The treatment offering the best chance for long-term survival in all types of hepatocellular cancer is complete surgical removal. Unfortunately, a very small percentage of patients with the common variety of hepatocellular cancer are candidates for surgical treatment because they have severely damaged liver that do not heal or regenerate normally after a partial liver resection.
What are the odds of winning the lottery?
Driving along the streets of your town or city, or down the major or minor highways throughout America, you will eventually encounter a billboard encouraging you to buy a lottery ticket to win the fantastic sum of money invariably displayed on the sign. Billboards are not sufficient; radio and television advertising is commonly employed to solicit participation in state or national lotteries. Once or twice a year the total in the lottery reaches hundreds of millions of dollars, and has even occasionally surpassed one billion dollars. Amounts this large lead to local and sometimes national news broadcast reports to comment on the feeding frenzy of ticket purchases throughout the nation.
Apparently I am inured to the entreaties from outdoor advertising and other media outlets because I do not buy lottery tickets. I have nothing against lottery tickets; it is not a personal issue. I am also not opposed to other individuals buying a lottery ticket. I have occasionally seen a recent lottery winner on the local news holding a check the size of a door displaying a value of tens or hundreds of millions of dollars. I have never seen a single individual who won the lottery frowning, in fact they usually have a huge “I can’t believe this happened” grin on their face.
I don’t buy lottery tickets because I never think to buy one. When I fill my car with gasoline, like many people I pay at the pump so I don’t go into the ever present mini market associated with the gas station. At grocery stores I am a man on a mission. I like to make a list for the week, grab a cart on my way through the double sliding doors, and begin my trip up and down the rows of produce, bakery products, drinks, and food items deemed necessary for my family’s weekly dining needs. Unless I start writing “buy a lottery ticket” on the weekly grocery list, I will not purchase a ticket because it is not on my radar.
What are the odds of winning one of the national big dollar lottery tickets? It is possible to calculate the odds and probabilities of winning hundreds of millions of dollars when intentionally choosing six specific numbers, which are no different from the odds if you allow the computer to pick the six numbers for you. The odds range from approximately 1 in 100,000,000 to 1 in 280,000,000 to win. In other words, if every man, woman, and child in the United States bought a lottery ticket twice a week, the odds suggest there should be one winner for each drawing based on our current population. Obviously, not everybody buys lottery tickets, but some people do make up for those of us who are miscreants by buying more than one set of numbers. I have a friend who admitted to me last year that he has been buying a lottery ticket every week for the last three years. He explained, “If you don’t buy one, you won’t win.” This is clearly a valid and correct statement, but not sufficient to influence me to begin buying tickets. When I pressed him to explain his sudden interest in high stakes, low probability gambling, he reported a winning ticket would cause him to retire immediately from his job and live out his life playing golf, visiting his children, and traveling the world with his wife.
He is still working every day.
You never know, however. One day it may be his grinning face I see holding a door-sized check for outrageously large amounts of money.
What are the odds of getting fibrolamellar hepatocellular cancer?
As usual, I am contemplating seemingly tangential topics because I am thinking about a specific patient of mine. Once or twice a year I meet a young patient with a rare form of liver cancer. This unusual liver malignancy is called fibrolamellar hepatocellular cancer. The fibrolamellar variant of hepatocellular cancer is very rare. There are only about 200 new cases of this type of cancer diagnosed worldwide every year. If we estimate there are currently approximately 7.5 billion people in the world, this equates to 1 in 3,750,000 chance of being diagnosed with this unusual cancer.
The more common form of hepatocellular cancer is a significant public health problem worldwide. There are roughly one million new cases of hepatocellular cancer diagnosed annually around the world. Unfortunately, the long-term survival probability in patients diagnosed with the common type of hepatocellular carcinoma is not good. Less than 5% of patients diagnosed this year with hepatocellular cancer will still be alive five years from now. The majority of patients with hepatocellular cancer have cirrhosis or some type of liver damage from chronic hepatitis B or C virus infection, alcohol abuse, exposure to substances toxic to the liver, or from genetic syndromes causing metabolic disorders leading to liver damage. Patients with the common variant of hepatocellular cancer are usually diagnosed in their 50s, 60s, or 70s.
The fibrolamellar variant of hepatocellular cancer is odd. Unlike garden variety hepatocellular cancer, almost all patients with this liver malignancy have normal, undamaged livers. They rarely show any evidence of hepatitis B or C virus infection, and the average age of patients diagnosed with fibrolamellar hepatocellular cancer is mid-20s. I have seen patients as young as 13 years old, and the oldest patient I have personally seen after being diagnosed with this variant was 38 years old. Patients with fibrolamellar hepatocellular cancer often have large tumors recognized after they produce unexplained upper abdominal pain, or when the patient palpates a mass in their upper abdomen. The majority of patients with the more common, aggressive form of hepatocellular cancer have elevation in a serum tumor marker called alpha fetoprotein, or AFP. In contrast, fibrolamellar patients rarely have elevated blood levels of AFP.
