Special Surgery 13. Primary and Metastatic Tumors of the Liver: Symptoms, Diagnosis, Treatment

I. Primary and Metastatic Liver Tumors

Main Categories

1. Primary malignant liver tumors
2. Metastatic liver tumors

• Metastases are the most common malignant tumors of the liver overall
• Hepatocellular carcinoma (HCC) is the most common primary malignant liver tumor in adults
• Intrahepatic cholangiocarcinoma is the second major primary liver malignancy, discussed mainly in the biliary malignancy topic
• Treatment always depends on tumor biology + liver function + patient performance status

Hepatocellular Carcinoma (HCC)

Definition and Epidemiology

• Malignant tumor of hepatocytes
• Most common primary liver malignancy in adults
• Male predominance
• Usually develops on background of chronic liver disease/cirrhosis

Etiology and Risk Factors

• Liver cirrhosis is the main risk factor:

• Alcohol-related liver disease
• Non-alcoholic fatty liver disease / NASH
• Chronic viral hepatitis
• Autoimmune liver disease
• Hemochromatosis and other metabolic liver diseases

• HBV infection can cause HCC even without established cirrhosis
• HCV infection, usually through cirrhosis
• Aflatoxin exposure: Aspergillus contamination of food
• Diabetes/obesity/metabolic syndrome increase risk

Surveillance

• At-risk cirrhotic patients: ultrasound every 6 months, often with AFP depending on local protocol
• Surveillance goal: detect early stage HCC suitable for ablation, resection or transplantation
• Surveillance is only useful if patient could receive treatment if cancer is found

Intrahepatic Cholangiocarcinoma

• Primary adenocarcinoma from intrahepatic bile ducts
• Risk factors:

• Primary sclerosing cholangitis
• Choledochal cysts
• Liver flukes
• Chronic biliary inflammation
• Cirrhosis/chronic viral hepatitis can contribute

• Symptoms: fatigue, weight loss, RUQ discomfort; jaundice less common than extrahepatic obstruction unless hilar/ductal involvement
• Diagnosis: CT/MRI, MRCP if ductal anatomy relevant, CA 19-9/CEA supportive, biopsy when diagnosis unclear or systemic therapy planned
• Treatment: liver resection if resectable; systemic/palliative therapy if unresectable or metastatic

Metastatic Liver Tumors

• Most common malignant liver tumors overall
• Liver receives portal venous drainage from GI tract → common site of GI metastases
• Common primary tumors:

• Colorectal cancer: most important surgically
• Pancreatic cancer
• Gastric cancer
• Lung cancer
• Breast cancer
• Neuroendocrine tumors
• Melanoma, renal cell carcinoma and others

II. Symptoms, Spread and Staging Logic

HCC: Clinical Features

• Early stage often asymptomatic
• May be detected by surveillance in cirrhosis
• Later symptoms:

• Right upper quadrant tenderness or pain
• Weight loss, anorexia, fatigue
• Hepatomegaly or palpable mass
• Jaundice
• Ascites or worsening liver decompensation
• Fever can occur

• Rare acute presentation:

• Tumor rupture → hemoperitoneum and shock
• Massive intratumoral bleeding

HCC Complications and Spread

• Vascular invasion is important:

• Portal vein tumor thrombus
• Hepatic vein invasion
• Can cause Budd-Chiari-like syndrome: hepatic venous outflow obstruction → painful hepatomegaly, ascites

• Intrahepatic spread / satellite nodules common
• Hematogenous distant metastases occur in advanced disease:

• Lung
• Bone
• Adrenal gland
• Lymph nodes

Metastatic Liver Disease: Clinical Features

• Often asymptomatic in early stage
• Detected during staging/follow-up of primary tumor
• Symptoms:

• RUQ discomfort or fullness
• Weight loss, anorexia, fatigue
• Hepatomegaly
• Fever/night sweats sometimes

• Late signs:

• Jaundice
• Ascites
• Liver failure
• Cachexia

Staging Logic

HCC

• Staging must combine:

• Tumor burden: size, number, vascular invasion, metastasis
• Liver function: Child-Pugh, MELD, bilirubin, portal hypertension
• Performance status

• BCLC staging is commonly used to link stage with treatment:

• Very early/early: ablation, resection or transplantation
• Intermediate: transarterial therapy
• Advanced: systemic therapy
• Terminal: best supportive care

Metastases

• Assess whether liver metastases are:

• Resectable
• Borderline resectable / convertible
• Unresectable liver-limited
• Part of widespread systemic disease

• Resectability is not only number/size; key is complete removal/ablation of all disease with sufficient future liver remnant and acceptable biology

III. Diagnosis

HCC Laboratory Tests

• Liver enzymes can be increased, especially AST/GOT
• Bilirubin, albumin, INR, platelets assess liver function/portal hypertension
• AFP = alpha-fetoprotein tumor marker:

• Supportive and useful for follow-up if elevated
• Not diagnostic alone
• Can be normal in HCC
• Can be elevated in active hepatitis/cirrhosis without HCC

• Viral hepatitis serology and liver disease workup guide background treatment

HCC Imaging

• Surveillance ultrasound detects suspicious nodules
• Confirmatory imaging:

• Multiphasic contrast CT
• Multiphasic contrast MRI

• Typical HCC vascular pattern in at-risk liver:

• Arterial phase hyperenhancement
• Portal venous/delayed washout
• Capsule appearance can support diagnosis

• Chest CT and abdominal/pelvic imaging assess extrahepatic spread before curative therapy

Biopsy in HCC

• Often avoided when imaging is diagnostic in a high-risk patient
• Reasons:

• Bleeding risk in cirrhosis
• Tumor seeding risk
• False negative sampling possible

• Biopsy indicated when:

• Imaging is atypical/indeterminate
• No background risk factor and diagnosis uncertain
• Histology or molecular testing is needed before systemic therapy/clinical trial

Preoperative Liver Function and Remnant Assessment

• Assess portal hypertension:

• Platelets/splenomegaly
• Varices
• Ascites
• Hepatic venous pressure gradient in selected centers

• Future liver remnant assessment:

• CT volumetry
• Functional tests, e.g. 99mTc-mebrofenin SPECT/CT where available
• ICG clearance in some centers

• If remnant too small but liver function adequate, hypertrophy strategies:

• Portal vein embolization
• Portal vein ligation
• Two-stage hepatectomy
• ALPPS: associating liver partition and portal vein ligation for staged hepatectomy, selected high-risk cases only

Diagnosis of Liver Metastases

• Laboratory:

• Liver enzymes can be normal or show cholestasis if extensive disease
• Tumor markers according to primary tumor, e.g. CEA in colorectal cancer
• CA 19-9 in pancreatic/biliary/GI tumors, CA 15-3 in breast cancer depending on context

• Imaging:

• Contrast CT: often multiple hypodense lesions
• Liver MRI: best for small lesions and preoperative mapping
• Contrast-enhanced ultrasound in selected lesion characterization
• PET-CT useful in selected primaries/staging, especially colorectal cancer when extrahepatic disease is a concern

• Biopsy:

• Sometimes needed if primary tumor is unknown
• Needed if imaging pattern is atypical and result changes treatment
• Avoid unnecessary biopsy if resectable colorectal metastasis is clear and biopsy would delay treatment or seed tract

IV. Treatment

HCC Treatment Principles

• Decision by liver tumor board / hepatobiliary MDT
• Depends on:

• Tumor size and number
• Vascular invasion
• Extrahepatic metastasis
• Liver function and portal hypertension
• Performance status

1. Local Ablation

• Radiofrequency ablation (RFA) or microwave ablation
• Best for very early/small tumors, especially <= 2-3 cm
• Useful when location allows safe ablation margin
• Can be curative in selected early HCC
• Limitations:

• Large tumors
• Near major bile ducts, bowel or vessels
• Heat-sink effect near large vessels

