ESOPHAGEAL CANCER
GENERAL PRINCIPLES
Definition
Primary carcinoma that arises from the cricopharyngeal sphincter to the gastroesophageal junction
Classification
Site: divided into upper, middle, and lower third.
Histology: most commonly adenocarcinoma (occurs predominantly at lower third of esophagus) and squamous cell carcinoma (occurs predominantly at middle and upper third); other less common types include mucoepidermoid carcinoma, small-cell carcinoma, sarcoma, leiomyosarcoma, and primary lymphoma.
Epidemiology
The incidence in the United States is ~5 per 100,000, although in African American men it may be as high as 18 per 100,000. China and Iran have an incidence of 20 per 100,000.
In the United States, 16,640 new cases and 14,500 deaths from this cancer were estimated in 2010. It is the seventh leading cause of cancer death in men.
Age: 6th to 7th decades.
Sex: M:F, 3 to 4:1.
Race: in the United States, esophageal adenocarcinomas are more common in white males, whereas squamous cell carcinomas are more common in African Americans.
Socioeconomic status: Lower socioeconomic status as defined by income, occupation, and education are associated with higher risk for squamous cell carcinoma.
Histology: in the United States, squamous cell carcinoma used to be the more prominent type until the early 1990s when it was surpassed by adenocarcinoma. Such shift is believed to be due to increased incidence of GERD, Barrett’s esophagus, and obesity.
Etiology and Pathophysiology
The exact etiology of esophageal carcinoma remains unclear but likely is an evolution of oncogenic changes within the esophageal epithelium following chronic exposure to known carcinogens or chronic irritation by gastric acid in patients with GERD. Conversely, patients with chronic atrophic gastritis caused by cagA-positive Helicobacter pylori are associated with decreased risk of esophageal adenocarcinoma.
Risk Factors
Alcohol, tobacco, nitrosamines, GERD, Barrett’s esophagus, obesity, Plummer– Vinson syndrome, history of head and neck cancer
High-fat, low-calorie, and low-protein diet
Prevention
Cessation from smoking and alcohol consumption
Raw fruits and vegetables, fibers, selenium, as well as vitamins A, C, and E
Associated Conditions
Barrett’s esophagus (30- to 125-fold increased risk of developing adenocarcinoma), Howel–Evans syndrome
DIAGNOSIS
Clinical Presentation
History
Due to the lack of initial symptoms, most cases are diagnosed at advanced stage. Typical presenting symptoms are dysphagia (95%), which typically progressed from solid to liquid, body weight loss (50%), odynophagia (20%), and gastric reflux (40%). Extraesophageal spread can cause pain, cough (20%), hoarseness (secondary to recurrent laryngeal nerve involvement), aspiration, tracheal narrowing, or tracheoesophageal fistula.
Physical Examination
Most patients lack obvious physical findings, but cervical or supraclavicular adenopathy may be appreciated in patients with nodal metastasis.
Diagnostic Criteria
Histopathologic diagnosis from endoscopic biopsy and/or transcutaneous lymph node biopsy (if applicable) is required.
Differential Diagnosis
Barrett’s esophagus, esophageal stricture, achalasia, gastric cancer
Diagnostic Testing
Laboratories
Complete blood count (CBC), comprehensive metabolic panel (CMP), prothrombin time (PT), partial thromboplastin time (PTT), and iron studies
Initial Diagnostic Test
Upper endoscopy with directed biopsy is the current gold standard.
Barium studies may show strictures or intraluminal lesions, but they are less sensitive and do not allow for biopsy.
Imaging Studies
Once the diagnosis is established, an initial CT scan of chest, abdomen with IV and oral contrast should be obtained to assess extent of primary disease, nodal and distant organ metastasis.
Bone scan is indicated in patients with bone pain or elevated alkaline phosphatase.
If no distant metastasis is seen from the initial CT scan, more sensitive diagnostic tests should be performed to provide more accurate staging. A positron emission tomography (PET) or PET-CT scan (preferred by the NCCN guideline) should be obtained. They have a higher sensitivity and specificity than conventional CT scan in detecting nodal and distant metastasis. In many medical centers, this PET scan has become part of the standard preoperative workup. If indicated, FDG-avid lymph nodes should be biopsied to confirm metastasis.
Diagnostic Procedures
Once distant metastasis is excluded by PET scan, an endoscopic ultrasonography (EUS) should be performed. This procedure allows the most precise assessment of tumor depth, length of esophagus affected, and magnitude of lymph node metastases, particularly paraesophageal and celiac nodes. A fine-needle aspiration of suspicious lymph nodes can be done during the study.
