pISSN 1598-298X / eISSN 2384-0749 J Vet Clin 36(3) : 180-183 (2019)
http://dx.doi.org/10.17555/jvc.2019.06.36.3.180
180
Lomustine Plus Hydroxyurea Chemotherapy for Primary Intramedullary Spinal Cord Tumor in a Maltese Dog
Joong-Hyun Song, Do-Hyeon Yu, Tae-Sung Hwang, Hee-Chun Lee, Su-Jin An, Jung-Hyang Sur*, Young Joo Kim** and Dong-In Jung1
Institute of Animal Medicine, College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Korea
*Department of Pathobiology, Small Animal Tumor Diagnostic Center, College of Veterinary Medicine, Konkuk University, Seoul 05029, Korea
**College of Veterinary Medicine, Western University of Health Sciences, California 91766-1854, USA (Received: March 25, 2019 / Accepted: June 03, 2019)
Abstract : A 7-year-old, male Maltese dog with a body weight of 2.8 kg was presented with a history of hind limbs ataxia that progressed to tetraparesis over a one-month period. Based on physical and neurological examinations, tetraparesis with concomitant UMN signs, kyphosis and severe neck pain were identified. On MRI scan, we tentatively diagnosed this patient as a primary intramedullary spinal cord tumor. Therapy with lomustine plus hydroxyurea and prednisolone was initiated and the clinical signs rapidly improved. The patient was regularly checked by MRI scan and the range of the mass was gradually reduced to complete remission for 11 months. About 19 months after treatment, the patient showed anemia and hematochezia which suspected as adverse effects of chemotherapy. The condition was getting worse over 2 months and the patient suddenly expired 657 days after initial presentation. On histopathological examination, the spinal cord sample was identified as a neuronal atrophy without evidence of tumor cell.
Key words : dog, hydroxyurea, lomustine (CCNU), magnetic resonance imaging, intramedullary spinal cord tumor.
Introduction
Although primary spinal cord tumor is uncommon in dogs (9,17), spinal neoplasia is an important differential diagnosis for dog presenting with neurologic dysfunction associated with spinal cord. Spinal neoplastic disease can involve the spinal cord, dura, peripheral nerves, or peri-spinal tissues and diagnosis is often presumptively made using advanced imag- ing such as computed tomography (CT) and magnetic reso- nance imaging (MRI) (1). Anatomical classification systems and MRI characteristics are used to categorize and assume spinal neoplasm before definitive diagnosis by histopatholog- ical examination (4).
Primary intramedullary tumors of canine spinal cord are rarely reported, and comprised 10% (35/331) of all canine spinal tumors (13). It usually includes astrocytoma, oligoden- droglioma, and ependymomas (11,17,21). These tumors arise from cells within the spinal cord parenchyma, and they are often poorly demarcated and sometimes difficult to differen- tiate from normal adjacent tissue (1). MRI and myelography typically has been used as a useful diagnostic tool before autopsy and histopathological confirmation. Treatment options for intramedullary spinal tumor include cytoreductive surgery and radiation therapy with or without chemotherapy (13). Surgi- cal removal of the tumor is usually impossible, and radiation therapy is sometimes beneficial and may prolong life (10,18).
Efficacy of chemotherapy in canine primary intramedullary spinal cord neoplasia have not yet been evaluated.
The objective of this report is to describe a successful treatment of primary unknown spinal cord tumor with lomus- tine plus hydroxyurea.
Case Description
A 7-year-old, male Maltese dog with a body weight of 2.8 kg was presented with a history of hind limbs ataxia that pro- gressed to tetraparesis over a one-month period. On conduct- ing physical and neurological examinations, tetraparesis with concomitant UMN signs, kyphosis and severe neck pain were identified. The cranial nerve reflexes were normal. The results of complete blood counts, serum chemistry profiles, and radiographs were not remarkable. On the basis of a neu- rological examination, the clinical signs were deemed to be likely due to the spinal cord lesion (C1-C5).
To evaluate the spinal cord lesions, we performed a spine MRI scan using a 0.4-T scanner (APERTO; Hitachi Medical Corporation, Tokyo, Japan), and cerebrospinal fluid (CSF) analysis. T1-weighted (T1W) images, T2-weighted (T2W) images and contrast-enhanced T1-weighted (CET1W) images were obtained on MRI scan. On MRI images (Fig 1A and 1B), there was an ill-demarcated mass within the dorsal aspect of vertebral canal at the level of the third and fourth cervical vertebrae. The diameter of affected spinal cord was increased.
The lesion appeared hypointense on T2W and T1W images with intensely and uniformly enhancement on CET1W images.
In addition, there was syringomyelia extending from cranial
1Corresponding author.
