Liver neoplasia in dogs most commonly represents metastatic disease from other tumour sites (eg pancreas and gastrointestinal tract), with primary liver tumours being less common, representing only 1.5 percent of all canine tumours (Patnaik et al., 1980). In dogs, most primary liver tumours are malignant and categorised into four main groups according to their origin. These are hepatocellular, bile duct, neuroendocrine (carcinoid) and mesenchymal. They are additionally described according to morphology: massive (solitary mass occupying one liver lobe), nodular (multiple masses/nodules affecting multiple liver lobes) and diffuse (multifocal nodules in all liver lobes or diffuse effacement of the liver).
This second article in this series on canine gastrointestinal tumours will discuss the clinical signs, clinicopathological abnormalities and diagnostic approach common to most canine liver tumours. It will then discuss the specific biological behaviour, treatment and prognosis for hepatocellular, biliary, neuroendocrine and mesenchymal liver tumours.
History and clinical signs
Most dogs with liver tumours will present with non-specific signs such as hyporexia, anorexia, vomiting, weight loss and lethargy, usually due to the mass effect of a large hepatic tumour. Systemic effects, such as icterus, signs of hepatic encephalopathy and paraneoplastic hypoglycaemia, can be seen in some cases. A palpable hepatic mass is present in up to 75 percent of cats and dogs with liver tumours. Haemoabdomen secondary to mass rupture has also been reported (Aronsohn et al., 2009).
Most dogs with liver tumours will present with non-specific signs such as hyporexia, anorexia, vomiting, weight loss and lethargy
Diagnosis and investigations
Haematological abnormalities, if present, are usually non-specific, although thrombocytosis is reported in 50 percent of dogs with hepatocellular carcinoma (HCC) (Liptak et al., 2004). Prolonged coagulation times may be observed in some dogs. Biochemistry frequently reveals elevations in liver enzymes: in primary liver tumours, ALP and ALT are most commonly increased, whereas AST and bilirubin are mostly elevated with tumours metastatic to the liver (Strombeck, 1978). Hypoglycaemia can also occur, most commonly in hepatic adenomas, and can be due to tumour production of IGF-2, increased glucose metabolism or production of hepatic glucose inhibitor (Bailey, 2020).
Diagnostic imaging is important for tumour localisation, assessment of morphology, staging and surgical planning, and in some cases may allow prediction of histological diagnosis
Diagnostic imaging
Diagnostic imaging is important for tumour localisation, assessment of morphology, staging and surgical planning, and in some cases may allow prediction of histological diagnosis.
Abdominal ultrasound (US) allows confirmation of the presence of a hepatic mass and aids morphological classification. Surgical planning can be performed based on US in smaller well-demarcated tumours but may not be as reliable in larger tumours, where it can be more challenging to assess mass interaction with adjacent structures such as the caudal vena cava. Triphasic CT (Figure 1) is often superior to US at assessing liver tumours as it allows detection of smaller lesions and can more accurately assess the relationship between large masses and adjacent soft tissue structures. In some studies, imaging features have also been used to differentiate benign from malignant tumours and even specific histological types (Griebie et al., 2017; Kutara et al., 2014). Visualisation of the tumour arterial supply is also essential for planning interventional treatments such as chemoembolisation. Thoracic imaging via either three-view radiographs or CT should be performed to screen for metastasis and complete staging in cases of malignant hepatic tumours.
Sampling
In most cases, diagnostic imaging will only provide information about the tumour location, size and morphology, as well as the presence or absence of metastasis. Sampling (US-guided) is therefore required to provide a definitive diagnosis and aid treatment planning and prognostication. Fine needle aspirate cytology can be a good initial test as this is relatively non-invasive but will often struggle to differentiate benign from well-differentiated malignant lesions. Therefore, a definitive diagnosis is not always achieved. Minimally invasive biopsies (eg Tru-Cut) for histopathology, however, will usually achieve a definitive diagnosis in the majority of cases. In some cases, such as very large solitary masses or cases with evidence of active haemorrhage, surgical excision of the mass could be performed for both diagnostic and therapeutic purposes without a definitive diagnosis preoperatively.
Hepatocellular tumours
HCC is the most common malignant primary liver tumour in dogs. No clear underlying aetiology has been identified, although 34 percent of Scottish Terriers with progressive vacuolar hepatopathy develop HCC, indicating a possible link (Cortright et al., 2014). Up to 80 percent are morphologically massive, up to 25 percent are nodular and up to 20 percent are diffuse (Cullen and Popp, 2002; Patnaik et al., 1980). Most massive HCCs occur in the left liver lobes. Metastatic rate depends on HCC morphology, with a 0 to 35 percent risk for massive HCC and a 93 to 100 percent risk for nodular or diffuse forms (Liptak, 2020).
