Long-Term Survival of Primary Intracranial Histiocytic Sarcoma Through Surgical Resection and Low-Dose CCNU
ABSTRACT
A 5 yr old chihuahua presented to our clinic with a complaint of decreased activity and focal seizures. Based on the findings of MRI and computed tomography, a primary brain tumor originating from the right frontal lobe region was suspected. Surgical resection was performed, and a diagnosis of histiocytic sarcoma was made via histopathological examination and immunohistochemical staining. Low-dose 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) (45 mg/m2 every 4–5 wk) was started postoperatively, and no apparent recurrence was found on two MRI scans until the patient’s death on day 359. We hypothesized that long-term survival might be achieved in dogs with solitary histiocytic sarcoma of the central nervous system with no metastatic lesions at diagnosis by combining local treatment with CCNU. We also suggested that CCNU may effectively suppress the recurrence of histiocytic sarcoma, even at low doses.
Introduction
Histiocytic sarcoma (HS) in dogs is a progressive and fatal malignancy that is mostly derived from interstitial dendritic cells. Depending on the location of the lesion, it is classified as either localized HS or disseminated HS. Although the subcutaneous tissue of the extremities has been suggested as the predilected site, the disease can occur in various organs, including the lungs and spleen.1–3 Distant metastasis rates for HS are reported as high as 70%–91%,1,4 suggesting the need for adjuvant systemic therapy in addition to local treatments such as surgical resection and radiation therapy. The efficacy of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in chemotherapy for HS has been demonstrated. The report on CCNU (60–90 mg/m2 every 3–4 wk) treatment alone for localized and disseminated HS showed overall response rates of 46% with median survival of 106 days.5 Currently, it is difficult to achieve long-term survival with chemotherapy alone, and drug-induced side effects are another concern. Although less commonly reported, central nervous system (CNS, including the brain and spinal cord) involvement has also been observed.6–13 Primary intracranial histiocytic sarcoma (PIHS) is a malignant tumor of dendritic cell origin in the meninges and choroid plexus that rarely occurs in dogs.9 As with HS in nonneural tissues, the prognosis is reportedly poor.7,8 In a recent large-scale Japanese study of primary intracranial tumors in dogs, PIHS was the third most common tumor after meningioma and glioma.6 However, available information on HS in the CNS is limited, and no effective treatment for this condition has been established so far. Therefore, it is desirable to develop treatments that can prolong the survival of affected animals. Herein, we report a case of PIHS in a chihuahua that achieved long-term survival after surgical resection and the postoperative administration of low-dose CCNU. To our knowledge, there have been no previous reports on PIHS in chihuahuas.
Case Report
Clinical Presentation
A 5 yr old, 3.4 kg spayed female chihuahua presented to a primary hospital for acute-onset hypoactivity and focal seizures. The seizures had resolved by the time the patient came to the hospital, and no obvious abnormalities were found on physical examination; therefore, follow-up care was indicated (day 1). However, seizures were then observed daily, so the patient was seen again at the primary hospital. Then, the patient was referred to our clinic for further investigation (day 10). The physical examination at our clinic indicated a body temperature of 38.9°C, a pulse rate of 120 beats/min, and panting. Based on the owner’s notification, the seizure symptoms were circling toward the right side, tremors, and forelimb elevation, all of which were suggestive of a motor focal seizure.
