Discussion
At first presentation, the cat showed corneal ulcers and exposure keratitis caused by eyelid restriction. Despite medical therapy, the clinical symptoms deteriorated, and CT images demonstrated an orbital mass. Orbital exenteration was performed, and histopathological examination revealed the presence of spindle tumor cells. After surgery, toceranib was administrated due to enlargement of the residual mass. This is the first report of using toceranib as adjuvant chemotherapy for treating FROMS in a cat.
Feline orbital neoplasms are commonly diagnosed in clinical practice28. Isaza et al. 3 reported the incidence of various types of orbital tumor in cats as follows: round cell tumors 47%, epithelial tumors 38%, mesenchymal tumors 13%, and neurologic origin tumors 1%. In their report, the most common diagnoses were lymphoma and squamous cell carcinoma. Among the mesenchymal tumors, FROMS was reported most frequently, and other malignant tumors including fibrosarcoma, osteosarcoma, unspecified sarcoma, and spindle cell tumors were also reported.3FROMS has unique clinical characteristics marked by eyelid restriction without discrete orbital mass formation. Based on these characteristic findings, this disease was previously considered to be an inflammatory disorder, but was re-defined as a neoplastic lesion by Bell et al. in 2011.4 FROMS is known to originate from the orbit and actively invades connective tissues of the orbit including eyelids and conjunctiva.4, 7 Cases of the tumor invading the contralateral eye causing bilateral symptoms have also been reported.6 Histopathology examination of FROMS shows infiltrative proliferation of low-grade atypical spindle cells with collagen matrix in the orbit and substantia propria of conjunctival tissue.4 Immunohistochemistry of FROMS shows positive staining for S100, vimentin, and alfa-SMA (αSMA).4From these histopathological findings, FROMS is suspected to originate from myofibroblast cells. On the other hand, fibrosarcoma is a malignant tumor originating from fibrous connective tissue and typically consists of highly atypical spindle cells with abundant mitosis. Feline fibrosarcoma usually forms a large mass with a strong infiltrate into the adjacent tissues. Other orbital mesenchymal tumors in cats, including osteosarcoma and spindle cell tumors, show various degrees of differentiation.3 In our case, proliferation of fibroblast-like spindle cells was observed by histopathological examination, leading to a high suspicion of mesenchymal tumor. In addition, positive staining for αSMA suggested that the tumor was derived from myofibroblasts. These findings were consistent with the histopathological features of FROMS. Regarding clinical presentation, findings such as eyelid restriction and the lack of discrete orbital mass at the initial ultrasound examination were also consistent with the clinical features of FROMS. Hence, The final diagnosis was made as FROMS. However, the mitotic count in this case was relatively high compared with previous reports. These differences from previous reports may imply the existence of subtypes of FROMS.
Regarding treatment, surgical resection is often selected as the first option for feline orbital tumors. As most orbital tumors in cats are malignant, frequent local recurrence and metastasis are a clinical issue.29 Therefore, surgical resection together with other effective treatments are needed to control the progression of the disease. Additional treatment following surgery is called adjuvant therapy. Adjuvant therapy includes radiotherapy and chemotherapy. Some purposes of adjuvant radiotherapy have been proposed, including curative and palliative intent. In a previous study that evaluated adjuvant radiotherapy for FISS, a finely fractionated radiotherapy protocol significantly prolonged the survival time compared with a coarse fractionated radiotherapy protocol.30 Regarding adjuvant chemotherapy in cats, doxorubicin and lomustine have been reported for FISS, and both anti-cancer drugs demonstrated tumor suppression.31, 32 In the present case, toceranib was selected as adjuvant chemotherapy. Since the tumor was considered highly malignant due to the rapid enlargement, we planned therapy according to the evidence-based treatment for FISS, which is also a mesenchymal tumor. Radiation therapy was not selected due to the lack of facilities at our clinic, and frequent procedures under anesthesia could lead to further deterioration of the cat’s general condition. Regarding chemotherapeutic agents, doxorubicin is known to have adverse effects including gastrointestinal and renal toxicity31, and lomustine has been reported to cause severe leukopenia leading to dose reduction.32 Considering the poor general condition of the cat, use of doxorubicin or lomustine was challenging due to the possibility of severe side effects. Therefore, we considered using molecular targeted drugs that are effective for sarcoma with mild adverse effects.
In recent years, molecular target drugs such as imatinib, masitinib, and toceranib have been used in veterinary medicine.11Toceranib has been shown to inhibit KIT, platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor, and tumor growth.13-16 Katayama et al. reported that inhibition of PDGFR suppressed feline fibrosarcoma in in vitroexperiments.33 Holtermann et al. treated FISS cases with toceranib as adjuvant therapy, but observed no significant tumor reduction.27 Holtermann et al suggested that toceranib may be potentially effective to some extent because all specimens of FISS were positive for PDGFR in immunohistochemistry. They also reported that gastrointestinal toxicity was the main adverse effect of toceranib, but all symptoms were mild and temporary, and improved after discontinuation of toceranib. In the present case, toceranib was administered at a dose of 2.17 mg/kg three times per week for one month, but the residual tumor enlarged and invaded connective tissues. The response to toceranib treatment was considered poor, and there was no noticeable tumor suppression effect. Some factors may account for the lack of effectiveness. First, toceranib may be ineffective for this tumor type. Since the origin of this tumor has not been identified, and molecular biological characterization remains unknown, it is unclear whether toceranib affects this tumor type. Second, the long interval between surgery and toceranib administration may be a factor. Since toceranib was administered three weeks after surgery and the tumor had already progressed, the effect of tumor suppression may not be fully demonstrated. Third, the dosage may be low. In previous reports, toceranib was used in the range of 1.6 to 3.5 mg/kg.17, 27, 34, 35 Since the general condition of the cat was deteriorating, toceranib was used at a lower dose compared with previous reports. Therefore, the effective blood concentration of toceranib needed to suppress tumor growth might not be reached. This cat manifested restriction of the eyelids and exposed keratitis at initial presentation without obvious mass lesion in the orbit by ultrasound examination, which led to a delay in performing surgical intervention. Some orbital mesenchymal tumors in cats, such as FROMS, progress rapidly and are already advanced at the time of deciding surgical intervention, making it challenging to perform radical resection. Therefore, early surgical treatment should be considered when findings in cats suggest an orbital tumor as in the present case. In addition, adjuvant therapy should also be considered due to local recurrence and metastasis. Although toceranib did not suppress the tumor in this case, early administration or higher doses might have some effect on it\sout.
In conclusion, this is the first case report of treatment with toceranib as postsurgical adjuvant chemotherapy for FROMS. Further study to examine the dosage and timing of toceranib administration is warranted.