INTRODUCTION

Chemotherapy has revolutionized the management of cancer in the past decades. Liver toxicity is commonly observed among different types of chemotherapy drugs. There are various manifestations of liver toxicity. Apart from clinical history and biochemical tests, radiological examinations can provide additional information in categorizing the type of liver injury. The aim of this pictorial review is to illustrate the radiological features of various chemotherapy-associated hepatic parenchymal changes in different imaging modalities. The potential complications of these liver injury patterns are demonstrated. Early recognition of these liver conditions allows prompt clinical action to be taken, thus optimizing management and avoiding severe complications. The radiological features of different types of chemotherapy-associated hepatic parenchymal changes are shown, which include pseudocirrhosis, chemotherapy-related hepatic steatosis, hepatitis, and cholangiopathy.

PSEUDOCIRRHOSIS

Pseudocirrhosis is a radiological finding describing hepatic morphological changes which mimic cirrhosis without the classical histopathological features of cirrhosis. This is reported to be mostly observed in breast cancer patients with liver metastasis, in the setting after treatment with systemic chemotherapy.[1] Common agents include gemcitabine, capecitabine, 5-fluorouracil, oxaliplatin, paclitaxel, and trastuzumab.[2] Radiological features of pseudocirrhosis resemble that of cirrhosis, showing capsular retraction, macronodular liver contour, widening of interlobular fissures and periportal space, and atrophic change [Figure 1a, 1b, 1c].

Figure 1: A 69-year-old woman with breast cancer and liver metastasis treated with chemotherapy. Images of (a) axial, (b) coronal, and (c) sagittal contrast-enhanced portal venous phase computed tomography performed 4 years after chemotherapy demonstrate features of pseudocirrhosis, including marked macronodular liver contour and widening of interlobular fissures, as well as gross ascites.

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The pathophysiology of pseudocirrhosis remains unclear. Possible mechanisms include hepatotoxic effect of systemic chemotherapy, tumor response to chemotherapy, with the combination of nodular regenerative hyperplasia, fibrosis, and desmoplastic reaction.[3]

Pseudocirrhosis is a progressive process and can develop early, in weeks,[2] after initiation of chemotherapeutic treatment. Figure 2 demonstrates the development and progression of pseudocirrhosis over 27 months in a breast cancer patient with liver metastasis, with radiological findings highlighted [Figure 2a-d].

Figure 2: A 54-year-old woman with breast cancer and liver metastasis treated with chemotherapy, demonstrating features of pseudocirrhosis. Images of axial contrast-enhanced portal venous phase computed tomography scan at similar levels, performed at (a) before commencement of chemotherapy, (b) 4-month, (c) 18-month, (d) 27-month after chemotherapy. Evidence of multiple liver metastasis. Before commencement of chemotherapy, the liver shows normal size, morphology, contour, and attenuation. After administration of chemotherapy, there are progressive capsular retraction and irregular and macronodular hepatic outline (b-d, white arrow).

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Pseudocirrhosis is not limited to metastatic breast cancer patients. Similar findings have been reported in non-breast cancer patients, including colorectal cancer, small-cell lung cancer, pancreatic cancer, and esophageal cancer.[3] Radiological features of pseudocirrhosis in a colon cancer patient with liver metastasis are shown [Figure 3a-c].

Figure 3: A 60-year-old man with colon cancer liver metastasis treated with chemotherapy, developed pseudocirrhosis and complicated by portal hypertension with gastroesophageal varices. (a) Image of axial contrast-enhanced portal venous phase computed tomography (CT) at time of diagnosis before commencement of chemotherapy, shows liver metastasis (white arrow) with preserved hepatic contour. (b-d) Images of (b) axial, (c) coronal, and (d) sagittal contrast-enhanced portal venous phase CT performed 30 months after chemotherapy demonstrate marked capsular retraction (b-c, white arrowhead), gross ascites, splenomegaly (c, asterisk), dilated and tortuous vessels compatible with gastroesophageal varices (b-d, white arrow).

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Although pseudocirrhosis is known to be a different disease process from cirrhosis of chronic liver disease, pseudocirrhosis can result in portal hypertension and liver failure. Patients can suffer from various forms of symptoms and signs, from local to systemic complications. Signs of portal hypertension can be observed radiologically, such as ascites, splenomegaly, gastroesophageal varices [Figure 3b-d], recanalization of the umbilical vein, and portosystemic shunts [Figure 4a-d].

