Gastrointestinal Tract Cancers
Steven R. Alberts
Axel Grothey
Cancers of the gastrointestinal (GI) tract account for 19% of all new visceral cancers and 24% of cancer deaths in the United States. The frequency and mortality of cancers of the various GI organs are shown in Table 9.1.
ESOPHAGEAL CANCER
I. EPIDEMIOLOGY AND ETIOLOGY
A. Epidemiology. The incidence of esophageal cancer is noted in Table 9.1.
1. Squamous cell esophageal cancer is the foremost malignancy in the Bantu of Africa. South Africa, Japan, China, Russia, Scotland, and the Caspian region of Iran also have relatively high incidence rates.
2. Incidence rates of squamous cell esophageal cancer can vary from 100- to 200-fold among different populations living in geographic adjacency.
3. In many Western countries and in some areas of Asia, the incidence of adenocarcinoma of the esophagus (distal esophagus and gastroesophageal junction) is rapidly rising and the incidence of squamous cell cancers is declining. The rise within the United States is now beginning to plateau.
B. Etiology
1. Carcinogens
a. Long-term use of tobacco and alcohol increases the incidence of both squamous cell carcinoma and adenocarcinoma of the esophagus.
b. Human papillomavirus (HPV) infection is associated with squamous cell carcinoma of the esophagus.
c. Dietary carcinogens relevant to the development of squamous cell esophageal cancers include the following:
(1) Plants growing in soil deficient in molybdenum have reduced vitamin C content and cause hyperplasia of esophageal mucosa, a precursor of cancer.
(2) Elevated nitrates in the drinking water and soup kettles that concentrate the nitrate
(3) Food containing fungi: Geotrichum candidum (pickles, air-dried corn), Fusarium sp., and Aspergillus sp. (corn)
(4) Bread that is baked once a week and eaten when moldy (G. candidum)
(5) Dried persimmons, a rough food that injures the esophageal mucosa when eaten (China)
2. Predisposing factors for squamous cell esophageal cancer
a. Howel-Evans syndrome or tylosis (hyperkeratosis of the palms and soles) is a rare genetic disease that is transmitted as a mendelian-dominant trait (nearly 40% develop esophageal cancer).
b. Lye stricture (up to 30%)
c. Esophageal achalasia (30%)
d. Esophageal web (20%)
Table 9.1 Occurrence of Digestive Tract Cancers in the United States (2010)a,b | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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e. Plummer-Vinson syndrome (iron-deficiency anemia, dysphagia from an esophageal web, and glossitis, 10%)
f. Short esophagus (5%)
g. Peptic esophagitis (1%)
h. Other conditions associated with squamous cell esophageal cancer
(1) Patients with head and neck cancer (field cancerization theory)
(2) Patients with celiac disease
(3) Chronic esophagitis without Barrett esophagus (see Section II.A)
(4) Thermal injury to the esophagus because of drinking boiling hot tea or coffee (Russia, China, and Middle East)
3. Predisposing factors for adenocarcinoma of the esophagus
a. Barrett esophagus is metaplastic replacement of squamous with intestinalized columnar epithelium.
(1) Adenocarcinomas associated with Barrett esophagus constitute the cancer whose incidence is most rapidly increasing worldwide, but particularly in white men.
(2) In the United States, the incidence of adenocarcinoma of the esophagus has increased six- to sevenfold since 1970. Patients with Barrett esophagus have a 30- to 125-fold increased risk for esophageal adenocarcinoma compared with the average US population.
b. Obesity
c. Reflux esophagitis
II. PATHOLOGY AND NATURAL HISTORY
A. Histology. While squamous cell tumors once constituted the majority of esophageal cancers, particularly in the upper and middle esophagus, adenocarcinomas are now the predominant form of esophageal cancer. A small portion of esophageal cancers will be sarcomas, small cell carcinomas, or lymphomas. Adenocarcinoma may arise from esophageal continuation of the gastric mucosa (Barrett esophagus) or may represent extension of a gastric adenocarcinoma.
B. Location of cancer in the esophagus
1. Cervical: 10%
2. Upper thoracic: 40%
3. Lower thoracic: 50%
C. Clinical course. Esophageal cancer is highly lethal; >80% of affected patients die from the disease. About 75% present initially with mediastinal nodal involvement or distant metastasis. Death is usually caused by local disease that results in malnutrition or aspiration pneumonia.
III. DIAGNOSIS
A. Symptoms and signs. Dysphagia is the most common complaint. Patients become unable to swallow solid foods and eventually liquids. Symptoms rarely develop until the esophageal lumen is greatly narrowed and metastasis has occurred. Pain may or may not be present. Physical findings other than cachexia, palpable supraclavicular lymph nodes, or hepatomegaly are rare.
B. Diagnostic studies
1. Preliminary studies include physical examination, CBC, LFT, chest radiograph, esophagoscopy, and barium esophagogram. Brushings can be obtained and lesions can undergo biopsy using endoscopy.
2. CT scan staging predicts invasion or metastases with an accuracy rate of >90% for the aorta, tracheobronchial tree, pericardium, liver, and adrenal glands; 85% for abdominal nodes; and 50% for paraesophageal nodes.
3. Endoscopic ultrasound (EUS) is more accurate than CT in assessing tumor depth and paraesophageal nodes. Transesophageal biopsy to sample enlarged lymph nodes is possible under EUS guidance.
4. Positron emission tomography (PET) is a potentially useful diagnostic tool for the preoperative assessment of patients with esophageal cancer. It has a greater sensitivity for the detection of nodal metastases when compared with CT.
5. Laparoscopy allows assessment of subdiaphragmatic, peritoneal, liver, and lymph node metastases. In patients who are getting chemotherapy and radiation, either preoperatively or in lieu of surgery, placement of a jejunostomy tube for enteral alimentation during laparoscopy is clinically useful. Thoracoscopy can allow patients who are noted to have intrathoracic dissemination to be spared radical resections.
6. Bronchoscopy for tumors of the upper or middle esophagus can diagnose direct tumor extension into the tracheobronchial tree and synchronous primary sites.
IV. STAGING SYSTEM AND PROGNOSTIC FACTORS
A tumor-lymph node-metastasis (TNM) staging classification is available. Stage groupings are different for squamous cell carcinomas and adenocarcinomas of the esophagus with regard to both TNM classification and histologic grades. Patients with earlier disease stage, particularly N0 and M0, have a better prognosis. Readers should consult an up-to-date staging manual because of the frequent revisions of staging systems.
Most patients die from their disease within 10 months of diagnosis. The 5-year survival rate ranges from approximately 35% with localized disease to <10% for distant disease despite all efforts at treatment.