The treatment offering the best chance for long-term survival in all types of hepatocellular cancer is complete surgical removal. Unfortunately, a very small percentage of patients with the common variety of hepatocellular cancer are candidates for surgical treatment because they have severely damaged liver that do not heal or regenerate normally after a partial liver resection. Patients with early stage disease may be candidates for a liver transplant, but very few patients qualify for this option. There is a marked paucity of organs available for transplant, so sadly many patients die while waiting on the list. Patients with common hepatocellular cancer who have metastases to lymph nodes near the liver have a poor prognosis, and very few survive more than one or two years. In contrast, regional lymph node metastases from the fibrolamellar type of liver cancer is not a contraindication to aggressive surgical treatment. There are fibrolamellar hepatocellular cancer patients who may survive for many years despite positive nodes, not dissimilar to the situation with other cancers like colon or breast cancer where lymph node metastasis can be treated successfully.
The patient on my mind was in her late 20s when she was diagnosed with fibrolamellar hepatocellular cancer. She was living what she described as a happy life with her husband in a small town at a latitude far higher than the sub-tropical climate of southeast Texas, and was an active and energetic young woman. She developed some difficulty eating and occasional pain after meals and noticed she was feeling less energetic than usual for her. Not long after, she noticed a firm bulge in her upper abdomen. She quickly made an appointment with her local physician who palpated a mass almost to the level of her umbilicus (belly button) and recognized this was likely associated with her liver. Blood tests were obtained and her liver enzymes were elevated, and a subsequent CT scan revealed a tumor involving the entire left lobe of her liver and extending to the gallbladder in the right lobe of her liver. This tumor was about the size of an extra-large Texas grapefruit. The scan also revealed numerous enlarged lymph nodes behind the stomach and along the blood vessels leading to her liver. A needle biopsy of the easily palpable liver mass was obtained revealing fibrolamellar hepatocellular cancer.
As usual for patients with this disease, this young lady had no risk factors for liver cancer. Her serum AFP level was normal. Scans of the lungs and all other areas showed no evidence of metastatic tumors beyond those in the lymph nodes near the liver. She was referred to one of my medical oncology colleagues.
The patient’s information, CT scans, and biopsy material were reviewed at a multidisciplinary liver cancer conference. The large tumor was occluding some of the blood vessels going to the left lobe of the liver, causing obstruction of bile ducts on the left side of the liver, and was abutting the blood vessels and bile ducts to the right lobe of the liver. It was decided surgical removal was not possible because of the location of the tumor. My medical oncology colleague initiated an aggressive regimen of chemotherapy drugs over the next three months. I met the patient and her family at the beginning of her chemotherapy treatments to introduce myself and to assure her I would follow her closely to consider surgical treatment if she showed reduction in the size of her liver tumor.
“I know this is a big deal, but what other chance do I have?”
When I saw her after her three months of treatment, I was initially stunned. Chemotherapy had caused her to lose all of her hair, including her eyebrows and eyelashes. She was wan, listless, and had dark circles under her eyes. Chemotherapy had knocked her down and left her weakened. Based on her appearance, I was concerned when I pulled up her new CT images I would be in for bad news and progression of her cancer.
My prediction based on her clinical appearance was incorrect. Her liver tumor was dramatically smaller and her tumor-bearing lymph nodes, which had been as large as 3-4 cm in diameter, were reduced to 2 cm in size. The liver tumor was still impinging on the bile ducts and blood vessels to the left lobe of the liver and was near the right lobe blood vessels and ducts, but I judged we had an opportunity to remove the tumor with a negative margin.
I had a long conversation with the patient, her husband, and parents. When I mentioned surgery was possible, her father launched himself out of the seat and nearly knocked me off of the rolling stool in the examination room with an embrace. There were cheers and tears in the room, and it took a few moments to restore some semblance of order to have a serious conversation describing the implications and impact of an operation for this young woman. I explained the operation would require removal of the entire left lobe and a portion of the right lobe of her liver. I would also remove all of the lymph nodes around the blood vessels going to her stomach and liver and these would be sent to our pathologists to evaluate. I told them honestly the presence of lymph node metastases in fibrolamellar hepatocellular cancer meant she had a lower probability of long-term survival and cure, but unlike other forms of liver cancer, this did not mean we had no chance of long-term success.