Patients presenting with cough, symptoms or radiographic evidence of aspiration pneumonia, tumor abutting/invading the trachea at or above carina should receive bronchoscopy to assess tracheal invasion or tracheoesophageal fistula.
TREATMENT
Treatment is based on TNM stage (Table 21-1):
Stage 0. Endoscopic mucosal resection followed by periodic surveillance
Stage I.
Esophagectomy if patients are medically fit, with esophageal carcinoma at mid or lower third esophagus, or if they have adenocarcinoma.
Concurrent chemoradiation is preferred for cancer in the upper third esophagus and is an alternative for patients who are not surgical candidates.
Stage II, III, or Iva.
Esophagectomy with regional lymphadenectomy is the main treatment, but is inadequate.
Neoadjuvant therapies with chemotherapy, radiation, or in combination have been studied, and conflicting results have been obtained.1 Current NCCN guidelines support the use of neoadjuvant chemoradiation in medically fit patients. Patients with adenocarcinoma of distal esophagus or gastroesophageal junction should receive neoadjuvant chemotherapy (epirubicin, cisplatin, and 5-FU) before esophagectomy.
Adjuvant chemoradiotherapy clearly has a role in the treatment of esophageal cancer. The most common regimen is cisplatin plus 5-FU with daily irradiation.
Patients with gross (R2 resection) or microscopic (R1 resection) residual disease following surgery should receive combined chemoradiation.
Adjuvant chemoradiotherapy in patients without residual disease (R0 resection) is less defined. In the current NCCN guidelines, observation is recommended for those with squamous cell carcinoma. Patients with adenocarcinoma, lymph node–positive disease, or large tumors (≥T3) should receive chemoradiotherapy.
Patients with localized unresectable disease or who are medically unfit for surgery should be considered for definitive chemoradiation consisting of cisplatin, 5-FU, plus daily irradiation. 2
Stage IVb. Metastatic esophageal cancer is incurable with a median survival of 9 months. Several chemotherapeutic agents including cisplatin, carboplatin, 5-FU, paclitaxel, docetaxel, vinorelbine, oxaliplatin, and irinotecan are commonly used.
In general, platinum-based doublets have the highest response rate and are typically used as first-line therapy.
Addition of cetuximab to platinum-based doublets can be considered in patients with epidermal growth factor receptor (EGFR)-overexpressing tumor.
Targeted therapies such as erlotinib and gefitinib as second-line monotherapy have been shown to offer some benefit to a small number of patients and can be considered for patients who cannot tolerate cytotoxic chemotherapy.
Other Non-Pharmacologic Therapies
Palliative care in swallowing and nutritional support is especially important. This includes esophageal dilation, stent placement, brachytherapy, external-beam radiation, and laser therapy. Patients with metastatic esophageal cancer frequently require a gastrostomy tube.
Lifestyle/Risk Modification
All patients should be encouraged to cease smoking and consuming alcohol. Patients with gastroesophageal reflux should be managed by dietary modification, exercise, and, if necessary, treated medically with H2-blockers or proton pump inhibitors.
Diet
Increase consumption of fresh fruits and vegetables and dietary fibers, and abstain from alcohol and high-fat diet.
Activity
Overweight or obese patients should be encouraged to exercise and lose weight.
COMPLICATIONS
Hemorrhage, obstruction, tracheoesophageal fistula, aspiration pneumonia, and mediastinitis.
REFERRAL
Nutritional consult should be obtained for all patients undergoing treatment of esophageal cancer.
MONITORING/FOLLOW-UP
Patients with Barrett’s metaplasia should receive surveillance endoscopy at least every 12 months with biopsy taken.
After definitive treatment, asymptomatic patients should typically be evaluated by history and physical examination every 3 months for 2 years, and then every 6 months for 3 additional years. CBC and CMP should be obtained during each routine follow-up, and imaging studies such as CT scan should be obtained at least every 6 months in the first 1 to 3 years or when clinically indicated.
OUTCOME/PROGNOSIS
The most important prognostic factor is initial staging; others include age, performance status, and weight loss (>10%). Neither histology nor grade has been shown to affect prognosis. Molecular profiling of tumor cells is an area of active investigation.
Five-year survival rates are >90% (stage 0), 70% to 80% (stage I), 10% to 30% (stage II), 5% to 10% (stage III), and rare in stage IV disease.