V. SCREENING AND EARLY DETECTION
In high-risk populations, such as in portions of Asia, mass screening using balloon-assisted brushings or endoscopy has been used. Early detection by these methods is of uncertain benefit. In the United States, screening for esophageal cancer is not effective in the general population, but patients such as those with lye-induced strictures or Barrett esophagus, who are at higher risk, should undergo periodic screening via upper endoscopy.
VI. MANAGEMENT
A variety of options exist for the treatment of esophageal cancer depending on its stage.
A. Resection of primary tumor. Results of surgical resection in cancer of the esophagus are poor. The operative mortality rate is about 5% to 10%. In the United States, the 5-year survival rate in patients undergoing R0 (complete) tumor resection is <20%. Aggressive surgery, however, may be justified, particularly for some patients with lesions in the lower half of the esophagus.
B. Palliating an obstructed esophagus can be accomplished by several procedures and permits enteral nutrition.
1. Laser therapy may relieve obstruction and bleeding. Endoscopic laser therapy has a <1% mortality rate but may require prior mechanical dilation. Although successful, laser therapy may require multiple endoscopic sessions, it can be done on an outpatient basis, and its overall cost is still much lower than the cost of palliative surgery. Photosensitization of esophageal tumors using an injectable porphyrin derivative can beneficially increase the laser energy absorbed by the tumor but is associated with generalized dermal photosensitivity to sunlight lasting 4 to 6 weeks.
2. Esophageal stenting. Multiple devices are available for esophageal intubation. About 15% of patients with malignant esophageal obstruction are candidates for tube placement. The tube may be introduced with a pusher tube, which is loaded either onto a bougie or over an endoscope and expands after placement. The latter method permits visualization of the obstructed lumen. The success rate is above 90%.
a. Advantages of tube placement are improved ability to swallow saliva, pleasure of oral alimentation, relief from pulmonary aspiration related to esophagopulmonary fistula, independence from physician or hospital for constant care, and ability to spend time with family and friends in relative comfort.
b. Contraindications to placement of endoprosthesis are carcinoma <2 cm below the upper sphincter, limited life expectancy (<6 weeks), and uncooperativeness.
c. Complications include perforation, dislocation, tumor overgrowth, reflux symptoms with stricturing, pressure necrosis, foreign body impaction with obstruction, bleeding, and failure of intubation. The complication rate (early and late) is 10% to 25%.
3. Feeding gastrostomy is not advisable because it does not palliate dysphagia, which forces patients with complete or nearly complete esophageal obstruction to expectorate saliva and secretions, does not increase life expectancy, and has its own morbidity and mortality.
4. Colonic interposition to bypass the obstructed segment is recommended only for surgical candidates in whom a suitable gastric remnant cannot be fashioned because of prior gastric resection, extent of disease, or underlying esophageal disease. The complication rate of this procedure is high.
5. External-beam irradiation or endoluminal brachytherapy can result in tumor regression with palliation in some cases. Up to 70% to 80% of patients with dysphagia may note improved swallowing after external-beam irradiation. Endoluminal brachytherapy can be useful in previously irradiated patients with local tumor regrowth causing dysphagia.
C. Single-modality treatment
1. Radiotherapy (RT) alone to a dose of 6,000 cGy resulted in 1-, 2-, 3-, and 5-year survival rates of 33%, 12%, 8%, and 7%, respectively, of patients treated on the radiation arm of a randomized trial in which responding patients were permitted to proceed to resection at physician discretion.
2. Surgery alone. The surgical procedures employed in esophagectomy depend on the location and preference of the surgeon and include principally transhiatal esophagectomy or the Ivor-Lewis procedure, which requires both thoracotomy and laparotomy. In the 25% to 30% of patients in whom complete resection is possible, 5-year survival rates are 15% to 20%.
3. Chemotherapy alone is seldom an effective palliative modality of the primary tumor in patients with esophageal cancer. When chemotherapy is employed, it should be coupled with mechanical or radiotherapeutic approaches for palliation of dysphagia. As in gastric cancer, discussed later, multiagent chemotherapy-induced responses tend to be short-lived.
D. Combined-modality therapy
1. Primary combined therapy without surgery. In patients not planning to undergo esophageal surgery because of comorbid disease or patient or physician choice, combined chemotherapy and RT can lead to long-term survival in some, as compared with surgery alone.
a. Currently, the following regimen is most commonly used and is given during the first and fourth weeks of RT:
Cisplatin, 75 mg/m2 IV on day 1 of the cycle, and 5-fluorouracil (5-FU), 1,000 mg/m2/d by continuous IV infusion for 4 days. Several other multiagent regimens have resulted in higher response rates but have increased toxicity without a clear overall survival benefit.
b. In a prospective randomized trial of patients with squamous cell or adenocarcinoma of the thoracic esophagus, combined-modality treatment (5-FU plus cisplatin plus 5,000 cGy) resulted in improved median survival (9 vs. 12.5 months) when compared with RT alone (6,400 cGy). The 2-year survival rate for patients randomized to combined chemotherapy and radiation was 38%, compared with 10% for those randomized to radiation alone. The patients receiving the combined-modality treatment experienced decreased local and distant recurrences but significantly more toxicity, much of which was serious or life-threatening. Only half of these patients received all of the planned cycles of chemotherapy. Currently, this approach should be reserved for patients unable to undergo surgery and for selected patients with squamous cell cancers.
2. Preoperative or postoperative RT alone may reduce the local recurrence rate but has no apparent affect on median survival.
3. Perioperative chemotherapy alone. Similarly, neither preoperative (as reported in six randomized trials) nor postoperative chemotherapy alone has improved outcomes in patients with esophageal cancer, though it may benefit patients
with gastroesophageal cancers (see Gastric Cancer, Section IV.B.1.c). Response rate to multiagent neoadjuvant chemotherapy can be as high as 40% to 50%, and up to 25% of treated patients may have apparent pathologic complete remissions. Preoperative chemotherapy using cisplatin and 5-FU, however, did not improve overall survival when compared with surgery alone in a randomized trial of 440 patients with squamous esophageal cancer.
with gastroesophageal cancers (see Gastric Cancer, Section IV.B.1.c). Response rate to multiagent neoadjuvant chemotherapy can be as high as 40% to 50%, and up to 25% of treated patients may have apparent pathologic complete remissions. Preoperative chemotherapy using cisplatin and 5-FU, however, did not improve overall survival when compared with surgery alone in a randomized trial of 440 patients with squamous esophageal cancer.
