Authors: Masanao ICHIMATA, Atsushi TOSHIMA, Fukiko MATSUYAMA, Eri FUKAZAWA, Kei HARADA, Ryuzo KATAYAMA, Yumiko KAGAWA, Tetsushi YAMAGAMI, Tetsuya KOBAYASHI
Categories: Internal Medicine, dog, doxorubicin, hemangiosarcoma, retroperitoneum, surgery
Source: The Journal of Veterinary Medical Science
Doi: 10.1292/jvms.22-0533
Retroperitoneal hemangiosarcoma (RPHSA) is a rare tumor in dogs with a poorly understood prognosis after surgery. The objectives of this study were to investigate the clinical features and prognosis of canine RPHSA that had undergone surgical resection. In this single-center, retrospective cohort study, we reviewed the medical records of dogs that had undergone surgical resection for retroperitoneal tumors and received a histopathologic diagnosis of HSA between 2005 and 2021. The median progression-free survival (PFS) and overall survival (OS) were 77.5 days and 168 days, respectively. In the present study, canine RPHSA had an aggressive biological behavior similar to visceral HSA. Further studies in larger canine populations are needed to evaluate the efficacy of adjuvant chemotherapy.
Keywords: dog, doxorubicin, hemangiosarcoma, retroperitoneum, surgery
Hemangiosarcoma (HSA) in dogs is a malignant tumor derived from vascular endothelial cells or vascular endothelial progenitor cells of the bone marrow [9]. Hemangiosarcoma is more common in dogs than other species and can occur primarily in the spleen [14, 15], skin, subcutis [4], right auricle, and right atrium [17]. Rupture of splenic or hepatic HSA can result in fatal hypovolemic shock due to intraperitoneal hemorrhage [2], while HSA in the right auricle or right atrium can cause cardiac tamponade, leading to fatal restrictive shock [17]. Except for HSA localized to the skin [16], canine HSA shows high recurrence and distant metastatic rates, and the biological behavior of these tumors is generally poor [11].
In people, primary angiosarcoma in the retroperitoneal space is rare, accounting for 3% of the total case numbers [13]. Although the frequency of retroperitoneal hemangiosarcoma (RPHSA) in dogs is unknown, only one dog with RPHSA (1.5%) was reported in a study of 67 dogs that underwent chemotherapy for stage III HSA [1]. In a study of 14 dogs diagnosed with retroperitoneal sarcoma by surgical resection or autopsy, 9 had RPHSA, and the median survival time (MST) of all 12 dogs that received surgical resection was 37.5 days [10]. Recently, the median overall survival (OS) of 12 dogs with HSAs arising from the pelvic cavity was reported to be 165 days [3]. In 2 case reports, dogs with pelvic RPHSA treated with surgery alone were either euthanized or died of multiple metastases 10 weeks after surgical resection [7, 18]. In contrast, the MST of 3 dogs with RPHSA treated with palliative radiation therapy and doxorubicin (DOX) was 408 days [6]. Previous reports describing the therapeutic outcomes of RPHSA have yielded variable results, creating uncertainty regarding the biological behavior and prognosis of these tumors. Doxorubicin is an anticancer drug with a strong antitumor effect as a single agent in dogs and has been used for various malignant tumors [5]. DOX is the standard chemotherapeutic adjuvant agent used in dogs with HSA after splenectomy [8]. Survival in dogs with viscera [11] and cardiac [17] HSA was significantly longer in those treated with surgery plus adjuvant DOX compared with those treated with surgery alone. However, there have been no reports on the efficacy of adjuvant DOX after surgery in dogs with RPHSA.
The primary objectives of this study were to investigate the clinical features and prognosis of canine RPHSA that underwent surgery with or without adjuvant DOX and to identify its biological behavior. The secondary objective was to investigate the effectiveness of adjuvant DOX in the treatment of dogs with RPHSA.