I ended the conversation with a ten minute diatribe regarding what I considered to be a mandatory accomplishment for me to perform an operation safely. The patient was already a slightly built young woman, and she had lost weight from nausea and malaise induced by her chemotherapy treatments. Her nutritional and energy status was poor. I had one of our nutritionists come into the room with me and we outlined techniques to increase her protein and calorie intake and to push herself with a daily walking program to overcome some of the chemotherapy-induced fatigue and malnutrition.
Three weeks later the patient reappeared the day before her scheduled operation. She was transformed. She had gained almost seven pounds, she was downright peppy, and her smile was dazzling. She informed me she had been eating like a proverbial horse and felt like she could be turned out to run with the horses in the field. We had the perfunctory and required conversation about the expectations of an operation along with the potential risks and complications. She listened intently to all I had to say, nodded once and said, “I know this is a big deal, but what other chance do I have?”
Playing the odds. The odds of her developing this cancer were unbelievably small, but here we were planning a major operation. The next day I began what I predicted would be an approximately four hour long operation. Instead it proved to be a six hour long operation. The intraoperative ultrasound I performed revealed there was a tongue of tumor extending from the large mass in the left liver into the left portal vein and extending slightly into the right portal vein. The operation included complete removal of the left lobe and part of the right liver where the gallbladder lies, and a reconstruction of the right portal vein where I extracted the tumor. Tumor was also near the right bile duct so a portion of this was also removed to assure complete removal of the liver tumor. The right bile duct was also reconstructed and a tube was placed into the duct. All of the enlarged lymph nodes were removed and at the end of the operation, a frozen section analysis by our pathologist indicated all detectable tumor had been removed with negative margins.
Life after surgery
Young patients often bounce back quickly from an operation and this lady was no exception. She was motivated and up walking the next day. However, by the third day after her operation, it was clear she had developed jaundice with a yellow color to her eyes and skin. Her blood tests revealed that her serum bilirubin level had risen. The value continued to rise for two more days and then leveled off. Notably, her pathology results came back showing significant killing of the tumor both in the lymph nodes and in the liver by her chemotherapy regimen, but the chemotherapy had also induced significant damage to the normal liver and had caused stasis, or precipitation and blockage, of bile in the microscopic bile ducts within the liver. We performed scans and other tests and confirmed her bile duct to the right lobe of the liver was open and there was normal blood flow to the liver, but she had high levels of bilirubin in her blood. She was walking, eating, and feeling well; she just had a yellow tint to her eyes and skin.
After I worried about this abnormal blood test for several more days, she insisted I discharge her because she was “bored.” I couldn’t argue with her as I was performing no active interventions on her and her liver function blood tests, including the bilirubin, had stabilized, albeit at an abnormal level. I didn’t realize it then, but this was to be her new set point. When I saw this young lady back in the office a week later, the blood levels of bilirubin had not changed. She was eating and feeling well and had decided she was not going to take any additional chemotherapy because of the severe toxicities she had endured with the initial treatment. I was concerned about her abnormal liver blood tests results, so I asked her to get blood work drawn by her physician in her home town every two weeks and send those results to me.
She dutifully complied and results arrived on my fax machine every other Friday. No change in the results, no improvement and no worsening. I saw her back three months after she was discharged from the hospital and a CT scan revealed her liver had regenerated nicely and there was no evidence of recurrent cancer in the liver, lymph nodes, or other sites. She felt well, had returned to normal activities, and simply looked like she had too much spray on bronzing agent applied. We discussed this at length and decided to watch. A few months later the patient developed a fever. She traveled south and we saw her in the office. Her liver blood tests were no different but her white blood cell count was elevated, indicating a possible infection. A CT scan was obtained which demonstrated a new collection of fluid adjacent to the blood vessels and bile duct at the base of her liver. I arranged for one of our interventional radiologists to put a tube into this fluid and the result was drainage of an infected collection of bile. We placed her on appropriate antibiotics and her fever and infection cleared rapidly. I wondered if placement of this tube might lead to a change in her serum bilirubin levels, but this was not to be. We also followed closely to check for any recurrence of cancer. We could find none based on the CT scans. Our radiologist did a study through the drain and realized there was a small bile duct along the edge of the liver that was open and her main right bile duct was scarred, but open. We decided to leave the drain in until bile leak from the liver resolved. Unfortunately, that never happened.