4. Triple-modality therapy. The combination of preoperative chemotherapy and RT has led to an increase in the 3-year survival rates and prolonged median disease-free survival in several randomized studies compared with surgery alone. While older trials have shown mixed results in regard to overall survival, more recent trials with predominantly adenocarcinoma patients have shown significant benefit to the use of neoadjuvant chemoradiotherapy followed by surgery compared to surgery alone. Current options for chemotherapy included (1) carboplatin and paclitaxel, (2) 5-FU and oxaliplatin, and (3) 5-FU and cisplatin. Based on outcomes and level of toxicity, carboplatin and paclitaxel appear to be the best option. Patients with complete pathologic response at surgery have about a 50% likelihood of long-term survival.
E. Advanced disease. The responses using single chemotherapeutic agents (15% to 20%) are usually partial and of brief duration (2 to 5 months). Combination chemotherapy, usually including cisplatin with 5-FU, a taxane, or both, is associated with reported response rates ranging from 15% to 80%, a median duration of response of 7 to 10 months, and many times with substantial toxicity. Higher response rates, however, do not necessarily translate into significant benefit for these patients, and the outcome remains poor. In most situations, the use of a doublet, rather than a triplet, chemotherapy combination will provide meaningful responses with acceptable levels of toxicity. For doublets, choices include FOLFOX, XELOX, as well as carboplatin and paclitaxel.
GASTRIC CANCER
I. EPIDEMIOLOGY AND ETIOLOGY
A. Incidence. The prevalence and death rates of gastric carcinoma (particularly distal cancers) have been markedly and significantly decreasing in all regions of the world and in all age groups by about 2% to 7% per year. Deaths due to gastric cancer have decreased to 20% of that seen in the 1930s in the United States, although it remains the second leading cause of cancer death worldwide. However, an increase in cardia and gastroesophageal tumors has been observed in the United States. Currently, one-third of all gastric cancers arise in the proximal stomach, predominantly the cardia and gastroesophageal junction.
Dietary factors and improvement in food storage are believed to be the major factors causing this decline. Improvements include reduction in toxic methods of food preservation (such as smoking and pickling), a decline in salt consumption, greater use of refrigeration, and increased consumption of fruits and vegetables.
Mortality from gastric cancer is highest in Costa Rica (61 deaths per 100,000 population) and East Asia (Hong Kong, Japan, and Singapore) and lowest in the United States (5 deaths per 100,000). Of interest, the Nordic and Western European countries have incidence rates two to three times higher than the United States. The incidence remains high in Japan and is intermediate in Japanese immigrants to the United States; first-generation Japanese Americans have an incidence comparable with other Americans. The average age of onset is 55 years.
B. Etiology. Two gastric cancer entities can be distinguished by their risk factors and histology. Diffuse gastric cancer is associated with hereditary factors and a proximal location and does not appear to occur in the setting of intestinal metaplasia or dysplasia. Intestinal-type gastric cancer is more distal, occurs in younger patients, is more frequently endemic, and is associated with inflammatory changes and with Helicobacter pylori infection.
1. Diet. Gastric cancer has been linked to the ingestion of red meats, cabbage, spices, fish, salt-preserved or smoked foods, a high-carbohydrate diet, and low consumption of fat, protein, and vitamins A, C, and E. Selenium dietary intake may be inversely proportional to the risk of gastric cancer but not to that of colorectal cancer.
2. Helicobacter pylori infection is associated with an increased risk for gastric adenocarcinoma and may be a cofactor in the pathogenesis of noncardiac gastric cancer. The H. pylori organism was identified in the malignant and nearby inflammatory tissue of 89% of patients with intestinal-type cancer, whereas it was present in 32% of tissues taken from patients with diffuse-type cancers. This raises the possibility now under investigation in prospective randomized trials that eradicating H. pylori through antibiotic treatment and bismuth administration may be preventive of both atrophic gastritis and intestinaltype gastric cancer.
3. Heredity and race. African, Asian, and Hispanic Americans have a higher risk for gastric cancer than whites. The diffuse histologic pattern is the predominant pathologic type seen in families with multiple affected members.
4. Pernicious anemia, achlorhydria, and atrophic gastritis. Pernicious anemia carries an increased relative risk for gastric cancer that is said to be 3 to 18 times that of the general population, based on retrospective studies. Although some controversy surrounds this finding, follow-up endoscopy is generally suggested for patients known to have pernicious anemia.
5. Previous gastric resection. Gastric stump adenocarcinomas, which occur with a latency period of 15 to 20 years, are more common in patients after surgical treatment for benign peptic ulcer disease, particularly in those who have hypochlorhydria and reflux of alkaline bile. These cancers are associated with dysplasia of gastric mucosa, elevated gastrin levels, and a poor prognosis. Two meta-analyses have supported this increased risk. Some populationbased studies do not support this finding.
6. Mucosal dysplasia is graded from I to III, with grade III showing marked loss in cell differentiation and increased mitosis. The finding of high-grade dysplasia by experienced pathologists in two separate sets of endoscopic biopsies is considered to be a marker for future gastric cancer. Intestinal metaplasia, replacement of gastric glandular epithelium with intestinal mucosa, is associated with intestinal-type gastric cancer. The risk for cancer appears to be proportional to the extent of metaplastic mucosa.
7. Gastric polyps. As many as half of adenomatous polyps show carcinomatous changes in some series. Hyperplastic polyps (>75% of all gastric polyps) do not appear to have malignant potential. Patients with familial adenomatous polyposis (FAP) have a higher incidence of gastric cancer. Patients with adenomatous polyps or FAP should have endoscopic surveillance.
8. Chronic gastritis. In chronic atrophic gastritis of the corpus or antrum, H. pylori infection and environmental and autoimmune (as in pernicious anemia) causes are thought to be associated with an increased risk for gastric cancer. In Ménétrier disease (hypertrophic gastritis), an increase in the incidence of gastric cancer is also observed.
9. Other risk factors. Gastric cancer is more common in men older than 50 years of age and in people with blood group A. Gastric cancer is consistently seen more commonly among those of lower socioeconomic class across the world.
II. PATHOLOGY AND NATURAL HISTORY
A. Histology and classification. About 95% of gastric cancers are adenocarcinomas; 5% are leiomyosarcomas, lymphomas, carcinoids, squamous cancers, or other rare types.