E-mail : [email protected]
Lomustine Plus Hydroxyurea for Primary Intramedullary Spinal Cord Tumor 181
aspect of the mass to the level of the second cervical verte- bra. Examination of the CSF revealed a normal nucleated cell count of 4 cells/µl (reference range, < 5 cells/µl) and a pro- tein concentration of 10 mg/dl (reference range, < 25 mg/dl).
Cytological examination of CSF revealed a mononuclear cell predominance. Based on the result of the MRI scan, we ten- tatively diagnosed this patient as an unknown primary intra- medullary spinal cord tumor.
The owner of this patient refused surgical treatment and we prescribed lomustine (CCNU; CeeNU®, BMS, Mon- treal, Canada; 60 mg/m2, q 6 week), hydroxyurea (Hydroxy- urea, Korea United pharm., Seoul, Korea; 50 mg/kg, PO, q
Fig 1. Serial sagittal T2W images (A, C, and E) and CET1W images (B, D, and F) of cervical spine MRI scan. A, B: At the initial presentation. C, D: 1 month after treatment. E, F: 11 months after treatment. There was an ill-demarcated mass (arrows) within the dorsal aspect of vertebral canal at the level of the third and fourth cervical vertebrae. Syringomyelia was identified at the level of the second cervical vertebra (empty arrows). After initiation of the treatment, the mass and the diameter of spinal cord gradually decreased, and syringomyelia also decreased dramatically as time went on.
Fig 2. Post-mortem MRI scans and necropsy with histopathologic examination. A: sagittal T2W image, B: sagittal T1W image, D:
x200, hematoxylin and eosin staining. (A and B) The mass completely disappeared (arrows) on MRI scan. Syringomyelia was newly identified at the site of the previous mass lesion (empty arrows). (C) The spinal cord showed complete remission on gross examination.
(D) On histopathological examination, the spinal cord sample was identified as a neuronal atrophy without evidence of tumor cell.
48 hr) and prednisolone (Prednisolone, Korea Pharm., Seoul, Korea; 0.5 mg/kg, PO, q 12 hr). The clinical signs rapidly improved and the patient could walk after 1 week. Approxi- mately 1 month after initiation of treatment, the ataxic gait was perfectly normalized, and second MRI scan was evalu- ated to assess the patient’s response to therapy. On rechecked MRI scan, the range of the mass and the diameter of the spi- nal cord were reduced at the level of the third cervical verte- bra, and the syringomyelia was also markedly reduced (Fig 1C and 1D). The dose of prednisolone was gradually tapered and the patient maintained stable state. The third MRI scan was performed 11 months after treatment (Fig 1E and 1F),
182 Joong-Hyun Song et al.
the MRI images showed complete remission of the mass lesion and the size of the syringomyelia was decreased com- pared with the initial scan.
About 19 months after treatment, the patient showed mild anemia (hematocrit, 31.7%; reference range, 37 to 55%) with hematochezia. We changed administration interval of the lomustine from 6 weeks to 7 weeks with supportive therapy for anemia and hematochezia. But the anemia condition with non-regeneration was getting worse (hematocrit, 27.7%) over 2 months, then we stopped administration of lomustine and hydroxyurea and started treatment with erythropoietin (EPO- KINE PREFILLED, CJ HealthCare, Leecheon, Korea; 100 Units/kg SC 3 times per week) plus ferrous sulfate (Norferro capsule, Nordmark Arznelmittel Gmbh & Co. KG, Uetersen, Germany; 100 mg per dog PO once daily). After 1 month, the patient was represented with severe anemia (hematocrit, 12.9%). We performed a whole blood transfusion and the patient showed temporary recovery. The patient showed severe depression a few days after discharge and was expired at home by abrupt cardiac arrest (657 days after initial treatment). The patient was donated by the owner and we performed post- mortem MRI scan and necropsy with histopathologic exam- ination.
On post-mortem MRI scan (Fig 2A and 2B), the mass completely disappeared on T2W and T1W images. Syringo- myelia was newly identified at the site of the previous mass lesion and it was thought to be a post-mortem change. At necropsy the spinal cord, we could not find any specific tumoral lesion aside from dilation of the cervical central canal which was considered as a syringomyelia on the MRI scan.
On histopathological examination (Fig 2D), the spinal cord sample was identified as a neuronal atrophy without evi- dence of tumor cell.
Discussion
Many tumors that can affect the spinal cord of dogs and cats have been reported in veterinary literatures and spinal cord tumors can be divided into primary and secondary tumors. In general, most patient with spinal tumors are older (e.g. more than 5 years) and larger breed dogs (especially golden retrievers and boxer) (2,14,20). Clinical signs of spi- nal tumor are not pathognomonic, but suddenly progressive myelopathic signs and severe pain can be noticed by owner and clinician (1,2). In the present case, based on this patient’s age, clinical history and results of neurological examination, we could highly suspect spinal cord tumor as a major cause of myelopathy. In addition, based upon results of CBC, serum biochemical analysis and radiographic examination, we could rule out the possibility of a metastatic tumor.
