Chapter 39: Upper Gastrointestinal Tract Cancers

Upper gastrointestinal cancers include malignancies arising in the esophagus, stomach, and small intestine.

INCIDENCE AND ETIOLOGY

Cancer of the esophagus is an increasingly common and extremely lethal malignancy. The diagnosis was made in 18,170 Americans in 2014 and led to 15,450 deaths. Almost all esophageal cancers are either squamous cell carcinomas or adenocarcinomas; the two histologic subtypes have a similar clinical presentation but different causative factors.

Worldwide, squamous cell carcinoma is the more common cell type, having an incidence that rises strikingly in association with geographic location. It occurs frequently within a region extending from the southern shore of the Caspian Sea on the west to northern China on the east, encompassing parts of Iran, central Asia, Afghanistan, Siberia, and Mongolia. Familial increased risk has been observed in regions with high incidence, although gene associations are not yet defined. High-incidence “pockets” of the disease are also present in such disparate locations as Finland, Iceland, Curaçao, southeastern Africa, and northwestern France. In North America and western Europe, the disease is more common in blacks than whites and in males than females; it appears most often after age 50 and seems to be associated with a lower socioeconomic status. Such cancers generally arise in the cervical and thoracic portions of the esophagus.

A variety of causative factors have been implicated in the development of squamous cell cancers of the esophagus (Table 39-1). In the United States, the etiology of such cancers is primarily related to excess alcohol consumption and/or cigarette smoking. The relative risk increases with the amount of tobacco smoked or alcohol consumed, with these factors acting synergistically. The consumption of whiskey is linked to a higher incidence than the consumption of wine or beer. Squamous cell esophageal carcinoma has also been associated with the ingestion of nitrates, smoked opiates, and fungal toxins in pickled vegetables, as well as mucosal damage caused by such physical insults as long-term exposure to extremely hot tea, the ingestion of lye, radiation-induced strictures, and chronic achalasia. The presence of an esophageal web in association with glossitis and iron deficiency (i.e., Plummer-Vinson or Paterson-Kelly syndrome) and congenital hyperkeratosis and pitting of the palms and soles (i.e., tylosis palmaris et plantaris) have each been linked with squamous cell esophageal cancer, as have dietary deficiencies of molybdenum, zinc, selenium, and vitamin A. Patients with head and neck cancer are at increased risk of squamous cell cancer of the esophagus.

For unclear reasons, the incidence of squamous cell esophageal cancer has decreased somewhat in both the black and white populations in the United States over the past 40 years, whereas the rate of adenocarcinoma has risen sevenfold, particularly in white males (male-to-female ratio of 6:1). Whereas squamous cell cancers comprised the vast majority of esophageal cancers in the United States as recently as 40–50 years ago, more than 75% of esophageal tumors are now adenocarcinomas, with the incidence of this histologic subtype continuing to increase rapidly. Understanding the cause for this increase is the focus of current investigation.

Several strong etiologic associations have been observed to account for the development of adenocarcinoma of the esophagus (Table 39-2). Such tumors arise in the distal esophagus in association with chronic gastric reflux, often in the presence of Barrett’s esophagus (replacement of the normal squamous epithelium of the distal esophagus by columnar mucosa), which occurs more commonly in obese individuals. Adenocarcinomas arise within dysplastic columnar epithelium in the distal esophagus. Even before frank neoplasia is detectable, aneuploidy and p53 mutations are found in the dysplastic epithelium. These adenocarcinomas behave clinically like gastric adenocarcinomas, although they are not associated with Helicobacter pylori infections. Approximately 15% of esophageal adenocarcinomas overexpress the HER2/neu gene.

CLINICAL FEATURES

About 5% of esophageal cancers occur in the upper third of the esophagus (cervical esophagus), 20% in the middle third, and 75% in the lower third. Squamous cell carcinomas and adenocarcinomas cannot be distinguished radiographically or endoscopically.