GASTRIC CANCER
GENERAL PRINCIPLES
Definition
Cancer that arises between the gastroesophageal junction and pylorus
Classification
Histology:
Adenocarcinoma (95%), primary lymphoma such as non-Hodgkin’s lymphoma, MALToma, GI stromal tumor (GIST), leiomyosarcoma, squamous cell carcinoma, small cell carcinoma, and carcinoid
Lauren classification of gastric adenocarcinoma:
Intestinal type: more common in Japan, associated with diet and possibly H. pylori infection
Diffuse type: more common in the United States, not associated with diet, associated with poorer outcome
Mixed type
Borrmann classification of gastric adenocarcinoma:
Type 1 (polypoid), II (ulcerated), III (ulcerated infiltrating), IV (diffusely infiltrating or linitis plastica)
Epidemiology
Gastric cancer is a relatively less common cancer in the United States but much more common in eastern Asia, especially Japan. It is the second most common cause of cancer deaths in the world.
In the United States, 21,000 new cases and 10,570 deaths from this cancer were estimated in 2010. Incidence and mortality of gastric cancer have been declining in the United States.
Age: 7th decade.
Sex: M:F, 2 to 3:1.
Race: slightly more frequent in African American than Caucasian.
Etiology and Pathophysiology
Oncogenic mutation of K-Ras and H-Ras, overexpression of Her2/neu and c-met, and loss of p53 are among the common genetic changes found in gastric adenocarcinoma.
C-kit (90% to 95%) or PDGFR (5%) mutations are found in most GISTs. MALT lymphomas are frequently associated with H. pylori infection and can be cured with antibiotics alone.
Risk Factors
History of atrophic gastritis or pernicious anemia, cigarette smoking, alcohol, H. pylori infection, chronic gastric ulcer, Barrett’s esophagitis, high salt, nitrate intake, smoked or pickled food, family history of gastric cancer.
Patients with germline E-cadherin (CDH1 gene) mutation are at extremely high risk of developing gastric cancer at young age.
Prevention
Because H. pylori infection is associated with 40% to 50% of gastric adenocarcinomas, it should be actively eradicated when diagnosed. Patients diagnosed with gastric ulcer should undergo repeat endoscopic surveillance in 3 to 6 months.
DIAGNOSIS
Clinical Presentation
History
Most gastric carcinomas are diagnosed at an advanced stage due to the lack of early warning symptoms. Most patients present with nonspecific constitutional symptoms such as weight loss (~80%), anorexia, fatigue, vague stomach pain, hematemesis (~15%), dysphagia (from gastroesophageal junction tumors), and vomiting (from gastric outlet obstruction).
Patients with GIST typically present with bleeding such as hematemesis, tarry stools or melena, epigastric pain, and nausea.
Physical Examination
The physical findings in gastric carcinoma are typically manifestations of metastatic disease. Virchow node describes metastasis to the left supraclavicular node. Sister Mary Joseph node is a periumbilical lymph node metastasis. A Krukenberg tumor is a gastric cancer metastatic to the ovaries. Blumer shelf describes a “drop metastasis” into the perirectal pouch. Other common physical findings in patients with metastatic gastric cancer include cachexia, palpable abdominal masses, and malignant ascites.
Diagnostic Criteria
Histopathologic diagnosis from endoscopic biopsy and/or transcutaneous lymph node biopsy (if applicable) is required.
In the case of GIST, tumor size and mitotic index are important factors in risk stratification.
Differential Diagnosis
Gastric ulcer, gastritis, non-Hodgkin’s lymphoma, GIST, esophageal cancer
Diagnostic Testing
Laboratories
CBC, CMP, PT, PTT, CEA, and iron studies
Initial Diagnostic Test
Upper endoscopy with directed biopsy is the current gold standard.
Barium studies with double contrast provide information on size of ulcerated lesion and gastric motility but are less sensitive and do not allow for biopsy.
Imaging
CT scans or PET/CT is frequently used to evaluate for extent of disease.
Diagnostic Procedures
In the absence of metastasis by CT, endoscopic ultrasound can be used to gauge tumor depth and involvement of local lymph nodes.
Metastatic peritoneal deposits may not be seen on routine imaging, and a diagnostic laparoscopy is necessary to rule this out before definitive resection.
TREATMENT
For gastric adenocarcinoma, treatment is based on TNM stage (Table 21-2):
Stage 0 and Ia. Endoscopic mucosal resection
Stage Ib. Subtotal gastrectomy if at distal stomach, otherwise total gastrectomy with at least D1 resection
Stage II to IV, but without distant metastasis.
