Tumors of the Liver and Biliary Tract

Primary liver cancers originate directly from liver tissue. The main types are:

• • Hepatocellular Carcinoma (HCC): accounts for approximately 75–85% of primary liver cancers. It arises from hepatocytes, the main liver cells, and often develops in a liver already affected by cirrhosis or chronic hepatitis

• • Intrahepatic cholangiocarcinoma: develops from the cells lining the bile ducts within the liver. It is less common than HCC but has been increasing in incidence in recent years

• • Rare cancers: including hepatoblastoma (most common in children), hepatic angiosarcoma, and other sarcomas, which are very rare in adults

Liver metastasis are far more common than primary liver tumors and results from the spread of cancer cells from other organs, including the colon and rectum, pancreas, stomach, lungs, breast, or skin (melanoma).

Ultrasound is usually the first imaging test performed when symptoms suggest possible liver disease. It can often identify benign lesions, such as cysts or hemangiomas, but solid lesions typically require further evaluation with more detailed imaging, such as a CT scan.

Ultrasound can also provide important initial information about the presence, extent, and distribution (unilateral or bilateral) of biliary tract dilation, and may help raise early suspicion of possible gallbladder cancer.

Chest and abdominal computed tomography (CT) with quadraphasic contrast (late arterial, portal, venous, and delayed phases) is a key tool for detecting liver lesions and often characterizing them based on their appearance and contrast uptake during the four phases.

This examination also provides detailed information on:

• The location of lesions within the eight hepatic segments
• Involvement of vascular or portal branches
• Presence of portal vein thrombosis
• Biliary tract dilatation and sites of obstruction
• Volume of the remaining liver for surgical planning
• Vascular abnormalities
• Presence of distant metastases or suspicious lymph nodes

All of these details are essential for accurate diagnosis, staging, and planning of potential surgical treatment.

Liver magnetic resonance imaging (MRI) with hepatospecific contrast agent can be useful in certain cases to:

• Improve characterization of liver lesions detected on a CT scan
• Identify lesions not visible on CT using specialized sequences, such as diffusion-weighted imaging

Cholangiography MRI (Cholangi MRI) is a specialized MRI technique that visualizes the intrahepatic and extrahepatic bile ducts, allowing it to:

• Better characterize strictures and determine the level of biliary obstructions
• Evaluate congenital abnormalities of the bile ducts

It is almost always used in cases of Klatskin tumors (tumors of the extrahepatic bile ducts at the biliary confluence) or in certain hilar-type gallbladder tumors that mimic these lesions.

Blood tests can also measure the levels of two proteins produced by liver tumor cells, known as tumor markers:

• Alpha-fetoprotein (AFP): often elevated in hepatocellular carcinoma
• Carbohydrate Antigen 19-9 (CA 19-9): may increase in biliary tract and gallbladder cancers

The concentrations of these markers are generally related to tumor burden and tend to rise as the disease progresses. When present, they are useful for assessing disease severity, monitoring progression, and evaluating the effectiveness of treatment.

The diagnosis of liver tumors can be established through histological examination of a needle biopsy, typically performed via a percutaneous ultrasound- or CT-guided approach.

For extrahepatic biliary tract tumors, diagnosis can sometimes be achieved through brushing during endoscopic retrograde cholangiopancreatography (ERCP). In this procedure, the papilla of Vater is cannulated, contrast is injected into the biliary and pancreatic ducts, and, if needed, a cytological sample of the lesion is collected. ERCP can also be used to place a biliary stent in cases of malignant biliary obstruction that cannot be surgically treated or as a bridge to surgery.

In hepatocellular carcinoma (HCC), diagnosis is often based on characteristic imaging findings combined with elevated AFP levels, or on concordant results from two imaging studies, so a biopsy is not always required.

For biliary convergence (Klatskin) tumors, obtaining a histologic diagnosis is frequently challenging and may require multiple biopsies, with a significant risk of non-diagnostic samples.

In tumor diagnosis, the pathologist examines the overall tissue architecture to determine the histologic type. The histologic type has biological significance and provides valuable information for treatment planning.

Hepatocellular carcinoma (HCC) is the most common primary liver tumor and originates from the liver’s main cells, the hepatocytes.

Cholangiocarcinoma arises from the cells lining the bile ducts (cholangiocytes), either within the liver (intrahepatic) or outside it (extrahepatic). Like gallbladder cancer, cholangiocarcinoma is most often of the adenocarcinoma type.