Figure 4: A 61-year-old woman with metastatic breast cancer treated with chemotherapy and developed pseudocirrhosis. Images of (a-c) axial and (d) coronal contrast-enhanced portal venous phase computed tomography performed 6 years after chemotherapy show liver surface nodularity and multifocal capsular retraction (a, d, white arrowhead). Evidence of portal hypertension is noted, with splenomegaly, recanalization of the umbilical vein (white arrow), and other portosystemic shunts. The patient suffered from an episode of severe upper gastrointestinal bleed requiring blood transfusion, varices band ligation, and subsequent long-term medical therapy. (e) Esophagogastroduodenoscopy showed columns of esophageal varices.

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Identification of features of portal hypertension should raise clinical attention. Further hepatic decompensation and complications of portal hypertension can be potentially life-threatening. Variceal bleeding is one condition that could be difficult to manage [Figures 4e and 5a-d]. Accurate and prompt identification of pseudocirrhosis can optimize management and avoid severe complications.

Figure 5: A 55-year-old woman with metastatic breast cancer treated with chemotherapy, developed pseudocirrhosis complicated by portal hypertension with gastroesophageal varices requiring repeated band ligation and sclerotherapy, with one episode of life-threatening variceal bleeding leading to cardiac arrest. (a) Image of axial contrast-enhanced portal venous phase computed tomography (CT) after commencement of chemotherapy shows multiple liver metastasis (white arrow head) and mild nodular liver contour (white arrow) compatible with early pseudocirrhosis. (b-d) Images of (b) axial and (c) coronal contrast-enhanced portal venous phase CT performed 7 years later demonstrate further progression of pseudocirrhosis, with hepatic capsular retraction and increase of periportal space. Note of curvilinear hyperdensities at gastric cardia region with artefact, compatible with prior sclerotherapy (b-c, white arrow). (d) Upper endoscopy image taken during episode of acute variceal bleed shows columns of bleeding esophageal varices.

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CHEMOTHERAPY-RELATED HEPATIC STEATOSIS

Chemotherapeutic agents can result in various forms of hepatotoxicity. Certain drugs can cause steatosis or steatohepatitis, also known as chemotherapy-induced acute steatohepatitis. The mechanism is mainly based on mitochondrial toxicity.[4] Mitochondria and peroxisomes are responsible for β-oxidation of fatty acids. Drugs, such as 5-fluorouracil, methotrexate, irinotecan, and tamoxifen, can induce mitochondrial and peroxisomal toxicity, in turn reducing the β-oxidation of fatty acids. Accumulation of medium and long-chain fatty acids in hepatocytes, and increased reactive oxygen species, can result in hepatic steatosis and hepatotoxicity.

Chemotherapy-induced hepatic steatosis is known to be potentially reversible.[4] These changes can be reversible in weeks or months after the discontinuation of treatment. Such changes can be observed radiologically in different modalities. On computed tomography, measurement of the Hounsfield unit of the liver parenchyma can quantitatively evaluate the degree of steatosis. Figure 6 demonstrates a case of chemotherapy-induced hepatic steatosis in a breast cancer patient, illustrating the progressive development of hepatic steatosis after the commencement of chemotherapy over 13 months [Figure 6a-c]. The condition reversed after withdrawal of treatment [Figure 6d].

Figure 6: A 56-year-old woman with breast cancer and mediastinal nodal metastasis, developed chemotherapy-related hepatic steatosis. (a) Unenhanced computed tomography (CT) image from positron emission tomography/CT (PET/CT) at diagnosis reveals mild diffuse hepatic steatosis (Red circle, 43.4 Hounsfield unit [HU]) before treatment. Neoadjuvant chemotherapy including epirubicin, cyclophosphamide, and paclitaxel was given. (b) Unenhanced CT image from PET/CT 4 months after neoadjuvant chemotherapy demonstrates worsening of hepatic steatosis (Red circle, 34.2 HU), with areas of focal fatty sparing near the gallbladder fossa (white arrowhead). Modified radical mastectomy was performed, followed by 8 cycles of adjuvant capecitabine. (c) Unenhanced CT image of PET/CT 13 months since the use of capecitabine demonstrates further worsening of hepatic steatosis (Red circle, 14.0 HU). Intrahepatic vessels (asterisk) appear hyperattenuated on the low density background. Left mastectomy is noted (white arrow). (d) Unenhanced CT image shows regression of hepatic steatosis, with liver attenuation returning to baseline (Red circle, 43.0 HU), 15 months after withdrawal of capecitabine.

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It is important to identify these changes, as hepatic steatosis and steatohepatitis could result in deranged liver function, which might warrant treatment regime adjustment after balance between risks and benefits.