For potentially resectable disease, either perioperative chemotherapy (such as ECF) for three cycles before and after total gastrectomy or adjuvant 5-FU-based chemoradiation can be considered.3,4
For medically unfit or unresectable localized gastric adenocarcinoma, 5-FU-based chemoradiation (45 to 50 cGy) is the standard of care. Only a very small percentage of patients can be cured with chemoradiation alone.
Metastatic disease. Incurable with median survival of 9 months. Chemotherapy offers improved life quality and survival. No clear standard of care first-line regimen exists, but commonly used regimens are ECF, DCF, EOX, EOF, ECF, FOLFIRI, and CF. Addition of trastuzumab to chemotherapy improves median survival in patients with Her2-positive gastric cancer.5
For GIST
Surgical resection is the treatment of choice. Adjuvant imatinib for 1 year is recommended by the NCCN for patients with intermediate or high risk (based on tumor size and mitotic index).
For advanced or metastatic GIST, imatinib should be used until disease progression. 6 Upon progression, increased imatinib dosage or switching to sunitinib can be considered.
SPECIAL CONSIDERATIONS
Given the rarity of gastric cancer in the United States, there is no justification for routine screening for esophageal or stomach cancer at this time. However, in countries of high incidence (e.g., Japan), screening for stomach cancer via endoscopy or upper gastrointestinal imaging is standard for those >50 years old.
COMPLICATIONS
Include hemorrhage, gastric obstruction, and malignant ascites.
Disseminated intravascular coagulation (DIC) is a rare complication that may occur in patients with advanced gastric carcinoma and bone marrow metastasis. Mortality is high at 1 to 4 weeks of onset and requires aggressive supportive management and, if possible, chemotherapy.
Patients who underwent total gastrectomy often develop dumping syndrome, vitamin B12 deficiency, and reflux esophagitis.
MONITORING/FOLLOW-UP
After definitive treatment, asymptomatic patients should typically be evaluated by history and physical examination every 3 months for 2 years, and then every 6 months for 3 additional years. CBC, CMP, and, if applicable, CEA should be obtained during each routine follow-up, and imaging studies such as CT scan should be obtained at least every 6 months in the first 1 to 3 years or when clinically indicated.
OUTCOME/PROGNOSIS
Five-year survival rates are stage I 60% to 80%, stage II 20% to 40%, and stage III 10% to 20%.
PANCREATIC CANCER
GENERAL PRINCIPLES
Definition
Cancer that arises from either the exocrine or the endocrine tissue of the pancreas
Classification
Site: Two-thirds of the cases originate from pancreatic head.
Histology: 95% of pancreatic cancers are exocrine ductal carcinoma, with the rest being acinar carcinoma or neuroendocrine tumors.
Epidemiology
Pancreatic cancer is the fourth leading cause of cancer death in the United States, with an annual incidence of ~12.3/100,000.
Up to 43,140 new cases and 36,800 deaths were anticipated in 2010.
Age: 6th to 7th decades.
Sex: slightly higher in males.
Race: higher in African Americans.
Etiology and Pathophysiology
Activation mutation of K-Ras and loss of tumor suppressor INK4a are found in >90% of pancreatic cancer. Recently, activation of Sonic hedgehog signaling pathway has been shown to be important in oncogenesis of pancreatic cancer.
Chronic inflammation is believed to accelerate mutagenesis and cancer formation.
Risk Factors
Cigarette smoking, positive family history, chronic pancreatitis, obesity, diabetes mellitus
Associated Conditions
Lynch syndrome, ataxia-telangiectasia, BRCA2 mutation, familial atypical mole melanoma syndrome, Peutz–Jeghers syndrome, HNPCC.
DIAGNOSIS
Clinical Presentation
History
Most patients are asymptomatic until advanced stage. Presenting symptoms may include abdominal or back pain, weight loss, nausea, vomiting, painless jaundice, fatigue, and depression.
Physical Examination
Palpable abdominal mass, jaundice, ascites, Courvoisier sign (painless palpable gallbladder), Virchow node, and Sister Mary Joseph node may occasionally be found.
Paraneoplastic syndromes, such as Trousseau syndrome (migratory superficial phlebitis), idiopathic deep venous thrombosis, myositis syndromes, and Cushing syndrome, are rarely seen.
Diagnostic Testing
Laboratories
CBC, CMP, PT, and PTT
CEA, CA19–9 levels should be obtained as a baseline and followed for response/recurrence.
Imaging
Initial imaging studies are usually abdominal CT scan or ultrasonography.
Dynamic-phase spiral CT of the abdomen (“pancreatic protocol”) is the current most accurate imaging modality in assessing pancreatic tumor. It allows detailed evaluation of the pancreas, extent of local invasion, and common sites of metastasis such as peripancreatic lymph nodes and the liver.
