A 43-year-old woman presents with a sudden onset of abdominal pain approximately 1 hour prior to coming to the emergency center. She denies previous abdominal complaints. Her systolic blood pressure is 88 mm Hg on evaluation and becomes stable at 120 mm Hg after the infusion of 2 L of intravenous fluid. The abdominal examination demonstrates no peritoneal signs, her bowel sounds are hypoactive, and there is mild right upper quadrant tenderness. The hematocrit value is 22%. A computed tomography (CT) scan is performed and demonstrates free intra-abdominal blood and a 5-cm solid mass in the right hepatic lobe with evidence of recent bleeding into the mass. By history, the patient denies recent trauma, weight loss, a change in bowel habits, hematemesis, or hematochezia. The only medication she takes is an oral contraceptive agent, which she has been using without problems for approximately 20 years.
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ANSWERS TO CASE 27: Liver Tumor
Summary: A 43-year-old woman who uses an oral contraceptive presents with acute abdominal pain, hypotension, anemia, and recent intra-abdominal hemorrhage. A CT imaging shows a right hepatic tumor.
• Next steps: Hemodynamic monitoring and admission to the intensive care unit with serial hematocrit determinations are indicated. Once the patient is stable, the etiology of the liver mass should be sought.
• Most likely diagnosis: Hepatic adenoma with hemorrhage.
1. Learn to develop appropriate differential diagnoses for hepatic masses based on patient characteristics and risk factors.
2. Know the pertinent differences in the management of primary and secondary liver masses.
3. Know the natural history and imaging characteristics of liver tumors to avoid unnecessary investigations and operations.
Most patients with liver tumors are asymptomatic or may have only vague symptoms. This patient’s dramatic presentation is unusual when compared to that of all patients with liver tumors but represents a classic presentation of hepatic adenoma complicated by hemorrhage. Hepatic adenomas were quite uncommon prior to the introduction of oral contraceptives, but this disease process is now recognized as being associated with exposure to estrogenic compounds. Benign focal liver masses are present in 9% to 10% of the general population, and most of these individuals are asymptomatic and can be treated with observation. Hepatic adenoma is an exception to this rule. Because of the propensity of these tumors to produce symptoms, cause hemorrhage, and undergo malignant transformation, most patients with hepatic adenomas should be under further evaluation and in many cases patients are advised to undergo tumor resection. Malignant degeneration of adenoma to hepatocellular carcinoma is reported to occur in 5% to 11% of patients with adenomas, occurring almost exclusively in adenoma greater than 5 cm. Most hepatic adenomas are hormonally stimulated; therefore, some patients with small asymptomatic adenomas can be initially treated with cessation of the use of oral contraceptives and close surveillance at 3- to 6-month intervals.
Recently, the molecular biology of hepatic adenomas has been elucidated, where the adenomas can be subcategorized as inflammatory, those containing hepatocyte nuclear factor 1 (HNF-1) alpha mutations, and those with β-catenin activation. The inflammatory type has increased risk for bleeding but low risk for malignant transformation. The HNF-1 alpha mutated type has no risk of malignant transformation or of bleeding. The β-catenin activated type has increased risk of malignant transformation and is often seen in patients with glycogen storage diseases.
APPROACH TO: Hepatic Tumors
PRIMARY LIVER TUMOR: A tumor originating from hepatocyte, bile duct epithelial, or mesenchymal tissue within the liver. This tumor may be benign, have a potential for malignant transformation, or be frankly malignant. The most common primary malignant tumors in adults are hepatocellular carcinoma and cholangiocarcinoma; the most common benign tumors are hemangioma, adenoma, and focal nodular hyperplasia.
SECONDARY LIVER TUMOR: A tumor that arises from tissue outside the liver and spreads to the liver by a metastatic process. This tumor is by definition malignant. The most common metastatic tumors found in the liver are colorectal carcinomas.
BENIGN TUMOR: A tumor that does not have the biologic ability to spread via the lymphatic or vascular system. This type of tumor may cause significant symptoms or may be locally aggressive.
MALIGNANT TUMOR: A tumor with the potential to spread by either a lymphatic or a hematogenous route.
FOCAL NODULAR HYPERPLASIA (FNH): The second most common benign liver tumor occurring most commonly in reproductive-age women. Most FNHs are asymptomatic and are discovered incidentally. An FNH is a truly benign tumor without malignant potential. Some FNHs may be difficult to distinguish from adenomas on the basis of radiographic criteria, and typical appearance is a “central scar” pattern on a CT scan. Biopsy may be needed if the tumor cannot be differentiated from hepatic adenoma. Surgery is indicated when malignancy cannot be excluded or when FNH produces severe symptoms. A telangiectatic variant of FNH has been described and is observed to undergo malignant degeneration; therefore, this tumor variant has been recently reclassified as hepatic adenoma.