Progressive dysphagia and weight loss of short duration are the initial symptoms in the vast majority of patients. Dysphagia initially occurs with solid foods and gradually progresses to include semisolids and liquids. By the time these symptoms develop, the disease is already very advanced, because difficulty in swallowing does not occur until >60% of the esophageal circumference is infiltrated with cancer. Dysphagia may be associated with pain on swallowing (odynophagia), pain radiating to the chest and/or back, regurgitation or vomiting, and aspiration pneumonia. The disease most commonly spreads to adjacent and supraclavicular lymph nodes, liver, lungs, pleura, and bone. Tracheoesophageal fistulas may develop, primarily in patients with upper and midesophageal tumors. As with other squamous cell carcinomas, hypercalcemia may occur in the absence of osseous metastases, probably from parathormone-related peptide secreted by tumor cells (Chap. 54).

DIAGNOSIS

Attempts at endoscopic and cytologic screening for carcinoma in patients with Barrett’s esophagus, while effective as a means of detecting high-grade dysplasia, have not yet been shown to reduce the likelihood of death from esophageal adenocarcinoma. Esophagoscopy should be performed in all patients suspected of having an esophageal abnormality, to both visualize and identify a tumor and also to obtain histopathologic confirmation of the diagnosis. Because the population of persons at risk for squamous cell carcinoma of the esophagus (i.e., smokers and drinkers) also has a high rate of cancers of the lung and the head and neck region, endoscopic inspection of the larynx, trachea, and bronchi should also be carried out. A thorough examination of the fundus of the stomach (by retroflexing the endoscope) is imperative as well. The extent of tumor spread to the mediastinum and para-aortic lymph nodes should be assessed by computed tomography (CT) scans of the chest and abdomen and by endoscopic ultrasound. Positron emission tomography scanning provides a useful assessment of the presence of distant metastatic disease, offering accurate information regarding spread to mediastinal lymph nodes, which can be helpful in defining radiation therapy fields. Such scans, when performed sequentially, appear to provide a means of making an early assessment of responsiveness to preoperative chemotherapy.

TREATMENT

GASTRIC ADENOCARCINOMA

Incidence and Epidemiology

For unclear reasons, the incidence and mortality rates for gastric cancer have decreased in the United States during the past 80 years, although the disease remains the second most frequent cause of worldwide cancer-related death. The mortality rate from gastric cancer in the United States has dropped in men from 28 to 5.8 per 100,000 persons, whereas in women, the rate has decreased from 27 to 2.8 per 100,000. Nonetheless, in 2014, 22,220 new cases of stomach cancer were diagnosed in the United States, and 10,990 Americans died of the disease. Although the incidence of gastric cancer has decreased worldwide, it remains high in such disparate geographic regions as Japan, China, Chile, and Ireland.

The risk of gastric cancer is greater among lower socioeconomic classes. Migrants from high- to low-incidence nations maintain their susceptibility to gastric cancer, whereas the risk for their offspring approximates that of the new homeland. These findings suggest that an environmental exposure, probably beginning early in life, is related to the development of gastric cancer, with dietary carcinogens considered the most likely factor(s).

Pathology

About 85% of stomach cancers are adenocarcinomas, with 15% due to lymphomas, gastrointestinal stromal tumors (GISTs), and leiomyosarcomas. Gastric adenocarcinomas may be subdivided into two categories: a diffuse type, in which cell cohesion is absent, so that individual cells infiltrate and thicken the stomach wall without forming a discrete mass; and an intestinal type, characterized by cohesive neoplastic cells that form glandlike tubular structures. The diffuse carcinomas occur more often in younger patients, develop throughout the stomach (including the cardia), result in a loss of distensibility of the gastric wall (so-called linitis plastica, or “leather bottle” appearance), and carry a poorer prognosis. Diffuse cancers have defective intercellular adhesion, mainly as a consequence of loss of expression of E-cadherin. Intestinal-type lesions are frequently ulcerative, more commonly appear in the antrum and lesser curvature of the stomach, and are often preceded by a prolonged precancerous process, often initiated by H. pylori infection. Although the incidence of diffuse carcinomas is similar in most populations, the intestinal type tends to predominate in the high-risk geographic regions and is less likely to be found in areas where the frequency of gastric cancer is declining. Thus, different etiologic factor(s) are likely involved in these two subtypes. In the United States, ~30% of gastric cancers originate in the distal stomach, ~20% arise in the midportion of the stomach, and ~40% originate in the proximal third of the stomach. The remaining 10% involve the entire stomach.