1. Useful characteristics of gastric cancer
a. Histologic classification (Lauren): Diffuse (scattered solitary or small clusters of small cells in the submucosa), intestinal (polarized columnar large cells with inflammatory infiltrates localized in areas of atrophic gastritis or intestinal metaplasia), and mixed types. This classification has proved to be the most useful for adenocarcinomas because the two major types (diffuse and intestinal) represent groups of patients with differing ages, sex ratios, survival rates, epidemiology, and apparent origin. Studies have shown that diffuse histology affects younger patients, with slight predominance among women. Diffuse histology occurred in 50% of all cases and in 55% of unresectable cases. Intestinal type predominates in highrisk regions of the world and among older people, and affects more men than women.
b. Clinical classification (gross anatomy): Superficial (superficial spreading), focal (polypoid, fungate, or ulcerative), and infiltrative (linitis plastica) types
c. Japanese Endoscopic Society (JES) classification: Type I (polypoid or mass-like), type II (flat, minimally elevated, or depressed), and type III (cancer associated with true ulcer)
2. Location of cancers
a. Distal location: 40%
b. Proximal: 35%
c. Body: 25%
B. Clinical course. About 20% of gastric cancer patients are long-term survivors in the United States. Gastric carcinoma spreads by the lymphatic system and blood vessels, by direct extension, and by seeding of peritoneal surfaces. The ulcerative and polypoid types spread through the gastric wall and involve the serosa and draining lymph nodes. The scirrhous type spreads through the submucosa and muscularis, encasing the stomach, and in some instances spreads to the entire bowel. The physical examination is often normal.
Widespread metastatic disease may affect any organ, especially the liver (40%), lung (may be lymphangitic, 40%), peritoneum (10%), supraclavicular lymph nodes (Virchow node), left axillary lymph nodes (Irish node), and umbilicus (Sister Mary Joseph nodule). Sclerotic bone metastases, carcinomatous meningitis, and metastasis to the ovary in women (Krukenberg tumor) or rectal shelf in men (Blumer shelf) may also occur.
C. Associated paraneoplastic syndromes
1. Acanthosis nigricans (55% of cases that occur in malignancy are associated with gastric carcinoma)
2. Polymyositis, dermatomyositis
3. Circinate erythemas, pemphigoid
4. Dementia, cerebellar ataxia
5. Idiopathic venous thrombosis
6. Ectopic Cushing syndrome or carcinoid syndrome (rare)
7. Leser-Trélat sign
III. DIAGNOSIS
A. Symptoms and signs. Gastric cancer often progresses to an advanced stage before symptoms and signs develop. Symptoms of advanced disease include anorexia, early satiety, distaste for meat, weakness, and dysphagia. Abdominal pain is present in about 60% of patients, weight loss in 50%, nausea and vomiting in 40%, anemia in 40%, and a palpable abdominal mass in 30%. The abdominal pain is similar to ulcer pain, is gnawing in nature, and may respond initially to antacid treatment but remains unremitting. Hematemesis or melena occurs in 25% and, when present, is seen more often with gastric sarcomas.
B. Diagnostic studies
1. Preliminary studies include CBC, LFT, esophagogastroduodenoscopy (EGD) or upper GI barium studies, and chest radiographs.
2. CT of the abdomen is useful for assessing the extent of disease. At laparotomy, however, half of patients are found to have more extensive disease than predicted by CT. Laparoscopy can identify patients with regionally advanced or disseminated disease who are not candidates for immediate potentially curative surgical intervention.
3. EUS is up to six times more accurate in staging the primary gastric tumors than CT, but differentiation between benign and malignant changes in the wall is often difficult. EUS is useful in imaging the cardia, which may be difficult to evaluate by CT. Lymph node biopsy can also be obtained by EUS guidance.
4. Endoscopy. The combination of flexible upper GI endoscopy with biopsy of visible lesions, exfoliative cytology, and brush biopsy is able to detect >95% of gastric cancers. Biopsy of a stomach lesion alone is accurate in only 80% of cases. Positive gastric cytology with no endoscopic or radiographic abnormalities indicates superficial spreading gastric cancer.
5. PET. PET has more limited value in the diagnostic workup of patients compared to its use in esophageal cancer. It may help to identify malignant adenopathy not seen by CT. Its use in patients with gastroesophageal junction cancers appears to be more comparable to esophageal cancer.
C. Differential diagnosis and gastric polyps. The differential diagnosis of gastric cancer includes peptic gastric polyps, ulcer, leiomyoma, leiomyoblastoma, glomus tumor, malignant lymphoma (and pseudolymphoma), granulocytic sarcoma, carcinoid tumors, lipoma, fibrous histiocytoma, and metastatic carcinoma. Gastric polyps rarely undergo malignant transformation (3% after 7 years), but many contain independent carcinoma.
1. Inflammatory gastric polyps are not true neoplasms. They are usually located in the pyloroantrum and are associated with hypochlorhydria but not with carcinoma.
2. Hyperplastic gastric polyps (Ménétrier polyadenome polypeux) are the most common polyps (75%). Randomly distributed throughout the stomach, these polyps are usually small and multiple. Coexisting carcinoma is present in 8% of cases.
3. Adenomatous polyps are usually located in the antrum of the stomach and are frequently single and large. Coexisting carcinoma is present in 40% to 60% of patients.
4. Villous adenomas rarely occur in the stomach but are more often malignant.
5. Polyposis syndromes
a. Familial gastric polyposis presents with multiple gastric polyps but no skin or bone tumors. The gastric wall is usually invaded with atypical carcinoma.
b. FAP is associated with gastric involvement in more than half of patients. The gastric polyps are adenomatous, hyperplastic, or of the fundic gland hyperplasia type. Gastric carcinoma and carcinoid tumor may occur.
IV. STAGING AND PROGNOSTIC FACTORS
A. Staging system. The TNM staging system developed for gastric cancer is shown in Table 9.2. The current TNM system does not take into account the location of the tumor within the stomach, the histologic type (Lauren classification), the pattern of growth (linitis plastica), or whether all disease could be resected (and if so, the type of resection).
B. Prognostic factors. Previously, data using three grave prognostic signs (serosal involvement, nodal involvement, and tumor at the line of resection) have shown that if none of these signs is present, the 5-year survival rate is 60%, and if all are present, the 5-year survival rate is <5%.
1. Stage. Multivariate analysis indicates that stage, invasion, and lymph node involvement are the most significant prognostic factors. The most
important prognostic determinant appears to be the number of positive lymph nodes. Interestingly, patients with one to three lymph nodes involved with metastasis have as good a prognosis as those without nodal involvement.
important prognostic determinant appears to be the number of positive lymph nodes. Interestingly, patients with one to three lymph nodes involved with metastasis have as good a prognosis as those without nodal involvement.
Table 9.2 TNM Staging System for Cancers of the Stomacha | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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2. Clinical classification. Survival is better with superficial than with focal cancer and worst with infiltrative types of cancer.
3. JES classification. Survival is better with type II (flat) than with type III (associated with ulcer) tumors and worst with type I (polypoid) tumors.
4. Grade. Tumors with high histologic grade have a poor prognosis.
5. Nature and extent of resection. Survival is better with curative resection (a resection with uninvolved margins, or R0 resection) versus palliative resection, distal gastrectomy versus proximal gastrectomy, and subtotal gastrectomy versus total gastrectomy.