Patients with confirmed pancreatic cancer should complete staging workup with chest and pelvic CT scan.
Diagnostic Procedures
Further tumor staging with an endoscopic ultrasound or endoscopic retrograde cholangiopancreatography (ERCP) may be necessary.
Tissue diagnosis can be obtained by percutaneous ultrasound or CT-guided-needle biopsy, laparoscopy, ERCP, or ascitic fluid cytology.
Staging can be done by TNM system (Table 21-3), or more commonly by resectability (localized/resectable, borderline resectable, locally advanced/unresectable and metastatic stages).
TREATMENT
In the absence of metastatic disease, surgical consult should always be obtained to assess resectability, which is the basis for subsequent management.
Localized, resectable disease
The standard procedure is a pancreaticoduodenectomy with choledochojejunostomy, cholecystectomy, and gastrojejunostomy (Whipple procedure). Surgical mortality is 1% to 4% even at high volume centers.
Adjuvant therapy is necessary after resection of the primary, since close to 80% of these patients later develop locoregional recurrence or distant metastases. Patients should be enrolled in clinical trials if available. Commonly used regimens include concurrent chemoradiation with 5-FU or gemcitabine, or gemcitabine followed by 5-FU-based chemoradiation.
Borderline resectable disease
This new category was introduced in 2009 and is defined by certain radio-graphic features in which upfront surgery is likely to result in positive surgical margin.
Neoadjuvant chemotherapy (5-FU or gemcitabine) with or without radiation have been proposed with hopes to downstage the tumor and improve the likelihood of complete resection, to exclude patients with rapidly progressive disease who may not benefit from surgery, and to avoid delay in chemoradiation due to prolonged postoperative recovery. While this approach is gaining popularity, its benefit has not been convincingly shown by large randomized-control studies.
Locally advanced disease
5-FU or gemcitabine-based concurrent chemoradiation is the standard therapy and yields comparable results. A minority of patients can become resectable using this approach.
Metastatic pancreatic cancer.
Metastatic pancreatic cancer is incurable. Chemotherapy has a low objective response rate (6% to 12%) but has been shown to improve quality of life and overall survival.
Clinical trials should be recommended if available.
Current recommended first-line chemotherapy is gemcitabine-based regimens. Gemcitabine plus erlotinib showed a marginal survival benefit over gemcitabine alone, but at the expense of more toxicity. 7 Combinations with other agents such as capecitabine, pemetrexed, irinotecan, cisplatin, cetuximab, or bevacizumab did not show additional benefit than gemcitabine alone. The combination of drugs in the FOLFIRINOX regiment does increase survival over gemcitabine alone.
Second-line chemotherapies include capecitabine and 5-FU/oxaliplatin.
Lifestyle/Risk Modification
All patients should be encouraged to cease smoking and consuming alcohol.
Diet
Most patients undergoing treatment suffer from pancreatic insufficiency and, therefore, should be prescribed pancreatic enzymes and told to avoid high-fat diet.
SPECIAL CONSIDERATIONS
Routine preoperative biliary stenting for obstructive jaundice secondary to localized pancreatic head cancer was recently shown to be associated with higher postoperative complications compared to patients who received early surgery. Therefore, discussion should be made between hepatobiliary surgeon and gastroenterologist before stenting.
COMPLICATIONS
Pain management is paramount in pancreatic cancer patients. In addition to standard analgesics, celiac plexus block may be an option in selected patients.
Biliary obstruction and subsequent cholangitis should be relieved by stenting or draining procedures.
Patients who undergo Whipple procedure will develop diabetes.
MONITORING/FOLLOW-UP
After definitive treatment, asymptomatic patients should typically be evaluated by history and physical examination every 3 months for 2 years, and then every 6 months for 3 additional years. CBC, CMP, and, if applicable, CA19–9 or CEA and CT scan of chest/abdomen/pelvis should be obtained during each routine follow-up.
OUTCOME/PROGNOSIS
Overall 5-year survival is 5%. Upon diagnosis, >50% of cases were metastatic, 25% locally advanced, and <20% were potentially resectable.
Most important prognostic factors include surgical margin, lymph node status, and tumor size. However, even patients who underwent curative resection have a 15% to 20% 5-year survival rate.
Median survival for unresectable disease has been as short as 6 months, but many trials are now reporting median survivals of treated patients closer to 12 months.