“Histological grade” or grading

describes how tumor cells appear under the microscope, indicating their degree of differentiation and potential growth rate.

Liver, gallbladder, and biliary tract tumors are classified into three grades:

• Grade 1 (low grade): tumor cells closely resemble normal cells and are well differentiated.
• Grade 2 (intermediate/moderate grade): tumor cells show moderate differences from normal cells.
• Grade 3 (high grade): tumor cells are poorly differentiated, meaning they deviate significantly from the normal cells from which they originate.

Higher-grade tumors tend to grow and spread more quickly than lower-grade tumors.

Lymph nodes are small glands located throughout the abdomen that collect lymph fluid from surrounding tissues, including tumors. If cancer cells enter the lymphatic vessels, they can spread to these lymph nodes, forming lymphatic metastases.

Surgery is offered as a treatment for these types of malignancy, provided the cancer has not spread to adjacent or distant tissues, which would make the tumor inoperable.

Hepatocarcinoma (HCC)

For hepatocarcinoma, the surgical approach may involve two options:

• • Liver resection
    It involves removing the portion of the liver containing the tumor, along with a safety margin of healthy tissue.
    This option is indicated when:
    • Lesions are few (less than three) and small (less than 3 cm each) or there is only one lesion not exceeding 5 cm; liver function is almost normal.

    Hepatocellular carcinoma (HCC) develops in approximately 80% of cases in a liver already affected by cirrhosis, which may result from viral infections, alcohol use, hemochromatosis (genetic iron overload), or other conditions.

    It is essential that enough healthy liver tissue remains after surgery to allow the organ to regenerate and maintain its function.

• • Liver transplantation (orthotopic liver transplantation)
    In this procedure, the diseased liver is replaced with a liver from a deceased donor. Transplantation is considered when the patient has both a tumor and cirrhosis causing significant liver dysfunction, and is generally limited to patients under 70 years of age. The selection criteria for transplantation are similar to those used for surgical resection.

Intrahepatic Cholangio Carcinoma (CCC)

When feasible, surgical treatment involves hepatic resection, removing the portion of the liver containing the tumor while preserving enough healthy liver to maintain proper function.

The procedure is performed with a disease-free margin and typically includes removal of lymph nodes from the hepatic pedicle, the structure containing the portal vein, hepatic artery and its branches, and the main bile duct, since this type of tumor frequently spreads through nearby lymphatic pathways.

Perilary cholangiocarcinoma (Klatskin tumor)

This type of tumor, which affects the central part of the biliary tract, usually requires complex surgery.
Treatment involves removal of the main biliary pathway along with extensive liver resection. In most cases, a right hepatectomy is performed (removal of segments 5, 6, 7 and 8) extended to segment 4 and segment 1 as well, since they are drained by the affected biliary tract.
This is followed by a gentle reconstruction of the biliary tract – which is very thin at that point – connecting it directly to the small intestine.

Carcinoma of the gallbladder

This type of cancer can be diagnosed at different times:

• • Before surgery (preoperative diagnosis)

• • During a cholecystectomy operation (intraoperative diagnosis)

• • After surgery, as an occasional finding on histologic examination of gallbladder removed for other reasons (postoperative diagnosis)

The type of surgery depends greatly on the time of diagnosis and the stage of the disease:

• • Very early tumors (T1a): cholecystectomy alone is sufficient, and in case of postoperative diagnosis, reintervention is not necessary.

• • Stage T1b tumors: in addition to cholecystectomy, the lymph nodes of the hepatic pedicle must also be removed (lymphadenectomy).

• • Stage T2 or T3 tumors: lymphadenectomy associated with hepatic resection (segments 4b and 5, or the hepatic bed of the gallbladder) is performed.

This strategy is indicated in tumors growing toward the portion of the gallbladder in contact with the liver (liver bed type).
For tumors that develop toward the hepatic hilum and biliary pathway, treatment is similar to that for perilar cholangiocarcinoma, with more extensive hepatic resections and removal of the biliary pathway.

In some cases, when extensive resection is necessary but the volume of remaining liver is insufficient, techniques can be adopted to stimulate the growth of the part that will be preserved, within 30 to 40 days:

• • Preoperative portal embolization (PVE): by interventional radiology, the branch of the portal vein carrying blood to the part of the liver to be removed is occluded so as to increase the flow and volume of the healthy part.