2. Liver Transplantation

• Best option when early HCC occurs with impaired liver function or clinically significant portal hypertension
• Treats both tumor and cirrhotic liver
• Milan criteria:

• Single tumor <= 5 cm
• Or up to 3 tumors, each <= 3 cm
• No macrovascular invasion
• No extrahepatic metastasis

• Bridging therapy while waiting: ablation, TACE or other locoregional therapy
• Downstaging can be considered in selected patients outside criteria if they respond and become eligible

3. Surgical Resection

• Curative option for localized HCC with sufficient liver reserve
• Best candidates:

• Non-cirrhotic liver, or well-compensated cirrhosis
• No clinically significant portal hypertension
• Preserved bilirubin/liver function
• No lymph node/distant metastasis
• Adequate future liver remnant

• Not limited to <2-3 cm if liver function and anatomy allow; larger solitary tumors may be resected in selected patients
• Recurrence risk remains high → postoperative surveillance with multiphasic CT/MRI

4. Transarterial Therapy

• TACE = transarterial chemoembolization
• Typical indication: intermediate-stage HCC, liver-confined, no main portal vein thrombosis, preserved liver function
• Mechanism:

• Catheter into hepatic arterial tumor supply
• Chemotherapy + embolic particles → ischemic tumor necrosis

• Other locoregional options: TARE/SIRT radioembolization in selected patients/centers

5. Systemic and Palliative Treatment

• Indications:

• Advanced HCC with vascular invasion or extrahepatic spread
• Progression after locoregional therapy
• Intermediate disease not suitable for TACE

• Preferred modern first-line systemic options in fit patients with preserved liver function include:

• Atezolizumab + bevacizumab, if bleeding/variceal risk is managed
• Durvalumab + tremelimumab
• Tyrosine kinase inhibitors such as sorafenib or lenvatinib if immunotherapy/anti-VEGF unsuitable

• End-stage HCC / poor liver function / poor performance status → best supportive care, symptom control, ascites/jaundice/pain management

Metastatic Liver Tumor Treatment

Colorectal Liver Metastases (CRLM)

• Most important liver metastases for surgical cure
• R0 liver resection can be potentially curative
• Resectability criteria:

• All visible disease can be removed/ablated
• Sufficient future liver remnant remains
• Inflow, outflow and biliary drainage preserved
• Patient fit for surgery
• Extrahepatic disease absent or also controllable in selected cases

• Number, size and bilobar distribution do not automatically exclude surgery if complete treatment is possible
• Systemic chemotherapy:

• Neoadjuvant/conversion chemotherapy for borderline or initially unresectable disease
• FOLFOX/FOLFIRI/FOLFOXIRI-based regimens with biologics depending on RAS/BRAF/MSI and sidedness
• Perioperative chemotherapy can be considered depending on disease biology and prior therapy

• Local techniques:

• Radiofrequency/microwave ablation for small lesions, often <= 2-3 cm or combined with resection
• Two-stage hepatectomy, portal vein embolization, ALPPS in selected extensive bilobar disease
• SBRT, TACE/TARE/SIRT or hepatic arterial infusion in selected unresectable/refractory cases

Neuroendocrine Liver Metastases

• Often slower-growing and liver-dominant
• Resection/debulking or ablation can improve symptoms and survival in selected patients
• Other options:

• Somatostatin analogues
• Peptide receptor radionuclide therapy (PRRT)
• Transarterial embolization/chemoembolization/radioembolization
• Systemic therapy depending on grade and primary site

Non-Colorectal, Non-Neuroendocrine Metastases

• Examples: breast, lung, stomach, pancreas, esophagus
• Usually treated primarily with systemic therapy according to primary tumor
• Liver resection only in highly selected oligometastatic cases after MDT discussion
• Palliative interventions:

• Biliary drainage/stent if obstructive jaundice
• Pain control
• Nutrition and cachexia management
• Local ablation/radiotherapy for selected symptomatic lesions