Outcome of Localized Bile Duct Carcinoma in Six Dogs Treated with Liver Lobectomy
ABSTRACT
The prognosis for bile duct carcinoma in dogs is generally believed to be poor. However, only a few studies have evaluated the postoperative outcomes in such cases. The objective of this case series was to describe the postoperative outcomes of localized intrahepatic bile duct carcinoma in dogs. The electronic medical records of 16 dogs with bile duct carcinoma were reviewed, and 6 dogs were included in the study. All cases were diagnosed as bile duct carcinoma using postoperative pathology, and five of them had already been diagnosed using preoperative core biopsy. The tumors in all of the dogs were confirmed as completely resected on histopathological examination. Two dogs received toceranib following the surgery. The median follow-up time was 693 days (range, 420–1386 days), with a median survival time of 894 days (range, 420–1386 days). Local recurrence or distant metastases were detected in two of the six dogs (33%) on 354 and 398 days following surgery, respectively. The median progression-free survival was 492 days (range, 354–1386 days). In conclusion, dogs with localized intrahepatic bile duct carcinoma had a good prognosis following complete surgical resection.
Introduction
Bile duct carcinoma, also known as cholangiocarcinoma, is the second most common malignant hepatic tumor in dogs.1,2 Canine bile duct carcinoma has an aggressive biological behavior, with a high frequency of metastasis (88%, n = 24).3 Metastatic sites include the lungs, lymph nodes, heart, spleen, adrenal glands, pancreas, kidneys, and spinal cord.3,4
Based on location, bile duct carcinomas are classified as intrahepatic, extrahepatic bile duct, and gall bladder. Based on morphology, bile duct carcinomas are classified as massive, nodular, or diffuse; the massive and nodular are most common (massive: 37–46%, nodular: 54%).5 Some massive or nodular intrahepatic bile duct carcinomas are operable via hepatic lobectomy. However, the literature contains a dearth of reports on the postsurgical outcomes of dogs with localized bile duct carcinoma. This is likely owing to the high proportion of dogs with metastatic carcinoma at initial presentation. In humans, surgical resection is the mainstay of treatment for bile duct carcinoma, and a complete resection prolongs survival.6–8 Dogs with localized intrahepatic bile duct carcinoma, which is a resectable massive or nodular type tumor without metastasis, may also have a favorable prognosis if they are treated with complete resection.
Only one case report has described hepatic lobectomy in a dog with bile duct carcinoma that died 6 mo following surgery.9 However, the report did not include details of the tumor such as size, morphological type, metastatic status, or surgical margin.
The objective of this study was to investigate the clinical outcomes of dogs treated with curative-intent surgery for localized intrahepatic bile duct carcinoma.
Materials and Methods
Cases
This was a retrospective study. Data of dogs diagnosed with bile duct carcinoma between March 2011 and March 2020 were obtained from the electronic medical records system of Gifu University Animal Medical Center. Dogs with diffuse-type tumors or metastatic lesions at the time of diagnosis or dogs that had not undergone surgery were excluded.
Data Collection
The following information was retrieved from the medical records: signalment (sex, breed, age, and weight), physical and clinicopathological findings, diagnostic imaging findings, operative procedure, histopathology reports, postoperative chemotherapy, date and cause of death, and follow-up findings. Whole-body computed tomography (CT) was performed during the first visit for all dogs to evaluate the tumor morphological type and possible metastasis. Dogs with a tumor in only one or two liver lobes without evidence of distant metastasis met the inclusion criteria. Data on outcomes were obtained from the medical records or contact with the referring veterinarians via faxed surveys.
Statistical Analysis
Because of the small sample size, quantitative descriptions are presented as medians and ranges. The study completion date was set as the last recorded follow-up date for each dog. Kaplan-Meier survival curves were used to estimate the median survival times and progression-free survival. Overall survival time was defined as the number of days between the date of surgery and the date of death from any cause. The survival times of dogs that were alive at the completion of the study were censored at the last follow-up date. Progression-free survival was defined as the number of days between the date of surgery and the documented date of tumor progression, death, or censored date. Prognostic factors were not analyzed owing to the small number of cases. The study completion date was the last day of follow-up for the last dog. All analyses were performed with EZR software,a which is a graphical user interface for R and a modified version of R commander.10
Results
Cases
Sixteen dogs with bile duct carcinoma were identified from the electronic medical records. Six dogs had diffuse bile duct carcinoma, and four had distant metastases. Overall, six dogs met the study inclusion criteria. Of the six dogs, four had massive intrahepatic carcinomas, and two had nodular disease (Table 1). All dogs had undergone hepatic lobectomy.
The median age of the dogs was 11 yr (range, 6–13 yr), and their median body weight was 10.9 kg (range, 3.7–23.0 kg). At initial examination, two dogs (33.3%) had clinical signs, including abdominal distension (2/6) and abdominal tenderness (1/6). Histological examination was performed preoperatively. Five dogs had bile duct carcinoma, and one had suspected hepatocellular carcinoma. On postoperative histopathological examination, it was confirmed that all dogs had bile duct carcinoma. Whole-body CT was performed at first presentation for all dogs to evaluate the tumor morphological type and possible metastasis. Although four dogs had single lesions, two had had multiple lesions. The tumor sites included the left lateral lobe (single lesion in three dogs), left medial lobe (single lesion in one dog), left lateral lobe (two lesions in one dog), and both the left lateral and left medial lobes (single lesion in one dog). The average longest tumor diameter measured with CT for all dogs was 5.1 cm (range, 3.6 – 10.7 cm).
