Malignant Liver Neoplasms


Primary Tumors

  1. Hepatocellular Carcinoma (HCC)
    1. Incidence
      • most common cancer worldwide
      • extremely common in Asia and Africa; relatively uncommon in Western Europe and the United States
      • ~25,000 cases / year in the U.S.
      • long-term survival is ~5%

    2. Etiology
      • closely associated with cirrhosis from chronic hepatitis B and C infection and alcohol abuse (chronic liver injury)
      • aflatoxins of the mold Aspergillus flavus contaminate the diet of many Asian and African communities
      • many chemicals have been implicated as hepatic carcinogens: nitrites, solvents, pesticides, vinyl chloride, Thorotrast
      • obesity, nonalcoholic fatty liver disease and nonalcoholic steatohepatitis are now important risk factors
      • no clear relationship between OCPs and anabolic steroids

    3. Pathology
      • may present as a single, large nodule, as multiple nodules, or as a diffuse permeation throughout the organ
      • vascularity is a prominent feature
      • frequently invades branches of the portal vein or hepatic vein

    4. Clinical Manifestations
      • small tumors may be asymptomatic and detected only by routine surveillance in high-risk patients

      1. Symptomatic Patients
        • weight loss and weakness occur in 80%
        • upper abdominal pain
        • palpable upper abdominal mass
        • hypoglycemia or hypocalcemia may rarely occur as the result of a paraneoplastic syndrome
        • physical signs may include hepatomegaly, jaundice, ascites, peripheral edema, and the manifestations of portal hypertension

    5. Imaging
      1. Ultrasound
        • important in screening and early detection in high-risk patients

      2. CT Scan or MRI
        • contrast-enhanced CT and/or MRI are the imaging studies of choice and take advantage of the hypervascularity of these tumors
        • arterial-phase images are mandatory to assess the extent of disease adequately
        • typical features of HCC on imaging are an arterially-enhancing mass with washout of contrast in delayed phases
        • MRI may be superior to CT in detecting HCC in cirrhotic livers
        • lesions can be stratified into LI-RADS risk categories based on radiologic criteria

        CT Scan - Hepatocellular Carcinoma
    6. Tumor Markers
      • alpha-fetoprotein (AFP) has low sensitivity and specificity
      • specificity and positive predictive value improves with higher cutoff levels (400 ng/mL)
      • AFP is most useful in monitoring recurrence in treated patients
      • most consistently elevated liver function test is alkaline phosphatase

    7. Biopsy
      • not usually necessary since most cases of HCC can be diagnosed by imaging
      • most common indication is for LR-4 cases where a tissue diagnosis is required to initiate treatment (ablation, liver transplantation)

    8. Metastatic Workup
      • most common metastatic sites are the lung, abdominal lymph nodes, bone, and peritoneum
      • CT chest is mandatory since lung metastases are often symptomatic
      • bone scan should be done only if symptoms suggest disease
      • extent of disease in the liver must also be fully determined

    9. Assessment of Hepatic Reserve
      • critical in determining treatment options for a patient
      • only ~ 10% of patients with HCC have adequate hepatic reserve to undergo resection
      • risk of postoperative liver failure after resection is related to the degree of cirrhosis, portal hypertension, amount of liver resected, and regenerative potential of the liver remnant
      • Child-Pugh classification or MELD score are commonly used to determine if a cirrhotic patient can safely undergo a major liver resection, but these tools are inaccurate for predicting which patients have adequate reserve to tolerate a major hepatic resection

      1. Future Liver Remnant (FLR)
        • FLR = total liver volume – planned resection volume, as calculated on three-dimensional CT volumetry
        • in a noncirrhotic patient, an FLR of 20% is adequate; in a cirrhotic patient, an FLR of 40% is usually adequate
        • portal vein embolization can be used to induce hypertrophy of the future liver remnant, allowing for a more extensive resection

        Portovenous Embolization
    10. Staging System
      • TNM system does not predict survival since it does not take into account underlying liver function or performance status
      • several different staging systems are in use: Barcelona Clinic Liver Cancer (BCLC), Okuda, and Cancer of the Liver Italian Program Score (CLIP)