Diagnostic Findings
At the primary hospital, the complete blood count (CBC) and serum biochemical examinations were normal, and thoracic radiographs revealed no abnormalities. Subsequent neurological examinations performed at our clinic revealed no obvious abnormal findings in postural responses, spinal reflexes, cranial nerve testing, or perception; however, observations during gait revealed circling toward the right side. These findings suggested structural epilepsy caused by forebrain lesion. Differential diagnoses considered were a brain tumor, meningoencephalitis, and caudal occipital malformation syndrome. Based on these findings, brain MRI and cerebrospinal fluid analyses were recommended. Brain MRI was performed on admission, under general anesthesia, using a 0.4-T MRI system with a permanent magneta, with the patient in the prone position. We used a human wrist coil and obtained T2-weighted images (T2WI: fast spin-echo, repetition time/echo time [TR/TE] = 4375/100), fluid-attenuated inversion recovery (fast inversion recovery, TR/TE = 8292/78), and T1-weighted images (T1WI: spin-echo, TR/TE = 400/15) with and without IV gadodiamide (0.2 mL/kg)b in the transverse, sagittal, and dorsal planes. MRI revealed a solitary extraparenchymal occupying lesion in the right frontal lobe region. The mass showed hypointensity and isointensity on T2WI and fluid-attenuated inversion recovery, hypointensity on T1WI, and heterogeneous enhancement effects on postcontrast T1WI with brain edema localized around the mass (Figure 1). Considering the possibility of a brain tumor based on MRI findings, a computed tomography (CT) was also performed. Whole-body CT performed using a CT scannerc revealed a mass with enhancement effects in the right frontal lobe region; however, no obvious abnormalities were detected in other body parts, including the chest and abdomen. Cerebrospinal fluid analyses (collected from a cerebellomedullary cistern) revealed pleocytosis with mononuclear cell predominance (7.67 WBCs/µL, reference range: <5.00 WBCs/µL) and increased protein concentrations (96.3 mg/dL, reference range: <25.0 mg/dL). Accordingly, a primary brain tumor was the most likely diagnosis, with granulomatous meningoencephalomyelitis as a differential diagnosis.
Citation: Journal of the American Animal Hospital Association 61, 1; 10.5326/JAAHA-MS-7458
Treatment
When the examination was performed under anesthesia, single doses of mannitold (2 g/kg continuous rate infusion for 30 min) and furosemidee (1 mg/kg IV) were administered to decrease cerebral pressure. Prednisolonef (0.7 mg/kg once a day) and zonisamideg (3.6 mg/kg twice a day) were initiated as a symptomatic therapy to reduce brain edema and control seizures. At the owner’s request, surgical resection of the mass lesion via the transfrontal sinus approach was performed (day 21). On intraoperative gross findings, the mass lesion was formed outside of the brain parenchyma with a well-defined perimeter, and the grossly visible lesions were generally resectable. In the postoperative period, the patient showed increased activity, seizure suppression, and the disappearance of gyrating movements. From day 33, CCNUh (one capsule once a day) was started at a dose of 45 mg/m2 every 4–5 wk to prevent postoperative recurrence and metastasis.
Histopathology and Immunohistochemical Staining
In the histopathological examination of surgically removed neoplastic lesions, polygonal cells grew infiltratively in the meninges and brain parenchyma. The tumor cells were mostly irregular in size, the cytoplasm was eosinophilic, and cell borders were indistinct. The nuclei were round and irregularly sized, with one clear nucleolus, and mitotic figures were rare. Multinucleated giant cells were also scattered. Hemorrhage, necrosis, and the infiltration of lymphocytes and plasma cells were observed in the tumor tissue with no perivascular cuffing (Figure 2). These findings led to suspicions of HS, which were confirmed by positive results of immunohistochemical staining for HLA-DR, Iba-1, and CD204 and negative results for CD3 and CD20 (Figure 2). Therefore, we diagnosed this animal with PIHS.
