Tumors of the liver and biliary tract

They originate directly from liver tissue. The main ones are:

• • Hepatocarcinoma (HCC – hepatocellular carcinoma): accounts for about 75-85% of primary liver cancers. It originates from hepatocytes, the main cells of the liver, and often develops on an organ already compromised by cirrhosis or chronic hepatitis;

• • Intrahepatic cholangiocarcinoma: arises from the cells lining the bile ducts within the liver. It is less frequent than HCC but increasing in recent years;

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

Liver metastasis is much more common than primary tumors and results from the spread of cancer cells from other organs, such as colorectal, pancreatic, stomach, lung, breast, or melanoma.

Ultrasound is the first instrumental examination which is usually performed in case of symptoms suggestive of possible liver injury, is sometimes able to confirm the presence of benign lesions such as cysts/angiomatous lesions but in case of solid lesions, further investigation by more in-depth examinations such as CT scan should be performed.

It can also give important initial information about the presence, extent, and distribution (unilateral/bilateral) of biliary tract dilatation and may be able to begin to raise suspicion of possible gallbladder cancer.

Chest abdomen computed tomography (CT) with quadraphasic contrast medium (late arterial-portal-venous-venous): Is able to demonstrate the presence of liver lesions and often to characterize them on the basis of modality and contrast-taking in relation to the four previously mentioned phases.

It is also able to assess the location within the liver in the various segments (eight hepatic segments), the involvement of vascular or portal branches, the presence of portal thrombosis and dilatation of biliary tracts, the site of relative obstruction to bile outflow, the volume of residual liver being planned for surgery, vascular abnormalities, the presence of distant metastases or suspicious lymphadenopathy: all of this is important information from the point of view of diagnosis, spread of disease (staging), and planning for possible surgery.

Liver magnetic resonance imaging (MRI) with hepatospecific contrast agent: may help in some cases to:

• Optimize the characterization of liver lesions after a CT scan,
• Detect lesions not visible on CT by imaging in a particular sequence (in “diffusion”).

Cholangiorisonance (Cholangio MRI) is a special type of MRI that can exclusively visualize the intra- and extrahepatic biliary tracts and thus:

• Better characterize stenosis and level of biliary obstructions.,
• Evaluate congenital abnormalities of the bile ducts.

It is almost always used in cases of Klatskin’s tumor (tumor of the extrahepatic biliary tract at the level of convergence or in some cases of “hylum type” gallbladder tumors that mimic the tumors described earlier).

Through a blood test it is also possible to measure the amount of two particular proteins that can be produced by liver tumor cells (which is why they are called tumor markers):

the Alfafetoprotein (AFP), which can have high serum concentrations in hepatocarcinoma and Carcinoembryonic Antigen 19.9 (Ca19.9) which may increase in biliary tract and gallbladder cancers.

Their concentration is related to the extent of the tumor and usually increases as the tumor progresses, so these markers, when present, help to assess the severity of the disease, to follow the progress of the disease, and to evaluate the effectiveness of treatment.

The diagnosis of the tumor can be obtained by thehistologic examination performed by the anatomo-pathologist on the needle biopsy performed by transparietal ultrasound-guided or CT-guided route. Sometimes for extrahepatic biliary tract tumors can be achieved by brushing (brushing) during endoscopic ERCP (Endoscopic Retrograde Cholangio Pancreatography) examination. The latter is a procedure in which the papilla of Vater is incannulated, the biliary pathway/pancreatic duct of Wirsung is contrasted and, if necessary, a cytological examination of the lesion is performed. By ERCP, a biliary endoprosthesis can be placed in cases of neoplastic biliary stenosis not amenable to surgery or in anticipation of surgery.

With regard to hepatocarcinoma, the diagnosis is often provided by the presence of a characteristic radiological examination associated with the presence of elevated neoplastic marker (AFP) values or two concordant radiological examinations, so biopsy should not be considered mandatory.

Finally, it is reported that for biliary convergence (Klatskin) tumors, histologic diagnosis is often difficult and may require repeated biopsies with a high percentage of non-directing sampling.

In tumor diagnosis, the pathologist describes the architecture as a whole (histologic type). The definition of histologic type has its own biological significance and is useful information for treatment planning purposes.

Hepatocarcinoma (or hepatocellular carcinoma) is the most common primary tumor of the liver and arises from the cells that make up the organ itself, the hepatocytes.
Cholangiocarcinoma originates from the cells of the bile ducts (cholangiocytes), whether they are inside (intrahepatic) or outside (extrahepatic) the liver. Similar to gallbladder cancer, it is in most cases of adenocarcinomatous type.

“Histological grade” or grading is a term conventionally used to describe the appearance of tumor cells under the microscope and indicates the degree of cell differentiation and how quickly they can grow.

Liver/cholecyst/biliary tract tumors are classified according to three grades:

• grade 1: low grade;
• grade 2: intermediate or moderate grade;
• grade 3: high grade.

In grade 1 tumors, cancer cells are very similar to normal cells thus “differentiated,” while grade 3 tumors are characterized by cells that are not very “differentiated” by deviating from the normal cell from which they originate.

Lymph nodes are glands found in the abdomen and receive lymph from the tumor. If the tumor cells enter the lymphatic vessels they give metastasis in the lymph nodes.