• • Portal ligation: a surgical procedure that ties the portal branch intended for the part to be removed, with the same goal as PVE.

• • In addition to the techniques already described (embolization or portal ligation), there are newer methods:

• • ALPPS (Associating Liver Partition and Portal vein ligation for Staged hepatectomy) and mini-ALPPS: consist of total or partial sectioning of the liver, without immediately removing the diseased part and without further ligation (apart from any already provided). This approach reduces the formation of collateral circles that could return blood to the excluded portion of the liver, thus promoting faster and more consistent growth of the healthy portion.

Preparation in case of tumors with high bilirubin values

In patients with perilous cholangiocarcinoma or “hylum type” gallbladder tumor and elevated bilirubin values, before proceeding with extensive hepatectomy (and possible portal embolization), it is essential to perform biliary drainage of the liver, which will need to be preserved.
Drainage is done by inserting a thin tube through the abdominal wall and liver, passing the narrowing of the bile duct. This step helps reduce bilirubin, improves liver function, and optimizes residual liver growth. For this reason, drainage should be performed before any portal embolization procedures.

Locoregional therapies are targeted treatments that act directly on the tumor or affected area of the liver without significantly involving the rest of the body.
They are mainly used in the management of hepatocarcinoma, but may also be proposed in other cases, depending on the assessment of the Interdisciplinary Care Group (GIC).

These treatments include procedures such as thermoablation, chemoembolization, or radioembolization, and are designed to reduce tumor size, control disease progression, and, in some cases, make surgery possible—all using the least invasive approach possible.

• Thermoablation: is a minimally invasive procedure that uses heat to destroy the tumor. A thin needle, guided by ultrasound, is inserted directly into the lesion (through the abdominal wall or during surgery). The needle emits microwaves for a time and at an intensity calibrated to the size of the tumor, generating heat that destroys diseased cells. Treatment covers not only the entire lesion but also a small margin of surrounding tissue to reduce the risk of recurrence. It is particularly indicated for tumors less than 3 cm in diameter and, in patients with other diseases, may be preferred to surgery for deep, small lesions;
  • Transarterial chemoembolization: the procedure involves the insertion of a thin catheter into the femoral artery, which is traced up to the arteries feeding the liver tumor. Here an embolizing material is released that has a dual action:

    • blocks blood flow to the tumor, reducing its supply of oxygen and nutrients;

    • administers chemotherapeutic drugs locally, so as to target cancer cells.

• Transarterial radioembolization: this procedure is similar to chemoembolization, but instead of chemotherapeutic drugs, a substance containing radioactive microspheres is used.
  The material is released in a targeted manner within the arteries that feed the tumor, so as to directly target it with localized radiation and preserve surrounding healthy tissue as much as possible. Radioembolization may also be indicated for large lesions (more than 6 cm) and may have either a purely therapeutic purpose or, in some cases, a preparatory role for surgery if the response to treatment is favorable.

Chemotherapy uses cytotoxic drugs with the aim of inhibiting the growth and multiplication of cancer cells until they die. Cancer cells multiply uncontrollably and rapidly – this characteristic makes them targets for chemotherapy, but it can also involve healthy cells that rapidly renew themselves, causing side effects.

In liver cancer, chemotherapy is mainly indicated in gallbladder and biliary tract cancers. Hepatocarcinomas rarely benefit.

When can it be used

• Before surgery (neoadjuvant) →reduces the tumor mass to facilitate its removal;

• after surgery (adjuvant) → reduces the risk of recurrence, depending on stage and risk factors;

• in advanced/metastatic disease → reduces symptoms, slows progression, and may prolong survival.

Most commonly used drugs

Administered alone, in combination, or in sequence, they include:

• 5-fluorouracil (5FU) + folinic acid (intravenously)

• Gemcitabine (intravenous)

• Irinotecan (intravenous)

• Cisplatin (intravenous)

• Oxaliplatin (intravenous)

• Capecitabine (intravenous)

The choice depends on the tumor site, general health status, and treatments already received.

Mode of administration

• Oral route → tablets or capsules, one or more times a day;

• Intravenous (EV) route → via needle-cannula or more frequently central venous catheters, which allow safe infusions of potentially irritating drugs:

  • PICC (peripherally inserted catheter, for medium- to long-term therapies)

  • Tunnellized catheter (for medium- to long-term therapy)

  • PORT-a-CATH (totally implantable device under the skin, for long-term therapies)

Infusions take place on an outpatient basis and can last from a few minutes to several hours.
Chemotherapy is administered “in cycles“: each cycle lasts a few days and is followed by a period of rest to allow the body to recover. The number of cycles depends on the type of tumor and response to treatment.