      1. Cancer of the Liver Italian Program Score (CLIP)
        • most well validated prognostic system
        • a score of 0 - 3 has the potential for long-term survival

        CLIP Score
    11. Treatment
      1. Surgical Resection
        • offered to patients with resectable disease and adequate hepatic reserve
        • anatomic resections (lobectomy, segmentectomy) are preferred when feasible
        • nonanatomic resections may be necessary to minimize the loss of functioning liver tissue
        • main predictors of survival are tumor size, number of tumors, and the presence of portal or hepatic vein invasion

      2. Liver Transplantation
        • ultimate surgical resection
        • not indicated in patients with tumors unresectable by standard approaches (20% 2-year survival)
        • treatment of choice for patients with small tumors and advanced cirrhosis
        • removes both the tumor and the underlying liver disease
        • Milan criteria are used to guide patient selection: solitary tumor up to 5 cm, or three tumors up to 3 cm each
        • 5-year survival rate of 70% when the Milan criteria are followed
        • because of long wait times for a liver, bridging strategies using RFA and TACE can be used to keep tumors within the Milan criteria

        Milan and UCSF Criteria
      3. Cryoablation/Radiofrequency/Microwave Ablation
        • may be used for patients who will not tolerate a resection
        • may also be used for patients who have multiple tumor nodules
        • could conceivably be combined with surgical resection
        • may be done percutaneously, laparoscopically, or open
        • heat sink effect of major blood vessels limits usefulness, as does a high complication rate

      4. Transarterial Therapy
        • transarterial embolization, transarterial chemoembolization (TACE) are associated with response rates as high as 80%
        • complications include postembolization syndrome (fever and abdominal pain), pancreatitis, gallbladder infarction, hepatic insufficiency, sepsis
        • interval treatments required every 3 – 6 months

      5. Chemotherapy
        • systemic chemotherapy is ineffective
        • sorafenib, which inhibits cell growth and angiogenesis, confers a small survival advantage over placebo

  2. Fibrolamellar Carcinoma (FLC)
    1. Epidemiology
      • accounts for < 1% of all primary liver tumors
      • occurs mainly in young patients (average age of diagnosis = 39)
      • cirrhosis and chronic viral hepatitis are not risk factors
      • has a much more favorable prognosis than HCC

    2. Clinical Presentation
      • most common symptoms are abdominal pain, abdominal mass and/or distention, anorexia, and weight loss
      • patients may also present with metastatic disease to the regional nodes, lungs, and peritoneum

    3. Diagnosis
      1. CT Scan
        • FLC appears as a large, sharply defined, heterogeneously enhancing mass within a noncirrhotic liver
        • often contains a central scar, making distinction with FNH difficult

      2. MRI
        • central scar is hypointense, unlike the central scar in FNH, which is hyperintense

        MRI - Fibrolamellar Carcinoma
        Arrowhead: portal vein thrombosis.  Arrow: hypointense central scar.

      3. Tumor Markers
        • AFP is usually negative, and rarely elevated over 200
        • neurotensin is elevated in some patients, suggesting that FNH may be a neuroendocrine tumor

    4. Management
      • surgical resection with regional lymphadenopathy is the primary treatment
      • since the patients are young and have noncirrhotic livers, extensive resections are well-tolerated
      • there is minimal experience with liver transplantation for FLC, and these patients are not prioritized on the transplant list

  3. Intrahepatic Cholangiocarcinoma (IHC)
    • second most common primary hepatic neoplasm
    • also associated with viral hepatitis and cirrhosis
    • intrahepatic bile duct cancers have a similar presentation and similar treatment as for HCC
    • pathologically, cannot distinguish IHC from metastatic adenocarcinoma, so IHC is a diagnosis of exclusion
    • alkaline phosphatase is typically elevated, and serum bilirubin is normal or slightly elevated
    • AFP levels are normal
    • CA 19-9 or CEA levels may be elevated

Metastatic Tumors

  • by far the most common malignant tumors of the liver
  • Approximately 40% of patients dying of a solid tumor will have liver metastases