Based upon previous surveys (2,7), it has been suggested that with MRI, tentative diagnosis of intramedullary spinal cord tumor can be achieved. Although, MRI features of intra- medullary spinal cord tumor are never pathognomonic, the MRI characteristic of intramedullary spinal cord tumor is the presence of an intraparenchymal mass that causes an increase in spinal cord diameter (19). This usually shows an intensive enhancing mass on CET1W MR images. A contrast-enhanced MRI or CT myelographic examination sometimes show an
annular narrowing of the adjacent subarachnoid space. Some of these MRI features (increase in spinal cord diameter and uniformly enhancement on CET1W images) were observed in the present case. According to these features, the patient was tentatively diagnosed with cervical intramedullary spi- nal cord tumor.
In general, surgical intervention with or without radiation therapy considered as optimal choice of spinal tumors and other CNS tumors (1,12,14). These treatments are some- times not feasible due to many factors such as behavior of tumors, patient states and financial constraint. Chemother- apy in canine primary spinal tumor has traditionally been regarded as adjunctive therapy or second option after failure of a first cytoreductive therapy (3). However, effective che- motherapy protocol of spinal cord neoplasia by means of a case-control study is still scarce and there is limited informa- tion on the prognostic data after chemotherapy.
Recently, some reports (5,6,12,16) indicated that the hy- droxyurea and lomustine showed relevant efficiencies for canine CNS tumor. In the present case, surgical removal was not performed according to the client’s refusal and we started chemotherapy with lomustine plus hydroxyurea based on previous studies. This patient’s survival time (survived for 657 days with treatment) was relatively long as compared to the times that were previously reported cases with the pri- mary intramedullary spinal cord tumor (mean survival time:
23 days) (13), and satisfactory improvement of clinical signs was identified. Furthermore, the present case demonstrated complete remission of the tumor on the MRI scan and histo- pathological examination. This previous reported cases showed highly variable response to palliative treatment, sur- gery, radiation, or chemotherapy, and overall prognosis for intramedullary spinal neoplasia was grave (10,13). The pres- ent case achieved complete remission with only chemother- apy without surgical resection and radiation therapy, which means that therapy with lomustine and hydroxyurea applied in the present case effectively and might be an effective treat- ment regimen of spinal intramedullary tumor in dogs. In addition, surgical resection of spinal cord tumor has the high probability of recurrence and the probability of complica- tions (14). And complete tumor resection is somewhat chal- lenging due to its intraparenchymal location and tight attachment to the adjacent structure. Therefore, we surmised that chemo- therapy using lomustine and hydroxyurea might be a good therapeutic option for canine intramedullary spinal tumor patient as a first treatment option. However, further long-term prospective studies in a larger number of dogs having intra- medullary spinal tumor are required to estimate the clinical efficacy and survival times of this chemotherapeutic regimen.
Bone marrow suppression and gastrointestinal effects (anorexia, vomiting, and diarrhea) are usual, potential side effects of lomustine and hydroxyurea in dogs (4,15). They can cause fatal adverse effects, particularly when used at higher dosages and for prolonged treatment periods, which can be attenuated before it becomes severe by temporarily decreasing the dose or discontinuing the medication when hematological abnormalities are detected during routine CBC monitoring (8). In the present case, the patient showed non- regenerative anemia about 19 months after treatment with
Lomustine Plus Hydroxyurea for Primary Intramedullary Spinal Cord Tumor 183
lomustine plus hydroxyurea. Unfortunately, the patient did not show any response for the dose decrement and discontin- uing of the lomustine and hydroxyurea with supportive ther- apy and eventually died for severe anemic condition. It is unclear whether the gradual decrease in hematocrit in this case was due to only hydroxyurea and/or lomustine induced myelosuppression, we postulated that the chronic lomustine plus hydroxyurea chemotherapy without medication adjust- ment and close monitoring could be very dangerous and lead to irreversible damage to bone marrow. Furthermore, further investigation of the optimal and safe dose range of these che- motherapeutic drugs for treating canine intramedullary spinal tumor and other CNS tumors is necessary, and the clinician should pay attention to side effects caused by long-term use of this chemotherapy regimen to patients.
In conclusion, this report describes the clinical finding, diagnostic imaging characteristic, and chemotherapeutic response of primary intramedullary spinal cord tumor in a Maltese dog. Although the present patient was not definitely diagnosed before complete remission and only a single case report, our experience suggests that chemotherapy with lomus- tine and hydroxyurea could be an effective and relatively noninvasive treatment option for canine primary intramedul- lary spinal tumor patients.
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