Side effects

They can be immediate, delayed, or late-onset:

• Immediate → nausea, vomiting, fever, rash, diarrhea, heart rhythm disturbances, allergic reactions, local inflammation if the drug leaks from the vein;

• delayed → decline in red blood cells (anemia), white blood cells (neutropenia), and platelets (plateletopenia), oral or gastrointestinal mucositis, alopecia, peripheral neuropathy (tingling hands and feet), renal/hepatic damage, cystitis;

• late-onset → cardiac toxicity, pulmonary fibrosis, infertility, second neoplasms.

Some frequent effects and how to handle them

• Reduced resistance to infection
  Chemotherapy can temporarily lower the number of white blood cells, which are essential for defending the body against infection. This can increase the risk of even serious infections, especially if fever occurs. If you have a fever above 38°C during treatment, it is important to notify your doctor immediately, as you may need to intervene quickly with specific therapies. To reduce this risk, some patients are given drugs that stimulate white blood cell production, helping the immune system recover faster;

• Anemia → causes intense fatigue;

• Plateletopenia → facilitates bruising or small bleeding;

• Alopecia → hair loss, often rapid 3-4 weeks after initiation of therapy; possible reduction of damage with cooling helmet;

• Hand-foot syndrome → pain and redness of palms and soles;

• Fertility alterations → to be discussed before initiation of therapy.

New therapeutic possibilities

Clinical trials are underway to develop drugs that are more selective toward cancer cells (molecular targeting) and have fewer side effects. In selected cases, the patient may participate in clinical trials with innovative therapies or combinations of chemo, targeted therapies, and immunotherapy.

• Biological therapies, also known as molecularly targeted therapies, are treatments that act on specific molecular targets – such as receptors, growth factors, or enzymes – primarily found in cancer cells. These targets play key roles in uncontrolled cell growth and spread, resistance to conventional treatments, and the formation of new blood vessels that support tumor development.
  
• Immunotherapy includes drugs that are not directed against tumor cells but work by activating the immune system response inhibited by the tumor.
• In cases of advanced hepatocarcinoma, medical therapies include:
  – Tyrosine kinase inhibitors (TKIs) lenvatinib, sorafenib, cabozantinib, regorafenib
  – Combination of immunotherapy (nivolumab) and antiangiogenic drugs (atezolizumab/bevacizumab)
  – Immunotherapy combinations (durvalumab/tremelimumab)
  – New agents
• In case of advanced cholangiocarcinoma, molecular profiling analysis of the tumor is performed to identify by NGS any specific genetic alterations (affecting FGFR2, IDH1, HER2, BRAF, MMR proteins.). At progression from first-line chemoimmunotherapy some patients
  may benefit from molecularly targeted drugs (depending on the molecular alteration: pemigatinib, ivosidenib, zanidatamab, dabrafenib, trametinib, pembrolizumab) compared to standard therapy, with
  A significant impact on prognosis and quality of life.

Radiation therapy can be used to treat localized liver tumors when surgery or locoregional treatments are not feasible.

It can also be employed in cases of recurrence or for palliative purposes to relieve symptoms.

At the Candiolo Cancer Institute, post-surgical recovery is guided by the Enhanced Recovery After Surgery (ERAS) protocol, which is designed to speed up the return to independence, shorten hospital stays, and reduce the risk of complications.

This approach involves a multidisciplinary team: a surgeon, anesthesiologist, dietitian, nurse, psychologist, physical therapist, and social worker, that follows the patient at every stage, from pre-surgery to return home.

The protocol is based on a few key points:

• effective pain control

• minimally invasive surgical techniques

• pre-operative counseling

• early rehabilitation

Measures include avoiding fasting before surgery through adequate nutritional support, using targeted anesthesia that allows rapid natural feeding, limiting the use of tubes, drains, and IVs, and encouraging early mobilization.

The result is a recovery process that is more comfortable, safer, and more effective.

Treatments for liver cancer can cause side effects that may affect quality of life to varying degrees. However, these effects can often be managed, or even prevented, through specific therapies and appropriate lifestyle measures.

At the Candiolo Cancer Institute, doctors and nurses from the multidisciplinary team (GIC) are available to provide patients with comprehensive support to help manage the side effects they may experience during the course of treatment.