V. SCREENING AND EARLY DETECTION.
Early detection of gastric cancers is clearly improved with relentless investigation of persistent upper GI symptoms. In Japan, mobile screening stations equipped with video gastrocameras have resulted in early detection of gastric cancer. Gastric cancer, which was detected in 0.3% of those screened, was associated with a 95% 5-year survival rate (50% of the patients had involvement of mucosa and submucosa only). Despite such screening programs, gastric cancer remains the most common cause of cancer death in Japan. Screening of populations with routine risk factors for gastric cancer is not recommended, however, in the United States.
VI. MANAGEMENT
A. Surgery
1. Curative resection. Subtotal gastrectomy with adequate margins of grossly uninvolved stomach (3 to 4 cm) and regional lymph node dissection is the treatment of choice, and is generally considered the only potentially curative approach for patients with gastric cancer. Total gastrectomy is not superior to subtotal gastrectomy for achieving cures and should be used only when indicated by the local extent of the disease. More extensive lymphatic dissection, known as D-2 resections (e.g., of the celiac lymph nodes), omentectomy, and splenectomy are of uncertain benefit, but do not appear to be advisable outside its use in Japan.
2. Palliative resections are performed to rid patients of infected, bleeding, obstructed, necrotic, or ulcerated polypoid gastric lesions. For these purposes, a limited gastric resection may suffice. Palliative resections succeed in ameliorating symptoms about half the time.
3. Vitamin B12 deficiency develops in all patients who undergo total gastrectomy within 6 years and in 20% of patients who undergo subtotal gastrectomy within 10 years unless parenteral B12 injections are administered.
B. Chemotherapy
1. Neoadjuvant, adjuvant, or perioperative chemotherapy
a. Neoadjuvant chemotherapy. Patients with potentially resectable disease treated in phase II studies with preoperative chemotherapy, RT, or both have shown a high response rate, and some have had pathologically negative resection specimens. There have not been any randomized trials published to help discern whether response translates into resectability, time to progression, or survival advantage over no neoadjuvant therapy.
b. Adjuvant chemotherapy. Individual trials have shown mixed results in regard to the benefit of adjuvant chemotherapy over surgery alone. However, a recent meta-analysis showed that the use of adjuvant therapy
with 5-fluorouracil based regimens does reduce the risk of death related to gastric cancer compared to surgery alone. Therefore, adjuvant chemotherapy or chemotherapy and radiation are appropriate options for patients who went directly to surgery without preoperative therapy.
with 5-fluorouracil based regimens does reduce the risk of death related to gastric cancer compared to surgery alone. Therefore, adjuvant chemotherapy or chemotherapy and radiation are appropriate options for patients who went directly to surgery without preoperative therapy.
c. Perioperative chemotherapy. In a randomized phase III trial of perioperative ECF chemotherapy (epirubicin, cisplatin, and infusional 5-FU), with three cycles of preoperative and three cycles of postoperative therapy, a significant improvement was seen in overall survival compared with surgery alone. While this trial enrolled primarily patients with stomach cancer, similar benefit appeared to extend to those with adenocarcinoma of the gastroesophageal junction or lower esophagus. Cycles are given every 3 weeks as follows:
Epirubicin 50 mg/m2 IV on day 1
Cisplatin 60 mg/m2 IV on day 1
5-FU 225 mg/m2/d by continuous IV infusion on days 1 to 21
In a separate randomized phase III trial, perioperative chemotherapy with 5-FU and cisplatin provided similar results. In this trial, approximately two-thirds of patients had gastroesophageal junction cancers.
2. Combined-modality therapy. Several clinical trials for potentially resectable gastric cancer have assessed sequential chemotherapy and radiation. A previously completed intergroup trial (Intergroup 0116) involving nearly 600 patients undergoing potentially curative resection randomized patients to either observation alone or to combined-modality therapy. Patients randomized to adjuvant therapy received one cycle of 5-FU and leucovorin followed by a combination of bolus 5-FU and RT. After the RT was completed, two additional cycles of 5-FU and leucovorin were given. Significant 3-year relapse-free and overall survivals were seen in the patients randomized to adjuvant therapy. The benefit of this approach appeared to be in a reduction of locoregional failures. Less benefit was seen with treatment in reducing distant failures.
3. Chemotherapy for advanced disease. Single agents produce low response rates. Combination regimens produce higher response rates but are more toxic and more costly. Cisplatin has been increasingly used in new combinations that also yield higher response rates, but the incidence of important toxic events exceeds 10%. The reported response rates are about 20% for 5-FU alone and 10% to 50% for combination chemotherapy; the median survival times range from 5 to 11 months.
After nearly two decades of using combination chemotherapy, including mitomycin, doxorubicin, epirubicin, etoposide, methotrexate, nitrosoureas, irinotecan, taxanes, or cisplatin, there is no regimen considered standard in the setting of advanced disease.
a. ECF. The chemotherapy regimen of epirubicin, cisplatin, and continuous infusion 5-FU (ECF) was shown to have superior activity over 5-FU, doxorubicin, and methotrexate (FAMtx) in a phase III trial. Dosages for ECF are shown in section VI.B.1.c.
b. EOX. A newer version of ECF, EOX (epirubicin, oxaliplatin, and capecitabine) showed an improvement in overall survival and less toxicity compared with ECF. The dosage schedule for EOX is as follows; cycles are repeated every 3 weeks:
Epirubicin, 50 mg/m2 IV on day 1
Oxaliplatin, 130 mg/m2 IV on day 1
Capecitabine, 625 mg/m2/dose twice daily days 1 to 21
c. DCF. The use of docetaxel (Taxotere) has also been of benefit. As assessed in a trial comparing docetaxel, cisplatin (DCF), and 5-FU versus cisplatin
and 5-FU (CF), the combination of DCF provided improved overall survival. However, both DCF and modified DCF may result in significant toxicity. Nearly 30% of patients receiving modified DCF were hospitalized. DCF is given in 3-week cycles as follows:
and 5-FU (CF), the combination of DCF provided improved overall survival. However, both DCF and modified DCF may result in significant toxicity. Nearly 30% of patients receiving modified DCF were hospitalized. DCF is given in 3-week cycles as follows:
(1) DCF
Docetaxel 75 mg/m2 IV on day 1 Cisplatin 75 mg/m2 IV on day 1 5-FU 750 mg/m2/d by continuous IV infusion on days 1 to 5
(2) Modified DCF using the following has shown comparable outcomes:
Docetaxel 40 mg/m2 IV on day 1
Cisplatin 40 mg/m2 IV on day 1
5-FU 400 mg/m2/d by continuous IV infusion on days 1 to 5
d. FOLFOX/XELOX. While triplets have generally shown the highest response rates and overall survivals, the toxicity of these combinations can make them difficult to administer. FOLFOX or XELOX may provide similar outcomes with less toxicity.
e. Carboplatin/Paclitaxel. This combination also has meaningful activity with manageable toxicity.
f. Trastuzumab. In patients with gastric or gastroesophageal junction tumors overexpressing Her2/neu, trastuzumab added to chemotherapy significantly enhances outcomes, including overall survival. All patients should be assessed for the use of trastuzumab unless contraindications exist. Overall approximately 25% of gastroesophageal adenocarcinomas will overexpress Her2/neu at a level appropriate for the use of trastuzumab. It is important to work with the pathologist to define the level of expression as the criteria differ from those used in breast cancer. Dosages are given in Chapter 4, Section VII.J.