HEPATOCELLULAR CARCINOMA
GENERAL PRINCIPLES
Definition
Primary cancer that arises from hepatocytes
Epidemiology
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, but it is rare in the United States. The incidence in the United States is around 5 per 100,000, but this has been rising over the last few decades due to the increase in hepatitis B and C infections.
Age: 7th decade.
Sex: M:F, 3:1.
Race: higher incidence in African Americans and Asians.
Etiology and Pathophysiology
Chronic inflammation, necrosis, and liver regeneration likely predispose hepatocytes to acquire mutations.
Integration of HBV DNA into hepatocyte genome can contribute to cancer formation.
Risk Factors
Hepatitis B, hepatitis C, and cirrhosis from any cause such as alcohol and nonalcoholic steatohepatitis, alpha1-antitypsin deficiency, hemochromatosis
Prevention
Vaccination against hepatitis B.
Treatment of chronic hepatitis B with lamivudine has been shown to decrease the risk of developing hepatocellular carcinoma (HCC).
Treatment of hepatitis C with interferon may decrease the subsequent risk of hepatocellular carcinoma. Patients with hepatitis C should be screened with annual alpha-fetoprotein levels and liver ultrasound.
Retinoids may have a role in secondary prevention of HCC.
Associated Conditions
Twenty percent to 30% of patients with chronic hepatitis C eventually develop cirrhosis. Cirrhotic patients have 2% to 6% per year risk of developing hepato-cellular carcinoma.
DIAGNOSIS
Clinical Presentation
History
Patients may have nonspecific complaints of abdominal pain, malaise, weight loss, or fever. Most patients have history of liver cirrhosis.
Physical Examination
Patients may occasionally have a palpable liver mass. Most patients have physical findings of cirrhosis, such as ascites, splenomegaly, spider angiomata, and collateral circulation muscle wasting.
Diagnostic Criteria
Alpha-fetoprotein (AFP) level of >200 ng/mL (in absence of chronic hepatitis B) or >400 ng/mL (in chronic hepatitis B), and presence of hepatic mass >2 cm with classic arterial enhancement by CT scan or MRA, is adequate for diagnosis.
Percutaneous needle biopsy (FNA or core biopsy) should be performed in uncertain cases (low AFP, small liver lesion or without vascular enhancement).
Differential Diagnosis
Adenoma, hemangioma, metastatic cancer
Diagnostic Testing
Laboratories
CBC, CMP, PT, PTT, and AFP (elevated in 85% cases)
Imaging studies
Abdominal ultrasound or CT scan with contrast is usually done initially.
If primary hepatocellular cancer is strongly suspected, more detailed imaging studies including triple-phase contrast enhanced CT scan or MRI are used to define anatomic relationships and vascular anatomy. Conventional angiography, CT or MR-angiography is usually needed to completely reveal the anatomy and characteristics of the tumor vasculature.
TREATMENT
Many staging systems have been proposed, which include the Okuda, CLIP, BCLC, and TNM staging.
The Barcelona Clinic Liver Cancer (BCLC) staging system integrates Okuda staging and Child–Pugh score and treatment recommendations, and is currently endorsed by the American Association for Study of Liver Disease.8
Stage 0. Solitary lesion <2 cm with preserved liver function. Surgical resection is the primary treatment. Unfortunately, <5% of patients are resectable because of advanced disease or cirrhosis at presentation. Recurrent local disease may also be treated surgically, with potential for cure.
Stage A. Patients who are not eligible for resection (primarily due to insufficient liver reserve) or who meet the Milan criteria (one tumor ≤5 cm or up to three tumors ≤3 cm, no extrahepatic manifestations, or vascular invasion). Liver transplantation is the treatment of choice with 5-year survival up to 75%. Patients who are not transplant candidates should be referred for percutaneous ethanol injection or radiofrequency ablation.
Stage B. Patients typically have multinodular disease. Transarterial chemoembolization (TACE) is the treatment of choice. This therapy involves catheter-guided embolization of tumor-feeding hepatic artery using materials such as Lipiodol or Gelfoam with or without chemotherapeutic agents such as cisplatin or doxorubicin. It may provide a survival benefit. Due to risk of liver failure, TACE is contraindicated in patients with portal vein thrombosis and most patients with Child C liver disease.
Stage C. Sorafenib was found to provide a survival benefit versus supportive care for unresectable hepatocellular carcinoma with Child A disease.9 The median overall survival improved from 7.9 to 10.7 months. Clinical trials should be recommended if available. Chemotherapeutic agents such as doxorubicin and capecitabine have a 10% response rate. Response rate is slightly higher (18% to 20%) with combinations such as cisplatin/capecitabine and oxaliplatin/gemcitabine.