Achieving a histologically complete excision is significantly associated with an improved prognosis
Liver lobectomy (Figure 2) is the treatment of choice for massive HCCs. Achieving a histologically complete excision is significantly associated with an improved prognosis, with reported recurrence rates of 12 percent versus 58 percent for completely excised versus incompletely excised HCCs, respectively (Matsuyama et al., 2017). Median survival times over five years are reported with complete excision. Negative prognostic factors include lack of surgical treatment, right-sided location, increased ALT/AST activity and incomplete histological excision (Liptak et al., 2004; Matsuyama et al., 2017). Nodular and diffuse forms of HCCs carry a poor prognosis as surgical excision is often not possible.
Non-surgical treatment options, usually reserved for inoperable HCCs, include bland embolisation or chemoembolisation techniques that occlude the tumour arterial supply (with or without the addition of intra-arterial chemotherapy), resulting in tumour ischaemia and cell death (Weisse et al., 2002). Microwave or radiofrequency ablation is possible for smaller tumours, and radiotherapy has also been described (Mori et al., 2015; Yang et al., 2017). Hepatocellular carcinomas are considered chemoresistant, but some responses to gemcitabine and sorafenib have been reported (Elpiner et al., 2011; Marconato et al., 2020).
Bile duct tumours
The two main bile duct tumours are bile duct adenomas (biliary cystadenoma) and bile duct carcinomas (cholangiocarcinoma), with the latter representing the second most common malignant liver tumour in dogs. Bile duct carcinomas are relatively equally distributed between massive, nodular and diffuse morphologies. They exhibit aggressive biological behaviour with metastasis, usually to the regional lymph nodes and lungs, reported in up to 90 percent of dogs (Patnaik et al., 1981a).
Surgical excision of a bile duct adenoma should prove curative. Liver lobectomy is only warranted for the massive form of bile duct carcinoma after thorough staging
Surgical excision of a bile duct adenoma should prove curative. Liver lobectomy is only warranted for the massive form of bile duct carcinoma after thorough staging; however, even with surgery, prognosis remains poor in companion animals, with survival in the region of just six months due to rapid local recurrence or metastasis (Fry and Rest, 1993; Lawrence et al., 1994). Unfortunately, there are no known effective treatment options for dogs with nodular or diffuse bile duct carcinomas.
Neuroendocrine tumours
Neuroendocrine tumours (carcinoids) are rare liver tumours in dogs. They arise from neuroectodermal cells and can be histologically identified via either silver stains that highlight secretory granules or immunohistochemistry with chromogranin-A, S-100 or NSE. They usually occur in younger dogs, are most commonly intrahepatic, demonstrate a diffuse morphology in 67 percent of cases and follow an aggressive clinical course with frequent regional and distant metastasis (Patnaik et al., 1980, 1981b).
Due to the rarity of solitary lesions and the high rate of metastasis, surgery is often not possible for hepatic carcinoids, and the prognosis is, therefore, considered poor (Patnaik et al., 1980, 1981b). The efficacy of radiotherapy and conventional chemotherapy has not been evaluated, although recently one case report has described the long-term survival of one dog treated with toceranib phosphate (Ichimata et al., 2021).
Mesenchymal tumours
Hepatic sarcomas are also rare. Leiomyosarcoma is the most common primary hepatic sarcoma in dogs, with haemangiosarcoma, fibrosarcoma, rhabdomyosarcoma and osteosarcoma also reported (Liptak, 2020). Approximately one third present as massive types and two thirds with nodular morphology. Mesenchymal liver tumours have an aggressive biological behaviour with metastasis, usually to the spleen and lungs, reported in 86 to 100 percent of cases (Kapatkin et al., 1992; Patnaik et al., 1980).
Mesenchymal liver tumours have an aggressive biological behaviour with metastasis, usually to the spleen and lungs, reported in 86 to 100 percent of cases
Liver lobectomy can be considered for massive non-metastatic hepatic sarcomas, but the prognosis is still considered poor due to the high likelihood of future metastasis. Although there is limited literature assessing the use of chemotherapy for hepatic sarcomas, doxorubicin-based protocols could be used, considering they have shown benefits with sarcomas in other locations, such as visceral haemangiosarcoma (Batschinski et al., 2018).
Summary
Overall, liver tumours are uncommon. Achieving a definitive diagnosis is indicated prior to treatment, if possible, as different types of liver tumours are associated with different prognoses. Obtaining a diagnosis may require a biopsy for histopathology. Hepatocellular carcinoma is the most common malignant primary liver tumour in dogs, and complete excision can be associated with a very good prognosis. Bile duct carcinomas, hepatic carcinoids and hepatic sarcomas have high metastatic rates and are often associated with poor prognoses.
