions

In this case, we achieved long-term remission in a cat with a histopathologically diagnosed anaplastic oligodendroglioma that was treated with RT followed by chemotherapy. We do not know how effective radiotherapy combined with chemotherapy can be in the treatment of oligodendrogliomas in a cat. However, the treatment strategy of the combination of radiotherapy followed by chemotherapy for cases of glioma in cats that showed tumour recurrence after surgical resection or where surgical resection might be difficult should be considered.