Etiology

The long-term ingestion of high concentrations of nitrates found in dried, smoked, and salted foods appears to be associated with a higher risk. The nitrates are thought to be converted to carcinogenic nitrites by bacteria (Table 39-3). Such bacteria may be introduced exogenously through the ingestion of partially decayed foods, which are consumed in abundance worldwide by the lower socioeconomic classes. Bacteria such as H. pylori may also contribute to this effect by causing chronic inflammatory atrophic gastritis, loss of gastric acidity, and bacterial growth in the stomach. Although the risk for developing gastric cancer is thought to be sixfold higher in people infected with H. pylori, it remains uncertain whether eradicating the bacteria after infection has already occurred actually reduces this risk. Loss of acidity may occur when acid-producing cells of the gastric antrum have been removed surgically to control benign peptic ulcer disease or when achlorhydria, atrophic gastritis, and even pernicious anemia develop in the elderly. Serial endoscopic examinations of the stomach in patients with atrophic gastritis have documented replacement of the usual gastric mucosa by intestinal-type cells. This process of intestinal metaplasia may lead to cellular atypia and eventual neoplasia. Because the declining incidence of gastric cancer in the United States primarily reflects a decline in distal, ulcerating, intestinal-type lesions, it is conceivable that better food preservation and the availability of refrigeration for all socioeconomic classes have decreased the dietary ingestion of exogenous bacteria. H. pylori has not been associated with the diffuse, more proximal form of gastric carcinoma or with cancers arising at the gastroesophageal junction or in the distal esophagus. Approximately 10–15% of adenocarcinomas appearing in the proximal stomach, the gastroesophageal junction, and the distal esophagus overexpress the HER2/neu gene; individuals whose tumors demonstrate this overexpression benefit from treatment directed against this target (i.e., trastuzumab [Herceptin]).

Several additional etiologic factors have been associated with gastric carcinoma. Gastric ulcers and adenomatous polyps have occasionally been linked, but data on a cause-and-effect relationship are unconvincing. The inadequate clinical distinction between benign gastric ulcers and small ulcerating carcinomas may, in part, account for this presumed association. The presence of extreme hypertrophy of gastric rugal folds (i.e., Ménétrier’s disease), giving the impression of polypoid lesions, has been associated with a striking frequency of malignant transformation; such hypertrophy, however, does not represent the presence of true adenomatous polyps. Individuals with blood group A have a higher incidence of gastric cancer than persons with blood group O; this observation may be related to differences in the mucous secretion, leading to altered mucosal protection from carcinogens. A germline mutation in the E-cadherin gene (CDH1), inherited in an autosomal dominant pattern and coding for a cell adhesion protein, has been linked to a high incidence of occult diffuse-type gastric cancers in young asymptomatic carriers. Duodenal ulcers are not associated with gastric cancer.

Clinical features

Gastric cancers, when superficial and surgically curable, usually produce no symptoms. As the tumor becomes more extensive, patients may complain of an insidious upper abdominal discomfort varying in intensity from a vague, postprandial fullness to a severe, steady pain. Anorexia, often with slight nausea, is very common but is not the usual presenting complaint. Weight loss may eventually be observed, and nausea and vomiting are particularly prominent in patients whose tumors involve the pylorus; dysphagia and early satiety may be the major symptoms caused by diffuse lesions originating in the cardia. There may be no early physical signs. A palpable abdominal mass indicates long-standing growth and predicts regional extension.

Gastric carcinomas spread by direct extension through the gastric wall to the perigastric tissues, occasionally adhering to adjacent organs such as the pancreas, colon, or liver. The disease also spreads via lymphatics or by seeding of peritoneal surfaces. Metastases to intraabdominal and supraclavicular lymph nodes occur frequently, as do metastatic nodules to the ovary (Krukenberg’s tumor), periumbilical region (“Sister Mary Joseph node”), or peritoneal cul-de-sac (Blumer’s shelf palpable on rectal or vaginal examination); malignant ascites may also develop. The liver is the most common site for hematogenous spread of tumor.