  1. Colorectal Metastases
    1. Incidence
      • > 50,000 cases/year of colorectal metastases in the United States
      • most of these are associated with widespread disease or unresectable liver disease
      • a small number of patients will have isolated metastatic disease amenable to resection or ablation
      • in these few patients, long-term survival and cure are possible

      Unresectable and Resectable Liver Metastases
    2. Presentation
      • symptomatic patients (pain, ascites, weight loss, jaundice) will rarely be candidates for liver resection
      • mild elevations in LFTs are common in metastatic disease, but they are not effective as screening tools
      • most resectable patients are found by serial imaging and rising CEA levels
      • rising CEA and a solid mass on CT scan is diagnostic of metastatic disease

    3. Metastatic workup
      • if a patient is a surgical candidate, a complete metastatic workup must be done
      • colonoscopy rules out local recurrence or a metachronous lesion
      • CT abdomen/pelvis rules out additional abdominal disease
      • PET/CT has not been proven to be superior to CT in looking for occult metastatic disease
      • in select patients, laparoscopy will spare patients a nontherapeutic laparotomy

    4. Natural History
      • retrospective studies have shown that untreated, but potentially resectable, liver metastases are associated with a 10% 3-year survival and a 2% 5-year survival rate
      • 5-FU chemotherapy is ineffective as sole therapy (median survival of 12 months)
      • modern combination chemotherapy with targeted anti-angiogenic antibodies or anti-epidermal growth factor antibodies show response rates of 50% and median survival of 20 months, but durable responses and 5-year survival are rare
      • multiple studies show that in carefully selected patients, resection of liver metastases can result in 25% - 58% 5-year survival and a 20% 10-year survival

      Milan and UCSF Criteria
    5. Prognostic Factors
      • predictors of poor outcome following resection: node-positive primary tumor, disease-free interval < 12 months, more than one tumor, tumor size > 5 cm, CEA > 200 ng/mL
      • traditionally, resection was only offered if there were less than 4 metastases
      • recent reports suggest that resection for 4 or more metastases can be done with the expectation of good results (33% 5-year survival)
      • resectability is now defined by the volume of the future liver remnant and overall liver health, rather than the number of tumors removed
      • close or involved margins do not preclude long-term survival, but overall, these patients do poorly
      • limited extrahepatic metastases (lung) may be resected simultaneously with liver metastases in highly selected cases

      Clinical Risk Score
  2. Neuroendocrine Metastases
    1. Natural History
      • slow-growing, indolent tumors for which long-term survival, even without treatment, is possible
      • tumors often secrete functional hormones, which can result in debilitating endocrinopathies

    2. Treatment
      • octreotide, a long-acting somatostatin analogue, alleviates hormonal symptoms and may have a cytostatic role as well
      • hepatic artery embolization and thermoablative techniques may also reduce the tumor load and improve hormonal symptoms

      1. Liver Resection
        • can be considered if all the liver disease can be resected
        • aggressive debulking (90% tumor removal) can be considered if the patient has refractory hormonal symptoms that have failed medical management
        • thermoablative approaches can also be considered







References

  1. Sabiston, 20th ed., pgs 1458 – 1469
  2. Schwartz, 10th ed., 1291 - 1296
  3. Cameron, 11th ed., pgs 328 – 332, 332 – 335
  4. UpToDate. Clinical Features and Diagnosis of Hepatocellular Carcinoma. Jonathan M Schwartz, MD, Robert L Carithers, Jr, MD, Claude B Sirin, MD. Apr 22, 2019. Pgs 1 – 32
  5. UpToDate. Overview of Treatment Approaches for Hepatocellular Carcinoma. Eddie K Abdalla, MD, FACS, Keith E. Stuart, MD. Apr 14, 2020. Pgs 1 - 29
  6. UpToDate. Epidemiology, Clinical Manifestations, Diagnosis, and Treatment of Fibrolamellar Carcinoma. Richard S Kalman, MD, Ghassan K Abou-Alfa, MD. Sep 05, 2019. Pgs 1 – 23