Liver biopsy or aspiration
Therefore, these cancers can look very similar to non-cancerous liver tissue under a microscope. Moreover, not all pathologists are trained to recognize the subtle differences between well-differentiated liver cancer and normal liver tissue.
Also, some pathologists can mistake liver cancer for adenocarcinoma in the liver. An adenocarcinoma is a different type of cancer, and as previously mentioned, it originates from outside of the liver. Most importantly, a metastatic adenocarcinoma would be treated differently from a primary liver cancer (liver cancer).
Therefore, all of this considered, it is important that an expert liver pathologist review the tissue slides of liver tumors in questionable situations. New advances in immunohistochemistry (staining the microscopic cells with proteins that identify cell types very specifically) have helped to be able to tell the difference among cell and cancer types more reliably.
Tissue can be sampled with a very thin needle. This technique is called fine needle aspiration. When a larger needle is used to obtain a core of tissue, the technique is called a biopsy. Generally, radiologists, using ultrasound or CT scans to guide the placement of the needle, perform the biopsies or fine needle aspirations.
The most common risk of the aspiration or biopsy is bleeding, especially because liver cancer is a tumor that is very vascular (contains many blood vessels). Extremely rarely, new foci (small areas) of tumor can be seeded (planted) from the tumor by the needle into the liver along the needle track.
The aspiration procedure is safer than a biopsy with less risk for bleeding. However, interpretation of the specimen obtained by aspiration is more difficult because often only a cluster of cells is available for evaluation.
Thus, a fine needle aspiration is not generally recommended. Moreover, a core of tissue obtained with a biopsy needle is more ideal for a definitive diagnosis because the architecture of the tissue is preserved.
The point is that sometimes a precise diagnosis can be important clinically. For example, some studies have shown that the degree of differentiation of the tumor may predict the patient's outcome (prognosis). That is to say, the more differentiated (resembling normal liver cells) the tumor is, the better the prognosis.
All of that said, in many instances, there is probably no need for a tissue diagnosis by biopsy or aspiration. If a patient has a risk factor for liver cancer (for example, cirrhosis, chronic hepatitis B, or chronic hepatitis C) and a significantly elevated alpha-fetoprotein blood level, the doctor can be almost certain that the patient has liver cancer without doing a biopsy.
Moreover, recent advances in MRI interpretation can identify small liver cancers as such with an extremely high degree of probability. However, recent understanding of gene variations in some liver cancers is beginning to be useful in helping to decide what kind of therapy might be best for an individual patient. Therefore, the patient and physician should always ask two questions before deciding on doing a liver biopsy:
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1. Is this tumor most likely a liver cancer?
2. Will the biopsy findings change the management of the patient?
The second is to determine the extent of disease when there are multiple areas of abnormalities (possibly tumors) seen by imaging in the liver.
Overall, no blanket recommendation can be given regarding the need for liver biopsy or aspiration. The decision has to be made on an individual basis, depending on the treatment options and the expertise of the medical and surgical teams.
The truth is, biopsies are not always definitive; people with cirrhosis have many small nodules in their livers, and while one might be cancerous, others are not. Occasionally, people have to undergo several biopsies over many months before a definite diagnosis can be made.
The natural history of liver cancer?
For example, a patient with a 1 cm tumor with no cirrhosis has a greater than 50% chance of surviving three years, even without treatment. In contrast, a patient with multiple tumors involving both lobes of the liver (multicentric tumors) with decompensated cirrhosis (signs of liver failure) is unlikely to survive more than six months, even with treatment.
What are the predictors of a poor outcome? Our knowledge of the prognosis is based on studying many patients with liver cancer, separating out their clinical characteristics, and relating them to the outcome. Grouped in various categories, the unfavorable clinical findings include the following:
- Population characteristics (demographics): male gender, older age, or alcohol consumption
- Symptoms: weight loss or decreased appetite
- Signs of impaired liver function: jaundice, ascites, or encephalopathy (altered mental state)
- Blood tests: elevated liver tests (bilirubin or transaminase), reduced albumin, elevated AFP, elevated blood urea nitrogen (BUN), or low serum sodium
- Staging of tumor (based on imaging or surgical findings): more than one tumor, tumor over 3 cm (almost 1¼ inches), tumor invasion of local blood vessels (portal and/or hepatic vein), tumor spread outside of the liver (to lymph nodes or other organs)
It makes the most sense to use a system that incorporates a combination of clinical and pathological elements. In any event, it is important to stage the cancer because staging can provide guidelines not only for predicting outcome (prognosis) but also for decisions regarding treatment.
