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.