This was a single-center retrospective study of dogs with a histopathologic diagnosis of HSA that had undergone surgery for retroperitoneal tumors at our institution or by referring veterinarians between April 1, 2005, and March 31, 2021. Based on imaging or intraoperative findings, dogs were excluded from the study if the retroperitoneal tumor originated from the rectum or organs within the retroperitoneum, including the kidneys, adrenal glands, ovaries, ureters, bladder, prostate, uterus and urethra. Data on signalment, history, medication history, clinical signs, blood tests, thoracic and abdominal radiography, abdominal ultrasonography, computed tomography (CT) histopathology, surgical records, details of adjuvant DOX, and prognosis were obtained from medical records, referring veterinarians, and owners. CT was performed on both the thorax and abdomen. One veterinarian with years of experience in interpreting CT scans reviewed all CT data (A.T). Perioperative death was defined as death within 14 days after surgery. Complete resection based on histopathology was defined when no tumor cells were observed in the surgical margins. Adjuvant DOX was defined as therapy initiated within 4 weeks after surgery in dogs with RPHSA. The RPHSA clinical stage was determined at the initial examination and was based on the modified World Health Organization (WHO) classification [12].
Progressive disease (PD) was defined as a local recurrence or metastasis of RPHSA confirmed on cytology or histopathology or as strongly suggested by image findings, such as in the case of pulmonary metastasis. OS was defined as the period from the date of surgery to death from any cause. Progression-free survival (PFS) was defined as the period from the date of surgery to the time of confirmed PD or death from any cause. Dogs that were lost to follow-up or remained alive were censored on the date of last contact, and those that died with an unknown date of death were also censored on the date of last contact. Age, body weight, packed cell volume (PCV), platelet count, coagulation test, and tumor size (the longest diameter of the RPHSA tumor) were recorded as the median and range. Age, body weight, tumor size, completeness of tumor resection, presence of hemoperitoneum, and use of adjuvant DOX were evaluated as factors associated with PFS and OS. To evaluate survival, the median was used as the cut-off value for age, body weight, and tumor size. The relationships between the use of adjuvant DOX and other factors were analyzed using Fisher’s exact test for categorical variables and the Mann-Whitney U test for continuous variables. Survival was analyzed using the log-rank test, and survival curves were depicted using the Kaplan-Meier curve method. P values <0.05 were considered significant. EZR software (Saitama Medical Center, Jichi Medical University, Saitama, Japan) was used for the statistical analysis.
Twelve client-owned dogs met the inclusion criteria. Referring veterinarians performed surgical resections of the tumors in 2 of the 12 dogs. Of the 12 dogs, 6 each were neutered males and females. The median age was 12 years (range: 7–14 years), and the dogs were of 8 three Jack Russell terriers, three Miniature dachshunds, and one each of a Bernese mountain dog, American cocker spaniel, Golden retriever, Labrador retriever, Beagle, and Pembroke Welsh Corgi. The median body weight was 8.25 kg (range: 5.9–29.0 kg). The RPHSA was found by the referring veterinarians with clinical symptoms detected in 8 dogs (66.7%). In 4 dogs, RPHSAs were incidentally found during a health check-up. The clinical symptoms on the day of the first visit to our institution were anorexia (n=4), lethargy (n=3), straining to defecate (n=2), and lameness (n=2). Other symptoms observed in the dogs were polydipsia, dysuria, depression, abdominal distension, emaciation, hematuria, collapse, vomiting, and diarrhea (most dogs had one or multiple symptoms). One dog with surgical resection by a referring veterinarian had a history of hemoperitoneum, and two dogs had hemoperitoneum on the day of the first visit to our institution.
Complete blood counts and serum biochemical testing were performed on all dogs during the initial examination. Table 1 shows the PCV, platelet count, and coagulation test results of the ten dogs that exhibited macroscopic RPHSA lesions on our initial examination. Nine dogs had PCV, platelet counts, prothrombin time, partial thromboplastin time, fibrinogen, and fibrin degradation products evaluated. One dog had PCV and platelet counts evaluated.