The doubling time for a cancer is the time it takes for the tumor to double in size. For liver cancer, the doubling time is quite variable, ranging from one month to 18 months. This kind of variability tells us that every patient with liver cancer is unique.
Therefore, an assessment of the natural history and the evaluation of different treatments are very difficult. Nevertheless, in patients with a solitary liver cancer that is less than 3 cm, with no treatment, we can expect that 90% of the patients will survive (live) for one year, 50% for three years, and 20% for five years. In patients with more advanced disease, we can expect that 30% will survive for one year, 8% for three years, and none for five years.
What are the treatment options for liver cancer?
They would argue that a small tumor can be surgically removed (partial hepatic resection) without the need for a liver transplantation. Moreover, they may claim that the one- and three-year survival rates for resection are perhaps comparable to those for liver transplantation.
However, most patients with liver cancer also have cirrhosis of the liver and would not tolerate liver resection surgery. In fact, in the United States, only 8% of people with liver cancer are able to undergo surgery.
But, they probably could tolerate the transplantation operation, which involves removal of the patient's entire diseased liver just prior to transplanting a donor liver. Furthermore, many patients who undergo hepatic resections will develop a recurrence of liver cancer elsewhere in the liver within several years.
In fact, some experts believe that once a liver develops liver cancer, there is a tendency for that liver to develop other tumors at the same time (synchronous multicentric occurrence) or at a later time (metachronous multicentric occurrence).
This makes sense, since whatever in the liver caused the cancer to develop in the first place is still there. Realistically, though, donor livers are a very limited resource, so many patients who need a transplantation will never receive one.
The results of the various medical treatments available (see below; chemotherapy, chemoembolization, ablation, and proton beam therapy) remain disappointing. Moreover, for reasons noted earlier (primarily the variability in natural history), there have been no systematic study comparisons of the different treatments.
As a result, individual patients will find that the various treatment options available to them depend largely on the local expertise.
How do we know if a particular treatment worked for a particular patient? Well, hopefully, the patient will feel better. However, a clinical response to treatment is usually defined more objectively. Thus, a response is defined as a decrease in the size of the tumor on imaging studies along with a reduction of the alpha-fetoprotein in the blood if the level was elevated prior to treatment.
One thing to keep in mind is that in a relatively healthy patient there is never just one answer to this question. Usually, people go through multiple different treatments sequentially. Something is chosen as the best place to start, and then other treatments are tried once the previous one stops working. The idea is to make sure someone is healthy enough to be able to try another therapy if they still desire it.
Chemotherapy and biotherapy
The most commonly used systemic chemotherapeutic agents are doxorubicin (Adriamycin) and 5-fluorouracil (5 FU). These drugs are used together or in combination with new experimental agents.
These drugs are quite toxic and results have been disappointing. A few studies suggest some benefit with tamoxifen (Nolvadex) but more studies show no advantage at all. Octreotide (Sandostatin) given as an injection was shown in one study to slow down the progression of large liver cancer tumors, but so far, no other studies have confirmed this benefit. Recent studies suggest that combinations of drugs such as gemcitabine, cisplatin, or oxaliplatin can shrink the tumors in some people.
Biotherapy
One of the most important recent advances in the filed of treating liver cancer has been the understanding of the genetic makeup of these tumors, as well as the cancer cells' reliance upon blood vessels and molecules produced in the body that can help them grow.
Many cancers grow by causing the development and recruitment of tiny new blood vessels to feed the tumor and enable it to spread to other parts of the body.
This is called angiogenesis, and this has become a very hot field in oncology and pharmaceutical development over the past decade. One drug, bevacizumab, has been approved for use in many cancers such as colon, lung, and breast, and is known to help standard chemotherapy shrink and control other types of cancer. It might be helpful in liver cancer as well, and similar drugs are still being investigated.
The best success so far has been with the oral drug sorafenib (Nexavar). This is a pill designed to block several components of the angiogenesis pathway, as well as other growth signals for individual cancer cells.