Citation: Journal of the American Animal Hospital Association 61, 1; 10.5326/JAAHA-MS-7458
Outcome
After the initiation of low-dose CCNU treatment, CBC and blood biochemistry tests were performed periodically to monitor for adverse effects. Although grade 2–3 neutropenia was frequently observed in the CBC, it was reversible and asymptomatic and did not lead to medication reduction or discontinuation until day 278, the last day of CCNU treatment. Although blood biochemistry tests performed on day 96 revealed elevated levels of alanine aminotransferase (336 U/L; reference range 17–78 U/L) and aspartate aminotransferase (77 U/L; reference range 17–44 U/L), the patient was started on ursodeoxycholic acidi (8.0 mg/kg once a day), and all tests performed in our hospital thereafter remained within normal limits. The patient remained in good condition with no apparent clinical manifestations, and another MRI scan was performed to evaluate recurrence (day 138). MRI revealed a small lesion with mild enhancement effects at the margins of the tumor resection site in the right frontal lobe, but no obvious mass formation was observed (Figure 1). This finding was assumed to reflect recurrent tumor lesions or postoperative scar tissue. From day 180, given the stable patient condition and the lack of obvious mass formation on imaging, the interval of CCNU administration was changed to every 5 wk per the owner’s request. The patient’s activity and appetite tended to decrease from day 285. Subsequently, CCNU administration was discontinued owing to persistent thrombocytopenia and further loss of appetite. Symptomatic treatment did not produce any apparent improvement, and the brain MRI performed on day 341 revealed nothing suggestive of the apparent recurrence of an intracranial tumor (Figure 1). On day 359, the patient’s condition deteriorated rapidly, and blood tests performed by the primary hospital revealed severe thrombocytopenia, anemia, jaundice, and renal failure. Inpatient treatment was initiated but did not stop the patient from dying on the same day. Consent for a postmortem examination was not obtained; thus, it was not possible to determine the immediate final cause of death.
Discussion
This report presents a case of PIHS in a chihuahua that achieved long-term survival after surgical resection and postoperative administration of low-dose CCNU. In this case, we diagnosed HS based on imaging findings, intraoperative gross findings, and histopathological examination findings, including immunohistochemical staining.
HS in nonneural tissues generally has high malignancy and metastatic rates and a poor prognosis. HS in the central nervous system (CNS HS), including PIHS, has shown similar trends, with reported median survival durations of 3 and 44 days.7,8 Our report includes only one case of PIHS; however, at 359 days, this is the longest-surviving case to the best of our knowledge. Several factors may be involved in the context of our patient’s long-term survival, as discussed further in this section. In previous studies on HS prognosis, disseminated HS has been reported to be a poor prognostic factor.14 As it is unclear which factors contribute to the similarity of results in CNS HS, we consider that it may have a corresponding trend. Furthermore, it has been suggested that local treatment for localized HS may lead to prolonged survival. A study on primary pulmonary HS found that a CCNU-based chemotherapy-alone treatment group was compared with a surgical resection-plus-chemotherapy group, with the combined surgical group showing a longer progression-free interval and overall survival.15 The study shows that the presence of metastases at diagnosis negatively impacts the overall survival and notes that surgical intervention may be beneficial in cases of resectable pulmonary HS with no metastases at diagnosis. To our knowledge, no large-scale studies have examined the efficacy of local treatment in CNS HS to date, although a few case reports of PIHS in which local treatment was implemented and long-term survival was achieved have been reported.10,11 A Pembroke Welsh corgi with PIHS treated with radiation therapy and prednisolone survived for 164 days.10 A golden retriever with PIHS treated with surgical resection and chemotherapy with CCNU (40–80 mg/m2 every 3 wk) survived for 278 days.11 This suggests that there are cases of CNS HS that may benefit from local treatment. Additionally, the high distant metastasis rate of HS suggests the need for systemic chemotherapy, especially for CCNU, with single-agent efficacy also reported.5 Furthermore, multiple studies suggest that the combination of local treatment and systemic chemotherapy with CCNU can effectively treat localized HS.2,3 In light of these reports, our results suggest that the combination of aggressive local therapy and adjuvant systemic chemotherapy for localized CNS HS such as PIHS (as in our case) could be beneficial (with respect to prolonged survival). However, the impact of chemotherapy on the prognosis of our case is debatable. Currently, there are no reported trials comparing surgery alone and combined chemotherapy for PIHS. Thus, careful decision must be made regarding the pros and cons of chemotherapy. Local treatment options include surgical resection and radiation therapy. A study reported that periarticular HS had an overall survival of 398 days in the surgical group and 240 days in the radiation group, with no statistically significant difference.16 Therefore, we believe that aggressive radiation therapy should be considered an option for localized CNS HS that is difficult to resect. However, because a histopathological diagnosis cannot be performed in these cases, a comprehensive judgment must be made based on the breed, presence of characteristic imaging findings, and cerebrospinal fluid findings6–8,17; CCNU must be used cautiously.