Thoracic and abdominal radiography and abdominal ultrasonography were performed during the initial examination of all dogs. Pulmonary metastases were not found in any of the dogs. Retroperitoneal soft tissue masses were confirmed on abdominal radiographs and ultrasound imaging in 10 dogs, except for 2 dogs with surgical resections at the referring veterinarians. One dog had echocardiography performed to diagnose a heart murmur, but no neoplastic lesions associated with myocardial structures were found. Contrast-enhanced CT of the thorax and abdomen was performed on 9 dogs as a part of the initial examination. The longest diameter and the location of the RPHSA tumors were evaluated on CT (n=9) or ultrasonography (n=1). The location but not the size of the tumors was confirmed in 2 dogs with surgical resections by the referring veterinarians. The median diameter was 58.8 mm (range: 17.9–89.9 mm). In all dogs, tumors were heterogeneous in texture on precontrast images. Dystrophic calcification was identified in two RPHSAs. Neither regional lymph node enlargement nor invasion into surrounding tissues was observed. Four dogs had peritoneal effusions. The RPHSA lesions were located near the right kidney (n=4), left kidney (n=2), and urinary bladder or in the pelvic cavity (n=6). In 3 of the 4 dogs with tumors near the right kidney, tumors were located caudal to the right kidney. In the remaining dog, the tumor was resected by the referring veterinarian, and the location of the tumor in relation to the right kidney was unknown. In 2 dogs with tumors near the left kidney, both were located caudal to the kidney. Comorbid masses observed in images included a hepatic caudate lobe mass in 1 dog and a splenic mass in another dog. Comorbidities included ischemic changes in the distal jejunum, splenic infarction, and periosteal reaction and bone destruction in the proximal metaphysis of the left humerus (one dog each). The lesion in the left humerus was diagnosed as purulent granulomatous inflammation by histopathology. On pre-contrast images, the masses showed heterogeneous contrast in all dogs. On post-contrast images, the masses in 8 dogs showed heterogeneous contrast enhancement with no visible enhancement in 1 dog. In the contrast-enhanced masses, localized and marked contrast enhancements were seen in 2 masses, and ring enhancements were seen in 1 mass. No findings to suggest metastasis of RPHSA were identified in all 9 dogs that had undergone CT.
One of the 10 dogs that had undergone surgery for RPHSA at our institution required emergency surgery for hemoperitoneum. The median hospital stay was 4 days (range: 2–16 days). Two dogs received perioperative transfusions, 1 dog with fresh frozen plasma (FFP) and the other with FFP and whole blood. Perioperative complications occurred in 3 dogs, including 1 dog, each with postoperative hypertension and postoperative fever, that had improved with symptomatic treatment. One dog had left hydronephrosis caused by left distal ureteral stenosis; the left ureter was relocated on day 5. There were no perioperative deaths. One of the 2 dogs that had surgery by the referring veterinarian had RPHSA near the right kidney, and both the right kidney and part of the ureter was removed. In the remaining dog, the RPHSA was resected from the pelvic cavity. Adjuvant DOX was administered after surgery in 6 dogs, 3 dogs at our institution and the others by the referring veterinarians. At our institution, DOX was administered intravenously for 30–60 min every 3 weeks at 20–25 mg/m^2^ for dogs weighing less than 15 kg and 30 mg/m^2^ for dogs weighing 15 kg or more. The DOX doses for the three dogs treated at the referring veterinarian were 1 mg/kg, 20 mg/m^2^, and 25 mg/m^2^ every 3 weeks (Table 2). The median time from surgery to the start of DOX therapy was 16.5 days (range: 14–24 days). The median number of times that DOX was administered was 6.5 (range: 1–7). One of the 6 dogs was switched to mitoxantrone after the cumulative DOX dose reached 175 mg/m^2^. One of the 6 dogs that did not receive adjuvant DOX underwent postoperative metronomic chemotherapy with low-dose cyclophosphamide; this dog developed multiple peritoneal masses on day 45 and died on day 60. The factors used in the survival analysis between the dogs receiving or not receiving adjuvant DOX were compared (Table 3). No significant factors were found between these groups. Two board certified veterinary pathologists (YK and TY) evaluated histopathology from each tumor and confirmed the diagnosis of HSA [12]. Complete resection was achieved in 6 of the 12 dogs (50.0%). Of the 6 dogs diagnosed with incomplete resection, 5 dogs had tumor invasion into the adipose tissue (n=3), omentum (n=1), or connective tissue around the RPHSA (n=1). In the remaining dog, tumor cells were identified at the surgical margins. In addition to the surgical resection of retroperitoneal tumors, 1 dog each underwent partial jejunectomy, hepatic lobectomy to resect a caudate lobe mass, splenectomy to resect a splenic mass, and a liver biopsy. The jejunal lesion was diagnosed as intestinal necrosis due to a thrombus in the jejunal artery, the hepatic caudate lobe mass was diagnosed as hepatocellular adenoma, the splenic mass was diagnosed as hematoma, and the liver biopsy was diagnosed as copper-associated chronic hepatitis.