HEMANGIOMA: The most common benign liver tumor. This lesion may produce vague abdominal pain but frequently is asymptomatic. Spontaneous rupture is rare. The diagnosis may be made on the basis of contrast CT imaging, magnetic resonance imaging (MRI), or tagged red blood cell scan. Biopsy is contraindicated because it may result in life-threatening hemorrhage. Indications for surgery are severe symptoms, inability to rule out the possibility of malignancy, and rupture.
Liver tumors may be found incidentally or during the evaluation of nonspecific abdominal symptoms; however, more frequently, they are identified in patients at risk for primary or secondary liver tumors (eg, a patient with cirrhosis or with a history of advanced breast carcinoma who develops upper abdominal pain). The approach to a hepatic mass in a patient begins with a thorough history and physical examination, imaging studies, measurement of serum tumor markers, and in some cases tissue biopsy. The primary goals of the evaluation are to determine whether the lesion in question is a primary versus a secondary liver tumor, characterize the nature of the tumor, and define the location and local extent of the mass.
Imaging Liver Tumors
Selection of the imaging modality is perhaps the most crucial aspect of the evaluation. Proper selection of imaging studies may help establish the diagnosis of many liver tumors, thus avoiding unnecessary biopsies and/or operations for some patients. Although liver tumors are readily visualized by ultrasonography and CT scans, these images generally provide insufficient information for patient treatment. CT with angioportography (triphasic CT), MRI, angiography, and laparoscopic ultrasonography are the modalities available for the further characterization of liver tumors. Table 27–1 lists the imaging selection criteria for primary and secondary liver tumors. It is important to bear in mind that visualization of liver lesions can be severely limited when the background liver contains abnormalities such as fatty changes, fibrosis, and cirrhosis. Evaluation of the explanted livers from liver transplant recipients shows that CT scan performed prior to explantation identifies only 68% to 77% of the hepatocellular carcinomas that were subsequently identified in the explanted livers.
Table 27–1 • IMAGING MODALITIES FOR LIVER TUMORS
Secondary Liver Tumors
The liver is a frequent site of malignant metastasis, most commonly involving colorectal carcinoma. Listed here are the characteristics associated with secondary liver tumors.
1. Resection of a primary tumor with known metastatic potential within the previous 5 years (eg, a history of stage III adenocarcinoma 2 years previously).
2. Current signs and symptoms of an untreated primary tumor with known meta-static potential (eg, a large left breast mass and multiple hepatic lesions in a 74-year-old woman).
3. Miliary or diffuse distribution of hepatic lesions.
4. Significant elevation of tumor marker levels (>10-fold) in the setting of a new liver mass.
When a secondary liver tumor of unknown primary origin is identified, an investigation to identify the primary malignancy should be undertaken. Important in this evaluation are the history and physical examination. Weight loss, a history of new narrow-caliber stools, and a rectal examination with Hemoccult-positive results should prompt further gastrointestinal tract evaluation. A history of long-time smoking in a man older than 50 years with hematemesis and a new hilar mass seen on chest radiography should prompt further evaluation of the respiratory tract, including a cytologic examination of the sputum, bronchoscopy, and subsequent CT-guided biopsy. The search for the primary tumor is important not only in treating the primary site but also in considering treatment of the liver metastasis. Although the presence of liver metastasis frequently indicates an advanced tumor stage and may preclude the possibility of cure, certain tumor types and distribution in carefully selected patients are amenable to curative resection or ablative therapy. A five-point clinical prognostic scoring system is generally applied to predict survival for patients undergoing liver resection for colorectal metastasis (Table 27–2). Liver transplantation has no role in the treatment of patients with secondary liver tumors.
Table 27–2 • FIVE-POINT SCORING SYSTEMa FOR PATIENTS UNDERGOING LIVER RESECTION FOR METASTATIC COLORECTAL CANCER
Primary Liver Tumors
Tumor markers are invaluable tools in the evaluation of both secondary and primary liver masses. Although the specificity of most tumor markers for a given primary cancer is not high, these assays are sensitive in most cases and are an important part of the workup for liver masses. Table 27–3 lists some of the primary tumor markers that are helpful in the diagnosis of liver masses.
Table 27–3 • TUMOR MARKERS POTENTIALLY USEFUL FOR IDENTIFYING THE ORIGIN OF SECONDARY LIVER TUMORS
Many liver tumors are either cancerous or have significant premalignant potential and significant morbidity such as bleeding or the production of abdominal pain. For this reason, early surgical consultation is recommended to facilitate the appropriate workup and diagnosis. When appropriate imaging studies are unable to verify the lesion as a tumor without malignant potential, biopsy of the mass or masses may be needed to determine the tumor type and subsequent therapy. Liver resection is both safe and in many cases may provide either a cure or long-term survival benefits. The cornerstone of workup for a liver mass is the development of an appropriate differential diagnosis based on history and physical examination and appropriate imaging to facilitate diagnosis.