The presence of iron-deficiency anemia in men and of occult blood in the stool in both sexes mandates a search for an occult gastrointestinal tract lesion. A careful assessment is of particular importance in patients with atrophic gastritis or pernicious anemia. Unusual clinical features associated with gastric adenocarcinomas include migratory thrombophlebitis, microangiopathic hemolytic anemia, diffuse seborrheic keratoses (so-called Leser-Trélat sign), and acanthosis nigricans.

Diagnosis

The use of double-contrast radiographic examinations has been supplanted by esophagogastroscopy and CT scanning for the evaluation of patients with epigastric complaints.

Gastric ulcers identified at the time of such endoscopic procedure may appear benign but merit biopsy in order to exclude a malignancy. Malignant gastric ulcers must be recognized before they penetrate into surrounding tissues, because the rate of cure of early lesions limited to the mucosa or submucosa is >80%. Because gastric carcinomas are difficult to distinguish clinically or endoscopically from gastric lymphomas, endoscopic biopsies should be made as deeply as possible, due to the submucosal location of lymphoid tumors.

The staging system for gastric carcinoma is shown in Table 39-4.

TREATMENT

PRIMARY GASTRIC LYMPHOMA

Primary lymphoma of the stomach is relatively uncommon, accounting for <15% of gastric malignancies and ~2% of all lymphomas. The stomach is, however, the most frequent extranodal site for lymphoma, and gastric lymphoma has increased in frequency during the past 35 years. The disease is difficult to distinguish clinically from gastric adenocarcinoma; both tumors are most often detected during the sixth decade of life; present with epigastric pain, early satiety, and generalized fatigue; and are usually characterized by ulcerations with a ragged, thickened mucosal pattern demonstrated by contrast radiographs or endoscopic appearance. The diagnosis of lymphoma of the stomach may occasionally be made through cytologic brushings of the gastric mucosa but usually requires a biopsy at gastroscopy or laparotomy. Failure of gastroscopic biopsies to detect lymphoma in a given case should not be interpreted as being conclusive, because superficial biopsies may miss the deeper lymphoid infiltrate. The macroscopic pathology of gastric lymphoma may also mimic adenocarcinoma, consisting of either a bulky ulcerated lesion localized in the corpus or antrum or a diffuse process spreading throughout the entire gastric submucosa and even extending into the duodenum. Microscopically, the vast majority of gastric lymphoid tumors are lymphomas of B-cell origin. Histologically, these tumors may range from well-differentiated, superficial processes (mucosa-associated lymphoid tissue [MALT]) to high-grade, large-cell lymphomas. Like gastric adenocarcinoma, infection with H. pylori increases the risk for gastric lymphoma in general and MALT lymphomas in particular. Large-cell lymphomas of the stomach spread initially to regional lymph nodes (often to Waldeyer’s ring) and may then disseminate.

TREATMENT

Leiomyosarcomas and GISTs make up 1–3% of gastric neoplasms. They most frequently involve the anterior and posterior walls of the gastric fundus and often ulcerate and bleed. Even those lesions that appear benign on histologic examination may behave in a malignant fashion. These tumors rarely invade adjacent viscera and characteristically do not metastasize to lymph nodes, but they may spread to the liver and lungs. The treatment of choice is surgical resection. Combination chemotherapy should be reserved for patients with metastatic disease. All such tumors should be analyzed for a mutation in the c-kit receptor. GISTs are unresponsive to conventional chemotherapy; yet ~50% of patients experience objective response and prolonged survival when treated with imatinib mesylate (Gleevec) (400–800 mg PO daily), a selective inhibitor of the c-kit tyrosine kinase. Many patients with GIST whose tumors have become refractory to imatinib subsequently benefit from sunitinib (Sutent) or regorafenib (Stivarga), other inhibitors of the c-kit tyrosine kinase.

Small-bowel tumors comprise <3% of gastrointestinal neoplasms. Because of their rarity and inaccessibility, a correct diagnosis is often delayed. Abdominal symptoms are usually vague and poorly defined, and conventional radiographic studies of the upper and lower intestinal tract often appear normal. Small-bowel tumors should be considered in the differential diagnosis in the following situations: (1) recurrent, unexplained episodes of crampy abdominal pain; (2) intermittent bouts of intestinal obstruction, especially in the absence of inflammatory bowel disease (IBD) or prior abdominal surgery; (3) intussusception in the adult; and (4) evidence of chronic intestinal bleeding in the presence of negative conventional and endoscopic examination. A careful small-bowel barium study should be considered in such a circumstance; the diagnostic accuracy may be improved by infusing barium through a nasogastric tube placed into the duodenum (enteroclysis). Alternatively, capsule endoscopic procedures have been used.