All dogs were staged according to the modified World Health Organization clinical staging system for canine HSAs. Four (33.3%) and 8 dogs (66.7%) were classified as stages 1 and 2, respectively. The median PFS and OS were 77.5 days (95% CI: 28–160 days) and 168 days (95% CI: 60–278 days), respectively (Fig. 1). None of the factors evaluated were significantly associated with PFS or OS in univariate analyses (Table 4). Median OS in the surgery only group and the surgery plus adjuvant DOX group was 129.5 and 241.5 days, respectively (Fig. 2, P=0.18). None of the factors was associated with survival in the surgery only group or the surgery plus adjuvant DOX group. A follow-up schedule was determined by the attending or referring veterinarians and was not standardized. At the end of the study, 10 dogs had died, and 2 were alive. Local recurrence or metastasis of RPHSA was confirmed in 7 of the 10 dogs that had died. Local recurrences or metastases were near the urinary bladder (n=1), and in the peritoneum (n=4), spleen (n=3), liver (n=2), and left adrenal gland (n=1) (some dogs had multiple metastases; see Table 2). Of the remaining 3 dogs, 1 dog developed disseminated intravascular coagulation and died on day 66, one died of respiratory failure under the care of the referring veterinarian on day 97, and 1 dog developed paresis of both hind limbs on day 229 and died on day 341. Of the 2 dogs alive at the end of study, 1 dog had no metastasis on day 220. The other dog had multiple peritoneal nodules on day 46, but follow-up assessments at the end of this study confirmed that the dog was alive on day 118. Of the 7 dogs with local recurrence or metastasis, splenectomy was performed on day 111 for splenic rupture in 1 dog, and the splenic mass was diagnosed as HSA on histopathology. Of the remaining six dogs, local recurrence or metastasis of RPHSA was diagnosed on imaging alone. No necropsies were performed on any of the dogs.
The primary objectives of this study were to investigate the clinical features and prognoses of canine RPHSA in dogs that had undergone surgical resection with or without adjuvant DOX. We also sought to understand the biological behavior of this rare tumor. These findings suggest that canine RPHSA has aggressive biological behavior. The median OS for dogs receiving adjuvant DOX after surgical resection of RPHSA was 241.5 days in our study, which was longer than 129.5 days for surgery alone but not statistically significant. Given the limited sample size, the lack of statistical significance in outcomes for those patients treated with or without DOX may have been caused by a type II error due to the small number of dogs in each group. The literature suggests the DOX, which has evaluated in both the adjuvant and neoadjuvant settings, is the most active agent against canine HSAs [12]. To date, no studies have evaluated the efficacy of postoperative adjuvant DOX for canine RPHSA, though Hillers et al. reported an MST of 408 days (range: 208–508 days) with a combination of palliative radiation therapy and DOX in three dogs with RPHSA, suggesting that adjuvant DOX might promote long-term survival in RPHSA [6].
The limitations of this study include the general limitations of retrospective studies, as well as the possible influence of recall bias by the owners and selection bias by the veterinarians. This study lacked information and analysis regarding the histopathologic factors, such as the degree of cell differentiation, mitotic index, pleomorphism, and necrosis, which could be related to prognosis. Our institution recommends postoperative adjuvant DOX for all dogs with RPHSA, but the final decision depends on the owners. In addition, the statistical power of the study was insufficient because of the small sample size, which might have precluded the identification of true prognostic factors. A follow-up schedule was determined by the attending or the referring veterinarians and was not standardized, which could have affected PFS. Necropsy was not performed on any dogs, and some dogs were determined to have progressive disease based on imaging alone without cytologic or histologic confirmation.
In conclusion, this study showed the clinical features and prognosis in 12 dogs that had undergone surgical resections with or without adjuvant DOX. Canine RPHSAs showed aggressive biological behavior similar to that of splenic HSAs. Due to various limitations, such as the small sample size, none of the factors evaluated in this study, including adjuvant DOX, were associated with survival. Further studies with larger sample sizes are needed to identify the prognostic factors of canine RPHSA and accurately evaluate the efficacy of adjuvant DOX.
None of the authors of this paper has any financial or personal relationships that could inappropriately influence or bias the content of the paper.
We thank our Japan Small Animal Cancer Center staff for help with the clinical data and care of patients.