I continued to see this lady every three months for the next several years and slowly increased the intervals to every four and then every six months. During the first five years after her extensive liver operation, her skin and eye color never changed. She did occasionally develop occlusion of the small drain tube exiting from her abdominal wall, and this problem was always resolved by exchanging the clogged tube for a new one. She was happy when she reached the five-year survival mark after removal of her fibrolamellar hepatocellular cancer because she had been told by her medical oncologists the presence of the lymph node metastasis portended a five-year survival probability of less than forty percent.
I always looked forward to visits by this lady and her family. I quickly learned to walk into the room and immediately announce there were no changes on her scans and no evidence of recurrent cancer. The entire entourage would collectively breathe a sigh of relief, and we would spend the next fifteen minutes talking about events, family trips, or other important life happenings. Despite her medical issues and a chronic external biliary drainage tube, this young lady was always involved in helping other people in her community and church, and always asked about me and my family. She was thoughtful, considerate, and as many of the trainees who worked with me over the years observed, “A really nice person.”
Stroke of fate #2
This routine went on for almost a decade. Unfortunately, we reached a tipping point. She began to develop problems with anemia, low platelet counts, and intermittent bleeding from her intestinal tract. CT scans revealed large dilated blood vessels around her entire upper abdomen, a situation called varices. This indicated the pressure in her liver was high, portal hypertension, and a manifestation of this high venous pressure was dilated blood vessels throughout her abdominal cavity and intestinal system. Her spleen was enlarged and platelets were being consumed, she was anemic from chronic blood loss from the dilated veins in her stomach and intestines. As this situation evolved, she began requiring transfusions of blood or platelets. Slowly, her liver function worsened. Her serum bilirubin levels, which had been stable for years in the high single digit range rose into the teens and into the low twenties. Her skin turned from a bronze color to pumpkin and finally a bright yellow hue. She had survived for over eight years after a diagnosis of advanced fibrolamellar hepatocellular cancer, but her liver was failing. At no point could I detect any evidence of recurrent or metastatic cancer; the combination of the toxic effects from the chemotherapy drugs she received combined with a major liver operation conspired to cause slow but progressive damage to her liver.
She was in her early 40s and otherwise healthy and apparently cancer-free, so I referred her to my colleagues in the liver transplant program. They performed an extensive evaluation and agreed she was an excellent candidate for a transplant. She went through the exhaustive pre-transplant testing and was placed onto the waiting list.
Eventually the day came when she and her family got the call a suitable donor liver had been found. She came into the hospital and I saw her, her husband, and her family in the surgical holding area. She was appropriately anxious. I wished her well, and promised to visit her daily during her hospitalization.
That was the final conversation I had with her. A few hours later my transplant surgery colleagues called me from the operating room. They had encountered an absolute viper’s nest of massively dilated, high pressure veins in and around the liver. She was bleeding vigorously from numerous areas and control of the active bleeding was difficult to maintain. The transplant team finally decided to pack her with sterile gauze pads to hold pressure in an attempt to stabilize her in the intensive care unit. Unfortunately, over the course of the next several hours her liver, kidney, heart, and lung function deteriorated rapidly. I had long conversation with the patient’s husband and parents and informed them she had developed multiple organ failure. This patient had very direct conversations and understanding with her family about end of life issues. She had told them in no uncertain terms she did not wish to be maintained on medications and machines, and it was clear that was the situation we found ourselves in. It is an appalling and painful conversation to have with a patient or their family members, but we discussed her wishes. Everyone agreed she did not want to be on the numerous high dose medications and a ventilator to maintain her blood pressure, heart, and lung function, and she would certainly not want kidney dialysis or other extraordinary means at this point. The decision was made not to withdraw any care, and to maintain her on high doses of pain medication to assure she was comfortable, but we did not escalate, and over the next few hours she quietly and peacefully slipped away.
I don’t like attending funerals, but I was at hers. Some can be morbid events. Hers was not. It was sad, but it was also a celebration of her spirit and the joy she exhibited in her life. I watched this lady over a dozen years bravely manage and enjoy a busy life despite toxic effects of chemotherapy and a major surgical operation. She lived with a plastic tube extruding from her abdominal wall. She was not a victim, she was a victor. She embraced and loved her family and her life, and was always ready and willing to help others. She epitomized unselfish, giving behavior by providing care for others heedless of her needs. She walked the walk.
She was a young patient vexed by an extremely rare cancer which we don’t understand and which she did nothing to cause. The lottery of life odds of her getting this cancer were incomprehensibly low, but she never demonstrated a, “Why me?” attitude. She had a happy soul who went out of her way to be helpful and kind to other people. I admire the positive spirit she and other cancer patients and family members exhibit every day as they survive and deal with the emotional and physical effects of the disease and our treatments.