BENIGN TUMORS

The histology of benign small-bowel tumors is difficult to predict on clinical and radiologic grounds alone. The symptomatology of benign tumors is not distinctive, with pain, obstruction, and hemorrhage being the most frequent symptoms. These tumors are usually discovered during the fifth and sixth decades of life, more often in the distal rather than the proximal small intestine. The most common benign tumors are adenomas, leiomyomas, lipomas, and angiomas.

Adenomas

These tumors include those of the islet cells and Brunner’s glands as well as polypoid adenomas. Islet cell adenomas are occasionally located outside the pancreas; the associated syndromes are discussed in Chap. 51. Brunner’s gland adenomas are not truly neoplastic but represent a hypertrophy or hyperplasia of submucosal duodenal glands. These appear as small nodules in the duodenal mucosa that secrete a highly viscous alkaline mucus. Most often, this is an incidental radiographic finding not associated with any specific clinical disorder.

Polypoid adenomas

About 25% of benign small-bowel tumors are polypoid adenomas (see Table 40-2). They may present as single polypoid lesions or, less commonly, as papillary villous adenomas. As in the colon, the sessile or papillary form of the tumor is sometimes associated with a coexisting carcinoma. Occasionally, patients with Gardner’s syndrome develop premalignant adenomas in the small bowel; such lesions are generally in the duodenum. Multiple polypoid tumors may occur throughout the small bowel (and occasionally the stomach and colorectum) in the Peutz-Jeghers syndrome. The polyps are usually hamartomas (juvenile polyps) having a low potential for malignant degeneration. Mucocutaneous melanin deposits as well as tumors of the ovary, breast, pancreas, and endometrium are also associated with this autosomal dominant condition.

Leiomyomas

These neoplasms arise from smooth-muscle components of the intestine and are usually intramural, affecting the overlying mucosa. Ulceration of the mucosa may cause gastrointestinal hemorrhage of varying severity. Cramping or intermittent abdominal pain is frequently encountered.

Lipomas

These tumors occur with greatest frequency in the distal ileum and at the ileocecal valve. They have a characteristic radiolucent appearance and are usually intramural and asymptomatic, but on occasion cause bleeding.

Angiomas

While not true neoplasms, these lesions are important because they frequently cause intestinal bleeding. They may take the form of telangiectasia or hemangiomas. Multiple intestinal telangiectasias occur in a nonhereditary form confined to the gastrointestinal tract or as part of the hereditary Osler-Rendu-Weber syndrome. Vascular tumors may also take the form of isolated hemangiomas, most commonly in the jejunum. Angiography, especially during bleeding, is the best procedure for evaluating these lesions.

While rare, small-bowel malignancies occur in patients with long-standing regional enteritis and celiac sprue as well as in individuals with AIDS. Malignant tumors of the small bowel are frequently associated with fever, weight loss, anorexia, bleeding, and a palpable abdominal mass. After ampullary carcinomas (many of which arise from biliary or pancreatic ducts), the most frequently occurring small-bowel malignancies are adenocarcinomas, lymphomas, carcinoid tumors, and leiomyosarcomas.

ADENOCARCINOMAS

The most common primary cancers of the small bowel are adenocarcinomas, accounting for ~50% of malignant tumors. These cancers occur most often in the distal duodenum and proximal jejunum, where they tend to ulcerate and cause hemorrhage or obstruction. Radiologically, they may be confused with chronic duodenal ulcer disease or with Crohn’s disease if the patient has long-standing regional enteritis. The diagnosis is best made by endoscopy and biopsy under direct vision. Surgical resection is the treatment of choice with suggested postoperative adjuvant chemotherapy options generally following treatment patterns used in the management of colon cancer.