Stage D. Best supportive care.
COMPLICATIONS
Liver decompensation is of major concern after surgical resection or TACE.
Complications of liver cirrhosis such as ascites, jaundice, bleeding diathesis, and variceal bleed are commonly seen.
MONITORING/FOLLOW-UP
Patients with chronic HCV or liver cirrhosis should be screened with AFP and liver ultrasonography every 6 to 12 months.
Due to high risk of recurrence, patients should be followed closely. A repeat CT scan should be obtained 1 month after surgical resection or local therapy. CBC, CMP, PT, serum AFP and abdominal CT/ultrasonography should be obtained every 3 months afterward.
Patients who underwent liver transplantation should be followed by a liver transplant team regularly.
OUTCOME/PROGNOSIS
Overall 5-year survival for stage 0 and A is 50% to 70%, 3-year survival of stage B/C is 20% to 40%, and 1-year survival for stage D disease is <10%, with median survival of 6 months.
GALLBLADDER CANCER
GENERAL PRINCIPLES
Classification
Histology: 85% adenocarcinoma, the rest being squamous cell carcinoma or mixed type
Epidemiology
Gallbladder cancer is a rare cancer of the biliary system, with ~5000 cases diagnosed per year in North America.
Age: 7th decade.
Sex: M:F, 1:1.7.
Risk Factors
Chronic cholecystitis, cholelithiasis, typhoid carriers. Seventy-five percent to 98% of patients with gallbladder cancer will have gall stones. Incidence of gallbladder cancer in patients with “Porcelain gallbladder” is up to 25%.
Prevention
Due to high risk of developing cancer, patients with porcelain gallbladder or gallbladder polyp >1 cm should be referred for surgery.
Associated Conditions
Gall stones, chronic cholecystitis, gallbladder polyp, typhoid carrier, inflammatory bowel disease
DIAGNOSIS
Clinical Presentation
History
These tumors may present with symptoms of acute or chronic cholecystitis, although jaundice and weight loss are more common.
Physical Examination
Scratch marks for pruritus, jaundice, hepatomegaly, right upper quadrant tenderness, or symptoms/signs of acute cholecystitis
Diagnostic Criteria
Histopathology diagnosis, usually after cholecystectomy, is required.
Differential Diagnosis
Cholecystitis, cholangitis, cholangiocarcinoma, biliary colic, choledocholithiasis, gallbladder polyp, primary HCC, metastatic cancer, primary sclerosing cholangitis
Diagnostic Testing
Laboratories
CBC, LFT, GGT, BMP, PT, PTT, AFP, and CEA
Imaging
Right upper quadrant ultrasonography is usually the first imaging modality to be ordered.
When gallbladder tumor is suspected, further imaging modalities such as liver MRI or abdominal CT should be obtained. MRCP is recommended to delineate tumor extent and nodal status in more details.
Diagnostic Procedures
Tissue diagnosis can be made by ERCP if the tumor is distal. However, diagnosis is often made at the time of surgery.
TREATMENT
The only curative treatment for gallbladder cancer is surgical resection, but <30% of patients have resectable disease at the time of presentation. Surgery typically involves cholecystectomy, en bloc hepatic resection, lymphadenectomy, and possible bile duct resection. Adjuvant therapy with 5-FU-based concurrent chemoradiation is recommended for most patients with resected gallbladder cancer, except for those with very small tumors (T1 N0).
For patients with unresectable but nonmetastatic gallbladder cancer, therapy with 5-FU-based concurrent chemoradiation is recommended, provided that the patient has an adequate performance status and is not jaundiced (total bilirubin ≤3 mg/dL is commonly used). Jaundiced patient should receive biliary decompression before chemotherapy.
For patients with metastatic disease, choices of chemotherapy include cisplatin plus gemcitabine,105-FU, or capecitabine. Cisplatin can be omitted in patients with poorer performance status.
COMPLICATIONS
Obstructive jaundice, cholecystitis, and cholangitis are commonly seen.
MONITORING/FOLLOW-UP
After definitive treatment, asymptomatic patients should typically be evaluated by history and physical examination every 3 months for 2 years, and then every 6 months for 3 additional years. CBC, CMP, and, if applicable, CA19–9 or CEA and CT scan of chest/abdomen/pelvis should be obtained during each routine follow-up.
OUTCOME/PROGNOSIS
Five-year survival rates for localized, regional, and distant disease are 40%, 15%, and <10%, respectively. The median survival for advanced disease is 2 to 4 months.