Surgery is a proposed treatment for the following forms of malignancy, provided that the cancer cells have not invaded adjacent or distant tissues thereby rendering the tumor inoperable.

Hepatocarcinoma (HCC)

For hepatocarcinoma, the surgical approach may involve two options:

• • Liver resection
    It consists of removing the part of the liver where the tumor is located, with a safety margin around the lesion.
    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.

    Hepatocarcinoma develops, in 80% of cases, in a liver already compromised by cirrhosis caused by viral infections, alcohol consumption, hemochromatosis (excessive iron accumulation due to a genetic disorder) or other diseases.
    It is important that sufficient functioning liver remains after surgery to ensure regeneration of the organ

• • Liver transplantation (orthotopic liver transplantation)
    In this case, the diseased liver is replaced with that of a deceased donor. Transplantation is considered when, in addition to the presence of the tumor, there is cirrhosis of the liver with severe impairment of liver function, and generally for patients under 70 years of age. The selection criteria are similar to those for resection.

Intrahepatic cholangiocarcinoma (CCC)

When possible, surgical treatment involves hepatic resection, that is, removal of the part of the liver where the lesion is located while still leaving enough organ volume to ensure good function.
The surgery is performed with a disease-free margin and associated with removal of lymph nodes from the hepatic pedicle-a structure that encloses the portal vein, the hepatic artery with its main branches, and the main biliary pathway-because this type of tumor tends to spread easily 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, aright 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 -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 ofhepatocarcinoma, but may also be proposed in other cases, depending on the assessment of the Interdisciplinary Care Group (ICG).

These treatments include procedures such as thermoablation, chemoembolization, or radioembolization, and aim to reduce the tumor mass, control the disease, and, in some cases, make it operable, all with as minimally invasive an approach as 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 it can 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 singly, 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 delayed:

• 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 in hands and feet), renal/hepatic damage, cystitis;

• late → 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 (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 called molecular targeted therapies or target therapies, are targeted therapies, that is, their action is directed against a molecular target (receptor, growth factor, enzyme). These targets, found primarily in cancer cells, are responsible for the uncontrolled growth and spread of cells, their resistance to traditional therapies, and the production of new blood vessels.
  
• 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 surgical or locoregional treatment is contraindicated.

In addition, it can be used in relapses or for palliative purposes.

At the Candiolo Institute, recovery after surgery is supported by theEnhanced Recovery After Surgery( ERAS ) protocol, designed to promote a rapid return to independence, reduce hospitalization time and decrease the risk of complications.

This approach involves a multidisciplinary team–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 more comfortable, safe and effective path to recovery.

Treatments for liver cancer often involve side effects that impact quality of life more or less severely. However, they can be mitigated and in some cases prevented by specific treatments and/or appropriate lifestyle.

At the Candiolo Institute, the doctors and nurses of the multidisciplinary team are available to provide the patient with all the support he or she needs to manage the various side effects he or she will face in the course of treatment.

The cancer patient is often a fragile patient, who needs help and support in his or her disease journey: when he or she experiences an ailment, whether related to the disease or a side effect of therapy, he or she should be able to receive a specialist’s opinion quickly, through a “fast track.”

For this reason, at the Candiolo Institute there is an assistance service every day, Monday through Friday from 8 a.m. to 5 p.m.: just call the secretary of the Oncology Day Hospital (011 993 3775) reporting the need for an urgent consultation, and the patient is quickly contacted by his or her specialist doctor.

The oncology patient is a complex patient who needs multidisciplinary support for the management, not only of his or her pathology, but also of all associated situations affecting both physical symptoms, such as pain or weight loss, and the psychological sphere.

At the Candiolo Institute, specialists from different disciplines are available at Candiolo for patients who need or request them to offer:

• • 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 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: 011 993 3059.

After surgery or completion of treatments, a course of regular checkups, called follow-up, is scheduled, lasting about 5 years. These checkups include medical examinations and some instrumental or radiological tests, useful for:

• Detect any recurrence of the disease, either local or distant;

• Monitor and manage the side effects of therapies performed;

• Assess overall health after treatments such as chemotherapy or radiation therapy, which in rare cases can cause effects even years later.

In the beginning, checkups are more frequent and, over time, the intervals between visits become longer. The frequency and type of examinations will be individualized according to the stage of the disease and the treatment given, and will be communicated by the oncologist at the end of therapy.

It is important to know that follow-up mainly focuses on early detection of local recurrences, whereas anticipating the discovery of distant metastases, before they give symptoms, has not been shown to improve the disease course. For this reason, additional or more frequent examinations than those indicated by the oncologist are not recommended.

Due to the high number of liver cancer cases treated each year, the Candiolo Institute is a national reference point for taking care of this disease. Our experience enables us to address even the most complex cases with a personalized approach built on the clinical and personal characteristics of each patient.

Establishing the treatment plan always starts 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 conditions permit, 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 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:

• 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, the Candiolo Institute combines clinical practice with a strong focus on scientific research. Patients with liver cancer can be evaluated forinclusion in active clinical trials, which provide a real opportunity to access innovative therapies not yet available in standard practice. This synergy between treatment and research is a distinctive value that offers new hope and possibilities.

The Interdisciplinary Care Team follows the person at all stages: 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.