LYMPHOMAS

Lymphoma in the small bowel may be primary or secondary. A diagnosis of a primary intestinal lymphoma requires histologic confirmation in a clinical setting in which palpable adenopathy and hepatosplenomegaly are absent and no evidence of lymphoma is seen on chest radiograph, CT scan, or peripheral blood smear or on bone marrow aspiration and biopsy. Symptoms referable to the small bowel are present, usually accompanied by an anatomically discernible lesion. Secondary lymphoma of the small bowel consists of involvement of the intestine by a lymphoid malignancy extending from involved retroperitoneal or mesenteric lymph nodes (Chap. 16).

Primary intestinal lymphoma accounts for ~20% of malignancies of the small bowel. These neoplasms are non-Hodgkin’s lymphomas; they usually have a diffuse, large-cell histology and are of T cell origin. Intestinal lymphoma involves the ileum, jejunum, and duodenum, in decreasing frequency—a pattern that mirrors the relative amount of normal lymphoid cells in these anatomic areas. The risk of small-bowel lymphoma is increased in patients with a prior history of malabsorptive conditions (e.g., celiac sprue), regional enteritis, and depressed immune function due to congenital immunodeficiency syndromes, prior organ transplantation, autoimmune disorders, or AIDS.

The development of localized or nodular masses that narrow the lumen results in periumbilical pain (made worse by eating) as well as weight loss, vomiting, and occasional intestinal obstruction. The diagnosis of small-bowel lymphoma may be suspected from the appearance on contrast radiographs of patterns such as infiltration and thickening of mucosal folds, mucosal nodules, areas of irregular ulceration, or stasis of contrast material. The diagnosis can be confirmed by surgical exploration and resection of involved segments. Intestinal lymphoma can occasionally be diagnosed by peroral intestinal mucosal biopsy, but because the disease mainly involves the lamina propria, full-thickness surgical biopsies are usually required.

Resection of the tumor constitutes the initial treatment modality. While postoperative radiation therapy has been given to some patients following a total resection, most authorities favor short-term (three cycles) systemic treatment with combination chemotherapy. The frequent presence of widespread intraabdominal disease at the time of diagnosis and the occasional multicentricity of the tumor often make a total resection impossible. The probability of sustained remission or cure is ~75% in patients with localized disease but is ~25% in individuals with unresectable lymphoma. In patients whose tumors are not resected, chemotherapy may lead to bowel perforation.

A unique form of small-bowel lymphoma, diffusely involving the entire intestine, was first described in oriental Jews and Arabs and is referred to as immunoproliferative small intestinal disease (IPSID), Mediterranean lymphoma, or α heavy chain disease. This is a B cell tumor. The typical presentation includes chronic diarrhea and steatorrhea associated with vomiting and abdominal cramps; clubbing of the digits may be observed. A curious feature in many patients with IPSID is the presence in the blood and intestinal secretions of an abnormal IgA that contains a shortened α heavy chain and is devoid of light chains. It is suspected that the abnormal α chains are produced by plasma cells infiltrating the small bowel. The clinical course of patients with IPSID is generally one of exacerbations and remissions, with death frequently resulting from either progressive malnutrition and wasting or the development of an aggressive lymphoma. The use of oral antibiotics such as tetracycline appears to be beneficial in the early phases of the disorder, suggesting a possible infectious etiology. Combination chemotherapy has been administered during later stages of the disease, with variable results. Results are better when antibiotics and chemotherapy are combined.

CARCINOID TUMORS

Carcinoid tumors arise from argentaffin cells of the crypts of Lieberkühn and are found from the distal duodenum to the ascending colon, areas embryologically derived from the midgut. More than 50% of intestinal carcinoids are found in the distal ileum, with most congregating close to the ileocecal valve. Most intestinal carcinoids are asymptomatic and of low malignant potential, but invasion and metastases may occur, leading to the carcinoid syndrome (Chap. 51).

LEIOMYOSARCOMAS

Leiomyosarcomas often are >5 cm in diameter and may be palpable on abdominal examination. Bleeding, obstruction, and perforation are common. Such tumors should be analyzed for the expression of mutant c-kit receptor (defining GIST), and in the presence of metastatic disease, justifying treatment with imatinib mesylate (Gleevec) or, in imatinib-refractory patients, sunitinib (Sutent) or regorafenib (Stivarga).