C. RT
1. Localized disease. RT alone has not proved useful for treating gastric cancer. RT (4,000 cGy in 4 weeks) in combination with 5-FU (15 mg/kg IV on the first 3 days of RT), however, appears to improve survival over RT alone in patients with localized but unresectable cancers. Intraoperative radiation therapy (IORT) allows high doses of radiation to the tumor bed or residual disease while permitting the exclusion of mobile radiosensitive normal tissues from the area irradiated. Trials are limited to single institutional experiences; therefore, generalizing from such trials is difficult. Selected patients may benefit from IORT, particularly when combined with supplemental external-beam radiation and chemotherapy. Long-term survival has been reported in some patients treated in this fashion for residual disease after surgery.
2. Advanced disease. Gastric adenocarcinoma is relatively radioresistant and requires high doses of radiation with attendant toxic effects to surrounding organs. RT may be useful for palliating pain, vomiting due to obstruction, gastric hemorrhage, and metastases to bone and brain.
COLORECTAL CANCER
I. EPIDEMIOLOGY AND ETIOLOGY
A. Incidence. Colorectal cancer is the second most common cause of cancer mortality after lung cancer in the United States and ranks third in frequency among primary sites of cancer in both men and women. Nearly one million cases are diagnosed annually worldwide, accounting for 9% to 10% of human cancers. Peak incidence
rates are observed in Europe, the United States, Australia, and New Zealand. The lowest incidence rates are noted in India and South America and among Arab Israelis. A 10-fold variability is noted from highest to lowest regional incidence rates. Both the incidence and the mortality rates have declined in the United States since they peaked in 1985, a phenomenon thought to be a consequence of increased screening for and removal of premalignant polyps as well as potentially a more widespread use of aspirin and other nonsteroidal antirheumatic agents. Studies of migrant populations have discerned that the incidence of colorectal cancer reflects country of residence and not the country of origin. This suggests that overall environmental influences outweigh genetic trends for populations in which the experiences of those people with inherited special risk are pooled with those of lesser risk. Rural dwellers have a lower incidence of colorectal cancer than do urbanites. In the United States, cancer of the colon/rectum is more common in the East and the North than in the West and the South.
rates are observed in Europe, the United States, Australia, and New Zealand. The lowest incidence rates are noted in India and South America and among Arab Israelis. A 10-fold variability is noted from highest to lowest regional incidence rates. Both the incidence and the mortality rates have declined in the United States since they peaked in 1985, a phenomenon thought to be a consequence of increased screening for and removal of premalignant polyps as well as potentially a more widespread use of aspirin and other nonsteroidal antirheumatic agents. Studies of migrant populations have discerned that the incidence of colorectal cancer reflects country of residence and not the country of origin. This suggests that overall environmental influences outweigh genetic trends for populations in which the experiences of those people with inherited special risk are pooled with those of lesser risk. Rural dwellers have a lower incidence of colorectal cancer than do urbanites. In the United States, cancer of the colon/rectum is more common in the East and the North than in the West and the South.
The risk for colorectal cancer increases with age, but 3% of colorectal cancers occur in patients younger than 40 years of age. The incidence is 19 per 100,000 population for those younger than 65 years of age and 337 per 100,000 among those older than 65 years of age. The median age of diagnosis is around 70 years. It was estimated that, in the United States in 2010, 143,000 new cases of colorectal cancer developed and an estimated 51,400 persons died from the disease. In the United States, a person of average risk has a 5% lifetime risk for developing colorectal cancer.
B. Etiology. Multiple forces drive the transformation of healthy colorectal mucosa to cancer. Inheritance and environmental factors, such as maintaining a low body mass index and exercising regularly, correlate with lower incidence rates, but the extent of the interdependence of these two factors as causative variables remains unknown.
1. Polyps. The main importance of polyps is the well-recognized potential of a subset to evolve into colorectal cancer. The evolution to cancer is a multistage process that proceeds through mucosal cell hyperplasia, adenoma formation, and growth and dysplasia to malignant transformation and invasive cancer. Environmental carcinogens may result in the development of cancer regardless of a patient’s genetic background, but patients with genetically susceptible mucosa inherit a predisposition to abnormal cellular proliferation. Oncogene activation, tumor suppressor gene inactivation, deficient DNA mismatch repair enzymes, and chromosomal deletion may lead to adenoma formation, growth with increasing dysplasia, and invasive carcinoma.
a. Types of polyps. Histologically, polyps are classified as neoplastic or nonneoplastic. Nonneoplastic polyps have no malignant potential and include hyperplastic polyps, mucous retention polyps, hamartomas (juvenile polyps), lymphoid aggregates, and inflammatory polyps. Neoplastic polyps (or adenomatous polyps) have malignant potential and are classified according to the World Health Organization system as tubular (microscopically characterized by networks of complex branching glands), tubulovillous (mixed histology), or villous (microscopically characterized by relatively short, straight glandular structures) adenomas, depending on the presence and volume of villous tissue. Polyps larger than 1 cm in diameter, those with high-grade dysplasia, and those with predominantly villous histology are associated with higher risk for colorectal cancer and are termed screen-relevant neoplasias. Colonoscopic polypectomy and subsequent surveillance can reduce the incidence of colon cancer by 90%, compared with that observed in unscreened controls.
b. Frequency of polyp types. About 70% of polyps removed at colonoscopy are adenomatous, 75% to 85% of which are tubular (no or minimal villous tissue), 10% to 25% are tubulovillous (<75% villous tissue), and fewer than 5% are villous (>75% villous tissue). The incidence of synchronous adenomas in patients with one known adenoma is 40% to 50%.
c. Dysplasia may be classified as low and high grade. About 6% of adenomatous polyps exhibit high-grade dysplasia and 5% contain invasive carcinoma at the time of diagnosis.
d. The malignant potential of adenomas correlates with increasing size, the presence and the degree of dysplasia in a villous component, and the patient’s age. Small colorectal polyps (smaller than 1 cm) are not associated with increased occurrence of colorectal cancer; the incidence of cancer, however, is increased 2.5- to 4-fold if the polyp is larger than 1 cm and 5- to 7-fold in patients who have multiple polyps. The study of the natural history of untreated polyps larger than 1 cm showed that the risk for progression to cancer is 2.5% at 5 years, 8% at 10 years, and 24% at 20 years. The time to malignant progression depends on the severity of dysplasia, averaging 3.5 years for severe dysplasia and 11.5 years for mild atypia.
e. Management of polyps. Because of the adenoma-cancer relationship and the evidence that resecting adenomas prevents cancer, newly detected polyps should be excised and additional polyps should be sought through colonoscopy. There are data to show that the miss rate for polyps that are potentially detectable during colonoscopy is lower when the operator exceeds an endoscope-withdrawal time of 6 minutes. A minority of polyps are flat and lack an easily detectable profile in the absence of special techniques, such as instillation of dye, to accentuate mucosal irregularities during screening.