Treatment
All six dogs underwent hepatic lobectomy (Table 2). The surgeries were conducted via open ventral midline abdominal approach, and caudal sternotomy was also performed in three dogs. The surgical resections performed were as follows: partial lobectomy of the left lateral lobe (two dogs), complete lobectomy of the left lateral lobe (two dogs), partial lobectomy of the left medial lobe (one dog), and partial lobectomy of the left lateral and medial lobe (one dog). All tumors were confirmed by histopathological analysis as completely resected.
Two dogs received toceranibb following surgery. In one dog (Case 2), toceranib (2.0 mg/kg, every other day) was administered as an adjuvant therapy 4 mo after surgery, even though the dog had no evidence of metastasis or local recurrence at that time. The dog received toceranib for 680 days, and no tumor recurrence was detected during the follow-up period. In another dog (Case 4), presumptive intrahepatic local recurrence was observed with CT imaging 354 days after the surgery, and administration of toceranib (2.5 mg/kg, every other day) was initiated. Although progression of the disease in the dog was observed at 102 days following initiation of toceranib, the treatment was continued; in total, the dog was treated with toceranib for 635 days.
Outcomes
Five of six dogs were deceased at the end of this study. The median follow-up period was 693 days (range, 420–1386 days). Two dogs died of tumor-related causes, and one died of cardiogenic pulmonary edema. The cause of death in two dogs (Cases 2 and 5) was unclear. Case 2’s death was presumably associated with the dog’s advanced age (16 yr). Case 5 died after developing seizures from an unknown cause.
The overall median survival time (MST) was 894 days (range, 420–1386 days) (Figure 1A). Distant metastases or local recurrence was detected in two of the six dogs (33%). One dog (Case 3) who presented with pleural effusion at 398 days following surgery had clusters of pleomorphic cells within the effusion, suggestive of pleural seeding; the dog died at 446 days owing to the progression of bile duct carcinoma. Another dog (Case 4) presumptively developed local recurrence of the disease at 354 days following surgery; however, the dog’s owner declined a biopsy. The dog had been treated with toceranib after the detection of recurrent disease and died after 1003 days (649 days after detection of local recurrence). The median progression-free survival was 492 days (range, 354–1386 days) (Figure 1B).
Citation: Journal of the American Animal Hospital Association 58, 4; 10.5326/JAAHA-MS-7199
Discussion
Our results suggest that surgery provides a favorable prognosis for localized intrahepatic bile duct carcinoma. A previous case report described the outcomes of partial hepatectomy (removal of the quadrate and right medial lobe) in a dog with bile duct carcinoma.9 Six months after the surgery, the dog developed an extensive abdominal tumor and extensive pulmonary miliary lesions and was euthanized. It was unclear whether the tumor resulted from metastases or a local recurrence. In contrast, in this study, the MST and progression-free survival were 894 and 492 days, respectively. Complete resection may improve the MST if it can be diagnosed using preoperative CT and biopsy as localized intrahepatic bile duct carcinoma. Postoperative metastasis or local recurrence was observed in two of the six dogs who underwent complete resection in this study (both of whom had a prolonged survival), suggesting that localized intrahepatic bile duct carcinomas can have a good prognosis after complete resection. Dogs with a massive hepatocellular carcinoma, which is the most commonly diagnosed type of hepatic tumor, generally have a good prognosis with a low rate of local recurrence and distant metastasis following complete resection.1,11,12 However, bile duct carcinoma may recur or metastasize even with complete resection, suggesting the importance of frequent postoperative monitoring. In this study, metastasis was detected in 4 of the 16 dogs (25%) at diagnosis, which is lower than the previously reported metastatic rate of 88% based on necropsy.3 One possible reason is that these dogs were likely euthanized before extensive work-up, precluding a definitive tissue diagnosis.
In humans, surgical resection of intrahepatic bile duct carcinomas is the only curative therapeutic option.7,8 The MST and 5 yr survival rate of potentially curative resection of intrahepatic carcinomas are approximately 30 mo and 32%, respectively; in contrast, the 5 yr survival rate of human patients with unresectable disease is approximately 5–10%.13 Surgical margin and metastatic status in the lymph node are strong prognostic factors after surgical resection.14–17 In addition, perineural invasion and portal vein invasion have also been reported as negative prognostic factors.17,18 The present study examined too few animals to identify significant prognostic factors in dogs. Additional studies with a larger population would be required to identify prognostic factors after hepatectomy in dogs.
There are no published studies describing the efficacy of chemotherapy for canine bile duct carcinoma. However, human bile duct carcinomas have been found to express vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and stem cell factor receptor.19–22 Bevacizumab, a vascular endothelial growth factor receptor inhibitor, has been shown to have anti-tumor potential and other features such as tolerability and safety for advanced human bile duct carcinoma.23 In this study, although two dogs were treated with toceranib, no response to toceranib was observed in the measurable lesion (Case 4). Further research is needed to assess the expression of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, which are toceranib targets, in canine bile duct carcinomas.
The limitations of this study are those inherent to a retrospective study with a small sample size. Particularly, selection bias that may have influenced the outcome and survival time was likely present, because only surgically resectable, single tumors were included.
Conclusion
This study suggests that favorable outcomes following complete surgical resection in dogs with localized intrahepatic bile duct carcinomas are possible. This study supports the use of surgery for dogs with nonmetastatic localized intrahepatic bile duct carcinomas. Further studies with larger sample sizes are needed to determine prognostic factors and assess the efficacy of specific adjuvant chemotherapy regimens.
(A) Kaplan-Meier curve of the overall survival time of six dogs with bile duct carcinoma treated surgically. The median survival time is 894 days (range, 420–1386 days). (B) Kaplan-Meier curve of the progression-free survival time of six dogs with bile duct carcinoma treated surgically. The median progression-free survival time is 492 days (range, 420–1386 days).
Contributor Notes