Cancer patients are often vulnerable and require timely support throughout their treatment journey. When they experience symptoms—whether related to the disease itself or to therapy side effects—they should have rapid access to a specialist’s evaluation through a “fast track” service.

For this reason, the Candiolo Cancer Institute offers an assistance service every weekday,  from Monday to Friday, from 8:00 a.m. to 5:00 p.m. Patients can call the Oncology Day Hospital secretary at +39 011 993 3775, report the need for an urgent consultation, and will be promptly contacted by their specialist physician.

Oncology patients are complex and require multidisciplinary support to manage not only their disease but also related issues affecting both physical health—such as pain or weight loss—and psychological well-being.

At the Candiolo Cancer Institute, specialists from various disciplines are available to patients who need or request them, providing:

• • nutritional support,

• • psychological support,

• • physical therapy,

• • dressing of venous access devices,

• • pain therapy,

• • management of other coexisting conditions.

The Social Service Department of the Candiolo Cancer Institute conducts information and orientation interviews for patients and their families on how to access services in the area and how to obtain welfare and social security benefits provided by law (disability, benefits for aids and prostheses, work leave, etc.).

The service operates on Wednesdays and Fridays from 9 a.m. to 1 p.m. – Phone: +39 011 993 3059.

After surgery or completion of treatment, patients enter a program of regular follow-up that typically lasts around five years. These checkups include medical evaluations and selected imaging or diagnostic tests, which serve to:

• Detect any recurrence of the disease, whether local or distant
• Monitor and manage side effects from previous treatments
• Assess overall health following therapies such as chemotherapy or radiation, which can occasionally cause long-term effects even years later

Initially, follow-up visits are scheduled more frequently, with intervals gradually lengthening over time. The frequency and type of examinations are personalized based on the stage of the disease and the treatments received, and will be clearly communicated by the oncologist at the end of therapy.

It is important to understand that follow-up primarily aims at early detection of local recurrences. Detecting distant metastases before they cause symptoms has not been shown to improve outcomes. Therefore, additional or more frequent tests than those recommended by the oncologist are not advised.

Thanks to the large number of liver cancer cases treated each year, the Candiolo Cancer Institute is a national reference center for the care of this disease. This extensive experience allows us to manage even the most complex cases, always using a personalized approach, tailored to the clinical and individual profile of each patient.

Establishing a treatment plan always begins with an accurate and timely diagnosis. Patients have access to state-of-the-art imaging technologies, such as ultrasound, contrast-enhanced CT, MRI, and cholangio-RM, which are critical for accurately assessing the extent of the tumor.

Advanced laboratory tests, including molecular analyses, are also available to help define biological features of the disease and guide treatment choices.

When appropriate, liver surgeries are performed using minimally invasive, laparoscopic or robotic techniques. These approaches involve the use of camera-equipped instruments introduced into the abdomen through small incisions, thus reducing surgical trauma. Benefits to the patient include shorter hospital stay times, faster recovery, and lower risk of complications compared with traditional open surgery.

The Candiolo Cancer Institute is equipped with state-of-the-art technologies, such as 4K laparoscopic columns and intraoperative fluorescence systems, which give the surgeon an extremely sharp and detailed view, facilitating even the most complex procedures.

Further support comes from the use of indocyanine green (ICG), a dye that, in combination with the Firefly mode found in robotic and laparoscopic systems, enables to:

• Highlight hepatocarcinoma lesions when ICG is injected intravenously about 24 hours before surgery, accumulating in the tumor and making it visible;

• Accurately identify liver segments during a resection: by clamping the vessels that supply blood to a particular segment or sector and injecting ICG during surgery, a visual “map” is obtained that guides the surgeon with extreme accuracy.

As an IRCCS (Scientific Institute for Research, Hospitalization, and Healthcare), the Candiolo Cancer Institute combines clinical care with a strong focues on scientific research. Patients can be considered for participation in active clinical trials, offering access to innovative therapies not yet available in standard practice. This integration of care and research is a distinctive strength that translates into tangible benefits for patients.

The Interdisciplinary Care Group  (GIC or MDT) supports the patient at every stage: from diagnosis, through treatment, to follow-up. Special attention is paid to nutritional support, psychological health and reintegration into daily life. The organization of checkups, examinations, and treatment is designed to ensure continuity, serenity, and a humane, caring approach to each patient’s needs.