The accuracy of colonoscopic examinations (94%) exceeds that of barium enema (67%), which is seldom used as a screening tool anymore. Additionally, with colonoscopy, therapeutic polypectomy can be accomplished during the diagnostic examination. CT colonography (virtual colonoscopy) is increasingly sensitive and specific, with refinements in software and radiologist expertise leading to sufficient improvements in the technique such that many centers offer this as a screening option, although a regular bowel preparation is required, and if relevant polyps are found, a colonoscopy will have to be performed. Fecal DNA assays that target genetic abnormalities specific to the malignant transformation of mucosal cells are now commercially available and are continuously being refined to improve their performance. The year 2000 recommendations of the American College of Gastroenterology for the management of colorectal polyps are discussed by Bond and colleagues (see Suggested Reading).
f. Intestinal polyposis syndromes. Table 9.3 summarizes familial polyposis syndromes and their histology distribution, malignant potential, and management (see Section V.B.3 for discussion of the potential benefit of anti-inflammatory drugs).
2. Diet. Populations with high intake of fat, higher caloric intakes, and low intake of fiber (fruits, vegetables, and grains) characterized as a westernized diet tend to have increased risk for colorectal cancer in most but not all studies. Higher calcium intake, calcium supplementation, vitamin D supplementation, and regular aspirin use are associated with a lower risk for colorectal polyps and cancer in some studies. Fewer tumors that overexpress Cox-2 occur in individuals who regularly use aspirin, which is known to reduce the
incidence of both polyps and cancers. Increased intake of vitamins A, C, and E and b-carotene does not appear to decrease the risk for polyp formation. The higher incidence of rectal and sigmoid cancer in men may be related to their greater consumption of alcohol. Women who have taken postmenopausal estrogen replacement therapy appear to have a lower risk for colorectal cancer than those who have not.
incidence of both polyps and cancers. Increased intake of vitamins A, C, and E and b-carotene does not appear to decrease the risk for polyp formation. The higher incidence of rectal and sigmoid cancer in men may be related to their greater consumption of alcohol. Women who have taken postmenopausal estrogen replacement therapy appear to have a lower risk for colorectal cancer than those who have not.
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3. Inflammatory bowel disease
a. Ulcerative colitis is a clear risk factor for colon cancer. About 1% of colorectal cancer patients have a history of chronic ulcerative colitis. The risk for the development of cancer in these patients varies inversely with the age of onset of the colitis and directly with the extent of colonic involvement and duration of active disease. The cumulative risk is 2% at 10 years, 8% at 20 years, and 18% at 30 years. Individuals with colon cancers associated with ulcerative colitis have a similar prognosis to sporadic cases.
The recommended approach to the increased risk for colorectal cancer in ulcerative colitis has been annual or semiannual colonoscopy to determine the need for total proctocolectomy in patients with extensive colitis of >8 years’ duration. This strategy is based on the assumption that dysplastic lesions can be detected before invasive cancer has developed. An analysis of prospective studies concluded that immediate colectomy is essential for all patients diagnosed with a dysplasia-associated mass or lesion. Most important, the analysis demonstrated that the diagnosis of dysplasia does not preclude the presence of invasive cancer. The diagnosis of dysplasia has inherent problems with sampling of specimens and with variation in agreement among observers (as low as 60%, even with experts in the field).
b. Crohn disease. Patients with colorectal Crohn disease are at increased risk for colorectal cancer, but the risk is less than that of those with ulcerative colitis. The risk is increased about 1.5 to 2 times.
4. Genetic factors
a. Family history may signify either a genetic abnormality or shared environmental factors or a combination of these factors. About 15% of all colorectal cancers occur in patients with a history of colorectal cancer in first-degree relatives. Individuals with a first-degree relative who has had colorectal cancer are more than twice as likely to develop colon cancer than those individuals with no family history.
b. Gene changes. Specific inherited (adenomatous polyposis coli [APC] gene) and acquired genetic abnormalities (ras gene point mutation; c-myc gene amplification; allele deletion at specific sites of chromosomes 5, 8, 17, and 18) appear to be capable of mediating steps in the progression from normal to malignant colonic mucosa. About half of all carcinomas and large adenomas have associated point mutations, most often in the K-ras gene. Such mutations are rarely present in adenomas smaller than 1 cm. Allelic deletions of 17p- are demonstrated in three-fourths of all colorectal carcinomas, and deletions of 5q- are demonstrated in more than one-third of colonic carcinoma and large adenomas.
Two major syndromes and several variants of these syndromes of inherited predisposition to colorectal cancer have been characterized. The two syndromes, which predispose to colorectal cancer by different mechanisms, are FAP and hereditary nonpolyposis colorectal cancer (Lynch syndrome or HNPCC).
(1) FAP. The genes responsible for FAP, APC genes, are located in the 5q21 chromosome region. Inheritance of defective APC tumorsuppressor gene leads to a virtually 100% likelihood of developing colon cancer by 55 years of age, leading to the recommendation of a total proctocolectomy for affected individuals during their 20s or 30s. Screening for polyps should begin during early teenage years. The FAP syndrome can be associated with the development of gastric and ampullary polyps, desmoid tumors, osteomas, abnormal dentition, and abnormal retinal pigmentation. Variants of FAP include Gardner and Turcot syndromes.
(2) HNPCC. The autosomal-dominant pattern of HNPCC includes Lynch syndromes I and II, both of which are associated with an increased incidence of predominantly right-sided colon cancer. This genetic abnormality in the DNA mismatch repair enzymes leads to defective excision of abnormal repeating sequences of DNA known as microsatellites (microsatellite instability [MSI]). Retention of these sequences leads to expression of a mutator phenotype characterized by frequent DNA replication errors (also called the RER+ phenotype), which predispose affected people to a multitude of primary malignancies, including cancers of the endometrium, ovary, bladder, ureter, stomach, and biliary tract.