CHEMOTHERAPY-RELATED HEPATITIS

Drug-induced hepatitis is another form of hepatotoxicity related to the use of chemotherapeutic agents, such as paclitaxel, carboplatin, cisplatin, vinblastine, and rituximab.[5] This is usually discovered biochemically, with the elevation of liver enzymes in hepatitis pattern. Radiological findings of hepatitis are more subtle and non-specific. Common findings include periportal edema, gallbladder wall edema, and hepatic parenchymal heterogeneity [Figure 7 a-b].

Figure 7: A 61-year-old woman with metastatic breast cancer, developed chemotherapy-related hepatitis. Course of paclitaxel and carboplatin was given. She developed gradual worsening of liver function. Contrast-enhanced computed tomography shows (a) periportal edema and hepatic parenchymal heterogeneity, in keeping with hepatitis. (b) There is also gallbladder wall edema (white arrow) related to concomitant hypoalbuminemia. The patient further deteriorated and developed liver failure.

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CHEMOTHERAPY-RELATED CHOLANGIOPATHY

Chemotherapy-induced cholangitis has been reported. This can be caused by hepatic arterial chemotherapy and systemic chemotherapy such as fluoropyrimidines, taxanes, and bevacizumab.[6] Similar to hepatitis, radiological findings of cholangiopathy or cholangitis can be subtle and non-specific. Figure 8 illustrates a case of pembrolizumab-related cholangiopathy, with findings in sonography [Figure 8a] and magnetic resonance imaging (MRI) [Figure 8b-f].

Figure 8: A 71-year-old man with metastatic programmed death-ligand 1 positive lung cancer. Pembrolizumab, programmed death-1 inhibitor, was given. The patient developed a new onset deranged liver function in a cholestatic pattern. (a) Ultrasound demonstrates wall thickening of common bile duct (white arrowheads). (b) Image from true fast imaging with steady-state-free precession sequence Magnetic Resonance Imaging (MRI) shows common bile duct wall thickening (white arrowheads), in keeping with ultrasound findings. (c) Image from T2-weighted fat-saturated sequence MRI demonstrates periportal edema (white arrows). (d-f) Images from contrast-enhanced T1-weighted volumetric interpolated breath-hold examination sequence MRI in (d) portal venous phase and (e and f) delayed phase show diffuse ductal wall thickening and enhancement (d-f, white arrows). These findings are compatible with cholangiopathy. Pembrolizumab was subsequently stopped, and ursodeoxycholic acid was started.

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Apart from the use of chemotherapy, these radiological findings can also be seen in various different underlying conditions. Thus, correlation with clinical course and biochemical profile is crucial. Histopathological evaluation is sometimes necessary, especially in cases where diagnostic dilemma is encountered [Figure 9a-e].

Figure 9: A 54-year-old man with diffuse large B-cell lymphoma received intravenous high-dose methotrexate for central nervous system prophylaxis prior bone marrow harvest for autotransplant. He developed acute-onset deranged liver function. (a) [F-18] Fluorodeoxyglucose positron emission tomography demonstrates patchy moderate increased activity (white arrow) in the left lobe of liver (maximum standardized uptake value 5.3). (b-d) (b) Axial, (c) coronal, (d) sagittal contrast-enhanced Computed tomography images show corresponding diffuse patchy hypoenhancement (b-d, white arrows) involving the entire left hepatic lobe. (e) Transfemoral transvenous liver biopsy was later performed. Histopathological findings reveal portal inflammatory infiltrates, increase in ductules, and bile plugs, compatible with cholangiopathic picture.

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NODULAR REGENERATIVE HYPERPLASIA

Hepatotoxic effects of chemotherapy, when prolonged with delayed evaluation, can result in irreversible liver damage, fibrosis, and atrophy. Areas of relatively unaffected liver parenchyma with adequate blood supply can develop nodular regenerative hyperplasia as a compensatory mechanism. Oxaliplatin is a well-known agent associated with sinusoidal obstructive syndrome and development of nodular regenerative hyperplasia.[7] Other associated agents include azathioprine, capecitabine, doxorubicin, paclitaxel, and trastuzumab.[8] Nodular regenerative hyperplasia is usually microscopic and not detectable on images. Sometimes, when large regenerative nodules are developed, they can present as focal nodular hyperplasia-like lesions radiologically, with the uptake of liver-specific contrast agent on delayed hepatobiliary phase.[8]

CONCLUSION

This pictorial essay illustrates the radiological features of various chemotherapy-associated hepatic parenchymal changes, with examples in different imaging modalities. The potential complications of these liver injury patterns are demonstrated. Early recognition of these chemotherapy-associated liver conditions are important so that prompt clinical action can be taken, optimizing management and avoiding severe complications.