27.1 A 30-year-old woman is noted to have a hepatic mass on laparoscopy for a sterilization procedure. She undergoes a liver biopsy that reveals focal nodular hyperplasia. Which of the following is the most accurate statement regarding this condition?
A. These tumors have malignant potential over 10 to 20 years.
B. Surgical excision is often the best therapy.
C. Angiography has high sensitivity and specificity for the diagnosis of this tumor.
D. Oral contraceptive use is a risk factor.
E. These lesions generally pose a problem during pregnancy.
27.2 A 65-year-old man is found to have a 6-cm mass in his liver on sonography of his gallbladder. He has a history of hepatitis B surface antigen present on serology, but his liver transaminase levels are within normal limits. Which of the following is the most appropriate therapy for this patient?
A. Superior mesenteric artery embolization procedure
B. Liver transplant
C. Intravenous interferon therapy
D. Prolonged antibiotic therapy for probable amebic abscess
E. Surgical resection
27.3 A 75-year-old icteric woman is noted to have multiple lesions in her liver that on CT imaging are suspicious for metastatic cancer. Which of the following is the most likely source of the primary cancer?
27.4 A 47-year-old man undergoes right colectomy for adenocarcinoma of the cecum that was causing obstructive symptoms. At the time of the operation, the 10-cm tumor appears to be confined to the cecum, several 2- to 3-cm lymph nodes are seen in the mesentery of the right colon, two metastatic deposits measuring 3 cm are noted on the right lobe of the liver, and three metastatic deposits measuring 2 cm are found in the left lobe. Which of the following is the most appropriate treatment option?
A. Biopsy the cecal mass, lymph nodes, liver tumors, and terminate the procedure.
B. Remove the right colon including the enlarged mesenteric lymph nodes, completely resect the liver tumors, and refer the patient for chemotherapy.
C. Remove the right colon including the enlarged mesenteric lymph nodes, biopsy the liver, and refer the patient for liver transplant.
D. Biopsy the colon mass, the liver mass, and refer the patient for systemic chemotherapy.
E. Remove the right colon including the enlarged mesenteric lymph nodes, biopsy the liver lesion, and refer the patient for chemotherapy.
27.5 A 46-year-old woman who underwent an abdominal CT scan for evaluation of nephrolithiasis was noted to have a 5-cm mass in the right lobe of the liver. A CT scan with contrast was done that revealed early contrast enhancement with peripheral outlining of the mass. The patient is asymptomatic from the standpoint of the liver mass. Which of the following is the most appropriate management?
A. Obtain serum alpha-fetal protein measurement and obtain a CT-guided biopsy to rule out hepatocellular carcinoma.
B. Perform colonoscopy to evaluate for a possible colorectal primary cancer.
C. Observe the patient clinically and repeat the imaging if the patient becomes symptomatic.
D. Refer the patient for liver transplant.
E. Perform a right hepatic resection.
27.1 C. Focal nodular hyperplasia is the second most common hepatic tumor. It is not associated with oral contraceptive use and is usually asymptomatic. It has no malignant potential and rarely needs biopsy for diagnosis because angiography is an excellent diagnostic tool for this disorder.
27.2 B. This patient is at risk for hepatocellular carcinoma because he has a large hepatic mass and a likely chronic hepatitis B infection (surface antigen positive). Surgical resection is the best therapy for early-stage disease and the only hope for cure in this condition. Interferon therapy is used for hepatitis C disease.
27.3 C. The colon is the most common primary site when metastatic disease is found in the liver.
27.4 E. Resection of the right colon, biopsy of the liver tumors, and chemotherapy are appropriate for this individual with apparent stage IV colon cancer. Resection of the liver tumor at this time is probably of limited benefit and may pose unnecessary morbidity for the patient. Liver transplant is not an option for patients with metastatic liver tumors. Because this patient has obstructive symptoms, concluding the operation without performing a colectomy to relieve the obstruction may place the patient at risk for continued obstruction and a worse quality of life.
27.5 C. The description of her presentation and CT findings are consistent with an asymptomatic liver hemangioma, which is a benign tumor with no malignant potential. Treatment in an asymptomatic patient is not indicated. Biopsy of hemangiomas should not be obtained because of the risk of bleeding; furthermore, CT findings are generally highly specific for diagnosis.
Hemangiomas are the most common benign tumors of the liver and usually asymptomatic.
Hepatic adenomas are associated with estrogen use and should be excised because of the risk of hemorrhage or malignant transformation.
The most common metastatic disease to the liver is colorectal cancer. Because of the risk of hemorrhage, hepatic hemangiomas should be ruled out prior to needle biopsy.
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