(a) Specific mutated genes on chromosomes 2 and 3, known as hMSH2, hMLH1, hPMS1, and hPMS2, have been linked to HNPCC. Patients with the RER+ phenotype may not have a germ line abnormality and may instead have acquired abnormal methylation of DNA as the source of the absence of expression of the genes previously noted. Abnormal methylation, which silences the promoter region of mismatch repair genes preventing protein synthesis, is more common in older patients and women. Germ line testing to determine if the RER+ phenotype is inherited or acquired is necessary as a part of genetic counseling when an individual is found to have a mismatch repair defect. Immunohistochemical stains can be used to determine if a tumor is devoid of the expression of mismatch repair enzymes, and then patients with absent gene expression should undergo germ line testing to enable appropriate counseling of family members.
(b) Patients with HNPCC have a tendency to develop colon cancer at an early age, and screening should begin by 20 years of age or 5 years earlier than the age at diagnosis of the earliest affected family member for relatives of HNPCC patients. The median age of HNPCC patients with colon cancer at diagnosis was 44 years, versus 68 years for control patients in one study.
(c) The prognosis for HNPCC patients is better than for those patients with sporadic colon cancer; the death rate from colon cancer for HNPCC patients is two-thirds that for sporadic cases over 10 years. One study suggests that patients with HNPCC may derive less benefit from adjuvant chemotherapy based on fluorouracil combinations than patients without this abnormality. Correlation with additional data from patients treated in the adjuvant setting and from patients with advanced disease is needed.
(d) It is important to note that apart from the genetic deficiency in mismatch repair enzyme expression, about 15% of colon cancers
exhibit the same biologic phenotype as HNPCC-derived tumors via the methylation of the promoter regions of DNA mismatch repair enzyme genes.
exhibit the same biologic phenotype as HNPCC-derived tumors via the methylation of the promoter regions of DNA mismatch repair enzyme genes.
c. Tumor location. Proximal tumors have a higher likelihood to exhibit the defective DNA mismatch repair phenotype and MSI. Distal tumors show evidence of greater chromosomal instability and may develop through the same mechanisms that underlie familial polyposis-associated colorectal cancer.
5. Smoking. Men and women smoking during the previous 20 years have three times the relative risk for small adenomas (<1 cm) but not for larger ones. Smoking for >20 years was associated with 2.5 times the relative risk for larger adenomas. It has been estimated that 5,000 to 7,000 colorectal cancer deaths in the United States can be attributed to cigarette use.
6. Other factors. Personal or family history of cancer in other anatomic sites (such as breast, endometrium, and ovary) is associated with increased risk for colorectal cancer. Exposure to asbestos (e.g., in brake mechanics) increases the incidence of colorectal cancer to 1.5 to 2 times that of the average population. Other than this association, there appears to be little relationship between occupational exposures and the incidence of colon cancer. Data indicate that HPV infection of the columnar mucosa of the colon may cause benign and malignant neoplasia.
II. PATHOLOGY AND NATURAL HISTORY
A. Histology. Ninety-eight percent of colorectal cancers above the anal verge are adenocarcinomas. Cancers of the anal canal are most often squamous cell or basaloid carcinomas. Carcinoid tumors cluster around the rectum and cecum and spare the rest of the colon and are distinguished from undifferentiated small cell neuroendocrine tumors of the colon by their tendency to be both well differentiated and indolent in their behavior.
B. Location. Two-thirds of colorectal cancers occur in the left colon and one-third in the right colon, although women more often develop right-sided tumors. About 20% of colorectal cancers develop in the rectum. Rectal tumors can be detected by digital rectal examination in 75% of cases. Nearly 3% of colorectal adenocarcinomas are multicentric, and the risk for developing a second primary tumor in the colon is estimated to be approximately 1% per year.
C. Clinical presentation. The common clinical complaints of patients with colorectal cancer relate to the size and location of the tumor. Right-sided colonic lesions are often asymptomatic but when symptoms are manifested, these tumors most often result in dull and ill-defined abdominal pain, bleeding, and symptomatic anemia (causing weakness, fatigue, and weight loss), rather than in colonic obstruction. Left-sided lesions lead commonly to changes in bowel habits, bleeding, gas pain, decrease in stool caliber, constipation, increased use of laxatives, and colonic obstruction. Sometimes, distant metastases, in particular liver metastases, can cause the initial clinical symptoms.
D. Clinical course. Metastases to the regional lymph nodes are found in 40% to 70% of cases at the time of resection. Venous or lymphatic invasion is found in up to 60% of cases. Metastases occur most frequently in the liver, peritoneal cavity, and lung, followed by the adrenals, ovaries, and bone. Metastases to the brain, while rare, are noted more commonly as survival with distant disease is extended by better treatments. Rectal cancers are three times more likely to recur locally than are proximal colonic tumors, in part because the anatomic confines of the rectum preclude wide resection margins and in part because the rectum lacks an outer serosal layer through most of its course. Because of the
venous and lymphatic drainage of the rectum into the inferior vena cava (as opposed to the venous drainage of the colon into the portal vein and variable lymphatic drainage), rectal cancers have a higher incidence of lung metastasis compared with colon cancers that more frequently recurs first in the liver.
venous and lymphatic drainage of the rectum into the inferior vena cava (as opposed to the venous drainage of the colon into the portal vein and variable lymphatic drainage), rectal cancers have a higher incidence of lung metastasis compared with colon cancers that more frequently recurs first in the liver.
III. DIAGNOSIS
A. Diagnostic studies. After the clinical diagnosis of colorectal cancer is made, several diagnostic and evaluative steps should be taken.
1. Biopsy confirmation of malignancy via colonoscopy or via CT-guided fineneedle aspiration is important.
2. General evaluation includes a complete physical examination with digital rectal examination, CBC, LFT, and chest imaging.
3. Carcinoembryonic antigen (CEA) screening is recommended by the American Society of Clinical Oncology (ASCO) as a means of identifying early recurrence despite the lack of elevation in 40% of individuals with metastatic disease. A preoperative CEA can be useful as a prognostic factor and in determining if the primary tumor is associated with CEA elevation. Preoperative CEA elevation implies that CEA may aid in early identification of metastases because metastatic tumor cells are more likely to result in CEA elevation in this circumstance.
4. CT or MRI with contrast of the chest, abdomen, and pelvis may identify small lung, liver, or intraperitoneal metastases.
5. Endoscopy (or CT colonography) is indicated to assess the entire colonic mucosa because about 3% of patients have synchronous colorectal cancers and a larger percentage have additional premalignant polyps.
6. EUS
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