Large studies have shown that patients taking this drug for advanced liver cancer live significantly longer than those taking a placebo pill.
Although the difference was not very long (three months) and is shorter in sicker patients, this is still the first study in decades to show that there is a reliable way to slow down this cancer's growth and to prolong patients' lives.
Sorafenib is thus the first, and so far, only, drug to be approved by the U.S. FDA to treat liver cancer. Current studies are under way to see if the drug works better when combined with other types of chemotherapy.
Hepatic arterial infusion of chemotherapy
The normal liver gets its blood supply from two sources: the portal vein (about 70%) and the hepatic artery (30%).
However, liver cancer gets its blood exclusively from the hepatic artery. Making use of this fact, investigators have delivered chemotherapy agents selectively through the hepatic artery directly to the tumor.
The theoretical advantage is that higher concentrations of the agents can be delivered to the tumors without subjecting the patients to the systemic toxicity of the agents.
In reality, however, much of the chemotherapeutic agents does end up in the rest of the body. Therefore, selective intra-arterial chemotherapy can cause the usual systemic (body-wide) side effects.
In addition, this treatment can result in some regional side effects, such as inflammation of the gallbladder (cholecystitis), intestinal and stomach ulcers, and inflammation of the pancreas (pancreatitis).
Liver cancer patients with advanced cirrhosis may develop liver failure after this treatment. Well then, what is the benefit of intra-arterial chemotherapy? The bottom line is that fewer than 50% of patients will experience a reduction in tumor size.
An interventional radiologist (one who does therapeutic procedures) usually carries out this procedure.
The radiologist must work closely with an oncologist (cancer specialist), who determines the amount of chemotherapy that the patient receives at each session. Some patients may undergo repeat sessions at six- to 12-week intervals.
This procedure is done with the help of fluoroscopy (a type of X-ray) imaging. A catheter (long, narrow tube) is inserted into the femoral artery in the groin and is threaded into the aorta (the main artery of the body).
From the aorta, the catheter is advanced into the hepatic artery. Once the branches of the hepatic artery that feed the liver cancer are identified, the chemotherapy is infused. The whole procedure takes one to two hours, and then the catheter is removed.
The patient generally stays in the hospital overnight for observation. A sandbag is placed over the groin to compress the area where the catheter was inserted into the femoral artery. The nurses periodically check for signs of bleeding from the femoral artery puncture.
They also check for the pulse in the foot on the side of the catheter insertion to be sure that the femoral artery is not blocked as a result of the procedure. (Blockage would be signaled by the absence of a pulse.)
Generally, the liver enzyme tests increase (get worse) during the two to three days after the procedure. This worsening of the liver tests is actually due to death of the tumor (and some non-tumor) cells.
The patient may experience some post-procedure abdominal pain and low-grade fever. However, severe abdominal pain and vomiting suggest that a more serious complication has developed.
Chemoembolization (trans-arterial chemoembolization or TACE)
But in TACE, there is the additional step of blocking (embolizing) the small blood vessels with different types of compounds, such as gel foam or even small metal coils.
Thus, TACE has the advantages of exposing the tumor to high concentrations of chemotherapy and confining the agents locally since they are not carried away by the bloodstream. At the same time, this technique deprives the tumor of its needed blood supply, which can result in the damage or death of the tumor cells.
In fact, TACE originally grew out of the observation that patients undergoing intraarterial chemotherapy who accidentally had their catheters clotted off did better!
By relying upon blocking blood flow to the tumor, TACE will also cause some damage to the surrounding liver, and this is its primary limitation.
Although the tumor may shrink up to 70% of the time, the associated liver damage can cause pain, fever, nausea, infection, fluid accumulation, and rarely, death. Nonetheless, TACE has been shown to be better than no treatment in several studies.
There are newer techniques for delivering chemotherapy intra-arterially and blocking the blood vessels at the same time (microscopic drug-eluting beads); while the side effects seem to be less, it is not clear whether this method is more effective.
While TACE is not suitable for people with very sick livers or who are otherwise medically compromised, it is one of the most widely used techniques to control liver cancer around the world. It is important to realize, though, that it is not a cure and can only control the cancer for a limited time. However, in many individual patients appropriately chosen by their physicians, TACE can help to keep them alive longer.
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