Doses of CCNU for HS in dogs have been reported to mainly lie in the 60–90 mg/m2 range,5 although a few cases of efficacy have been reported even at doses as low as 40 mg/m2.11,18 The major known adverse reactions to CCNU treatment in dogs include neutropenia and thrombocytopenia associated with myelosuppression and delayed hepatotoxicity. In a study examining risk factors for CCNU-induced neutropenia in 115 cancer-bearing dogs,19 various grades of neutropenia were observed in 75 (65%) dogs with a median dose of 63.5 mg/m2 (range: 27.7–84.9 mg/m2). In addition, a diagnosis of HS, use of CCNU as first-line therapy, a dose ≥70 mg/m2, absence of comorbidities, and a history of anthracycline use were significantly associated with an increased risk of neutropenia development, including high-grade events. Meanwhile, the mortality rate from this adverse event is reportedly 1.7%. Hepatic injury (particularly elevated alanine transaminase levels) appears commonly with CCNU, as well as the development of delayed chronic hepatotoxicity associated with cumulative doses, suggesting that it can be often irreversible and fatal.20 In our case, CCNU treatment was administered at a relatively low dose of 45 mg/m2 every 4–5 wk, and the total dosing period was 278 days with a cumulative dose of 400 mg/m2. MRI scans performed on days 138 and 341 revealed no obvious recurrent intracranial lesions. From this single case report, it is impossible to know whether complete resection of the tumor or the addition of adjuvant chemotherapy with low-dose CCNU was responsible for preventing local recurrence. Moreover, grade 2–3 asymptomatic neutropenia and the elevation of liver enzyme levels were observed. However, both were reversible and long-term treatment was feasible. These results suggest that the low-dose CCNU may allow for long-term administration with minimal adverse events and prolonged survival while reducing tumor recurrence. The final cause of death could not be determined because no necropsy was performed. However, the circumstances immediately before death suggested that it was unlikely to be related to tumor recurrence. Severe thrombocytopenia, anemia, jaundice, and renal insufficiency were observed, which could have caused disseminated intravascular coagulation, possibly complicated by CCNU-accumulated myelosuppression or sepsis. It was assumed that the patient eventually developed multiorgan failure. From these results it should be noted that CCNU, even at low doses, can cause potentially fatal adverse events. Further studies will be needed to clarify the efficacy and adverse events, including appropriate dosing periods and cumulative dose limits of low-dose CCNU.
Conclusion
Solitary CNS HS with no evidence of metastasis at diagnosis may benefit from aggressive local therapy, and adjuvant CCNU chemotherapy may further prolong survival. In addition, even low-dose CCNU may be expected to suppress tumor recurrence. Large-scale comparative studies with more CNS HS cases should be conducted to further investigate our findings.
K.H., Y.N., J.C., K.U., I.M., and M.N. assisted with the diagnosis of this case and participated in clinical case management. K.H. and Y.N. participated in the review and editing of the manuscript. All authors contributed significantly to the article and approved the submitted version. Ethical review and approval were not required for the animal study as it is not required for retrospective case reports. Written informed consent was obtained from the patient’s owner for the publication of this report. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. The authors declare that the study was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Contrast-enhanced T1-weighted sagittal and transverse MR images at diagnosis (A and B), day 138 (C and D), and day 359 (E and F). A and B show a solitary extraparenchymal occupying lesion with a distinct contrast effect in the right frontal lobe area (white arrow). A mild contrast enhancement effect was observed at the margins of the resected area of the tumor (white circle: C and E). This finding suggested the possibility of a micro-recurrent lesion of the tumor or scar tissue associated with resection.
Micrograph of the brain tumor (×20) (A). The tumor cells were mostly irregular in size, the cytoplasm was eosinophilic, and cell borders were indistinct. The nuclei were round and irregularly sized, with one clear nucleolus, and mitotic figures were rare. Multinucleated giant cells were also scattered. In immunohistochemical staining (×10), the tumor was positive for HLA-DR (B), Iba-1 (C), and CD204 (D) and negative for CD3 (E) and CD20 (F).
Contributor Notes