CHOLANGIOCARCINOMA
GENERAL PRINCIPLES
Definition
Cancers that arise from the biliary duct and before the ampulla of Vater
Classification
Site: intrahepatic (<10%) and extrahepatic origin (>90%). Intrahepatic cholangiocarcinomas arise in the small intrahepatic ductules or the large intrahepatic ducts proximal to the bifurcation of the right and left hepatic ducts. Extrahepatic cholangiocarcinomas originate in any of the major hepatic or biliary ducts. Klatskin’s tumor refers to extrahepatic cholangiocarcinoma that arises in the hilum of left and right hepatic duct.
Histology: >95% adenocarcinoma, further subtyped into sclerosing, nodular, and papillary variants; <5% squamous cell carcinoma.
Epidemiology
Cholangiocarcinoma is a rare cancer of the biliary tree, accounting for ~2500 new cases each year in the United States.
Age: 6th decade.
Sex: M:F, ~1:1.
Etiology and Pathophysiology
Largely unknown but chronic inflammation may result in accelerated mutagenesis and dysplastic change.
Risk Factors
Primary sclerosing cholangitis, hepatolithiasis, choledochal cysts, ulcerative colitis, and liver fluke infection
DIAGNOSIS
Clinical Presentation
History
Up to 98% of patients with cholangiocarcinomas present with jaundice, and quite frequently right upper quadrant pain, fever, pruritus, and body weight loss.
Physical Examination
Jaundice, hepatomegaly, or right upper quadrant mass.
Diagnostic Criteria
Histopathology diagnosis is required.
Differential Diagnosis
Cholecystitis, cholangitis, gallbladder cancer, primary HCC, pancreatic cancer, cancer of ampulla of Vater, metastatic cancer, primary sclerosing cholangitis
Diagnostic Testing
Laboratories
CBC, BMP, LFT, PT, PTT, CA19–9, and CEA
Imaging
Abdominal CT or ultrasonography is usually the first imaging studies performed.
When cholangiocarcinoma is suspected, further imaging modalities such as liver MRI should be obtained. MRCP is recommended to delineate tumor extent and nodal status in more details.
Diagnostic Procedures
Tissue diagnosis can be made by ERCP if the tumor is distal or by CT-guided biopsy if proximal or intrahepatic. Occasionally, diagnosis is often made at the time of surgery.
TREATMENT
Complete surgical resection offers the only chance of cure. Overall management depends on location and stage of the disease.
Proximal third including intrahepatic cholangiocarcinoma: hilar resection, lymphadenectomy, and possibly en bloc hepatic resection. If surgical margin is positive, adjuvant 5-FU- or gemcitabine-based chemoradiation, radiofrequency ablation, or repeat surgery should be recommended.
Mid-ductal lesion: bile duct resection and portal lymphadenectomy followed by adjuvant 5-FU- or gemcitabine-based chemoradiation. Further chemotherapy with gemcitabine or 5-FU can be considered.
Distal ductal lesion: Pancreaticoduodenectomy plus lymphadenectomy followed by adjuvant 5-FU- or gemcitabine-based chemoradiation. Further chemotherapy with gemcitabine or 5-FU can be considered.
Due to lack of standard adjuvant therapy, participation in clinical trials should be recommended.
Unresectable cholangiocarcinomas or medically unfit patients can be treated with 5-FU- or gemcitabine-based chemoradiation, or chemotherapy with 5-FU or gemcitabine alone. The prognosis is poor, with a median survival of 7 to 12 months.
Metastatic disease is typically treated with chemotherapy such as cisplatin plus gemcitabine.10 In these patients, priority should be palliation of obstructive jaundice and pain.
COMPLICATIONS
Obstructive jaundice, cholecystitis, and cholangitis are commonly seen.
MONITORING/FOLLOW-UP
After definitive treatment, asymptomatic patients should typically be evaluated by history and physical examination every 3 months for 2 years, and then every 6 months for 3 additional years. CBC, CMP, and, if applicable, CA19–9 or CEA and CT scan of chest/abdomen/pelvis should be obtained during each routine follow-up.
OUTCOME/PROGNOSIS
Prognosis depends on stage and performance status. However, >70% of patients presented with advanced stage and <10% patients are surgical candidate.
Patients with distal extrahepatic tumors that are completely resected have a 5-year survival rate of up to 40%. Overall median survival duration in patients with localized disease who undergo resection and adjuvant chemoradiation is 17 to 27.5 months.
Patients who are not surgical candidates and received chemoradiation alone have a median survival 7 to 17 months.
Patients who can tolerate biliary stenting alone have median survival of a few months.
REFERENCES
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