CARCINOMA OF STOMACH
Gastric cancer affects more than 22,000 Americans yearly. Cancer of the stomach is seen more than twice as often in men as in women. It is essentially a disease of middle and old age, about 85% of cases arising after the age of 40. Gastric cancer was previously the most common malignant neoplasm causing death in the male population, but today its incidence has slowly decreased, to between 16% and 25%. The increased incidences of lung carcinoma and esophageal cancer, primarily esophageal adenocarcinoma, have now caused these cancers to become the leading malignant causes of death in men. In women, cancers of the uterus and of the breast are more frequent than of the stomach.
The most common type of gastric cancer is adeno- carcinoma, which arises from the glands in the stomach lining. Other kinds of gastric cancer are lymphomas, GISTs, and carcinoid tumors.
Gastric cancer is a multifactorial disease and has several potential contributory factors. H. pylori infection is a risk factor in 70% of gastric cancers worldwide, but only 2% of people with the infection develop stomach cancer. The mechanism by which H. pylori induces stomach cancer potentially involves the action of H. pylori virulence factors such as CagA and chronic inflammation. Smoking increases the risk of developing gastric cancer; in smokers most tumors occur in the upper part of the stomach near the esophagus. Some studies show increased risk with alcohol consumption. Dietary factors are not proven causes, although nitrates and nitrites in cured meats can be converted into com- pounds that have been found to cause stomach cancer in animals. People may possess certain risk factors, such as those that are physical or genetic, that can alter their susceptibility for gastric cancer. Heredity may well play a part, because not too infrequently gastric cancer has been observed for several generations in members of the same family. A genetic risk factor for gastric cancer is a defect of the CDH1 gene known as hereditary diffuse gastric cancer. Atrophic gastritis, though by no means invariably leading to cancer, is considered by many a precancerous, or at least a potentially precancerous, lesion. Transitional changes from an atrophic mucosa to hyperplastic and papillomatous areas have been demonstrated. Chronic gastric ulcers can rarely undergo malignant transformation. About 17% of all gastric cancers arise in ulcers, and approximately 10% of benign nonhealing ulcers may later become malignant. It is always a matter of primary concern for the physician to exclude malignancy of a gastric ulcer with endoscopic evaluation and biopsies, with follow-up to ensure complete healing of benign gastric ulcers.
The treatment of stomach cancer generally involves a team approach, with surgical, medical, and radiation oncologists. Surgical resection with an adequate lymphadenectomy is essential for a cure. Team members treat patients with chemotherapy and radiation therapy before or following surgery; this has recently been proven to improve the cure rate for this disease. Some patients may undergo only chemotherapy before and after surgery.
CARCINOMA NEAR THE CARDIA AND IN THE FUNDUS
Gastric cancer may develop in any part of the stomach. From a clinical point of view, by reason of the diagnostic, prognostic, and operative-technical aspects, it is reasonable to differentiate two types of carcinoma in the upper portions of the stomach, namely, those located in the cardia (which involves the gastroesophageal junction) and those occupying the fundus.
The cardiac carcinoma, even in its earlier stages, inter-feres with the free passage of food, causing marked dysphagia. This fact often permits a relatively early diagnosis. Thus, it is not surprising that the operative treatment of these tumors yields probably the best long-term results of treatment of all carcinomas of the stomach. In contrast, fundic carcinoma, like other neoplasms in the so-called “silent” gastric zones, remains undiscovered usually for a long time. It often infiltrates in the direction of the major curvature. Because the tumors have a marked tendency to bleed once they have reached a certain size, severe chronic anemia or a sudden hemorrhage may give the first late clue to their existence.
The cardiac carcinoma often exceeds the bounds of the stomach, either by submucosal infiltration or by more superficial extension, and narrows the cardiac orifice or even the most distal portions of the esophagus. In such instances, it is difficult to differentiate by x-ray or even endoscope a cardiac carcinoma from primary cancer of the distal esophagus. This question may sometimes be decided by endoscopic biopsies with evaluation by a pathologist. Otherwise, the x-ray diagnosis of cancer in the upper part of the stomach is relatively easy, particularly if the growth has altered the anatomic relation of stomach and esophagus. If a stenosis is present, the adjacent portion of the esophagus will be dilated and entry of the barium meal into the stomach will be delayed. When doubts exist as to the diagnosis, the age of the patient, the past history, and endoscopic results may help to exclude achalasia and other benign stenotic lesions (esophagitis, peptic esophageal ulcer, strictures deriving from corrosion). If passage through the cardia is not disturbed, the tumor may be overlooked, particularly if one fails to examine the fundic region. Occasionally, a fundic carcinoma may be flat and infiltration may have proceeded so superficially and broadly that the gastric contour is altered very little.
Surgically, the cardiac carcinoma is best approached by a left thoracotomy or thoracoabdominal incision, because these approaches provide space for additional resection of the esophagus if necessary. Tumors of the fundus, located at a reasonable distance from the cardiac orifice, can be handled through the abdominal approach, because a subdiaphragmatic transsection of the esophagus seems to fulfill the requirements of a radical removal of the neoplastic tissues. Should doubts arise during operation that the subdiaphragmatic esophageal resection is adequate, the field can be widened by prolonging the incision into the thoracic wall and the diaphragm, or by continuing the operation by means of a separate thoracotomy. The distal portion of the stomach should not be removed unless absolutely necessary, because of the extension of the tumor. The physiologic significance of preserving a segment of the stomach has been demonstrated experimentally as well as clinically.
EARLY CARCINOMA OF STOMACH
Some gastric cancers start with a relatively sharply circumscribed area of infiltration, spreading superficially on an almost even level, without polypoid proliferation and showing little, if any, ulceration. Of the numerous pathologic-anatomic forms in which carcinoma of the stomach can make its appearance, this is the one that most often escapes early clinical recognition, because it leaves the mucosal pattern and the contour of the stomach unchanged for a long time, until the malignant growth has involved a large area. In the early stages, this type expands only within the mucosal layer; then it seizes the submucosa and only much later encroaches upon the muscular coat. Its most frequent location is the lesser curvature between the pylorus and the angular incisure. Irregular flattening and breaks in the mucosal folds; distortion of the rugae, particularly where they begin and end; more or less frank epithelial defects; and, sometimes, small bleeding areas of erosion are the macroscopically visible characteristics of this slow-growing tumor in its early stages. As time passes, local inflammatory reactions and the extension of the neoplasm in the muscularis takes place. On x-ray examination, first a scarcely noticeable but then an increasingly striking stiffening of the region appears. The normal peristaltic waves are interrupted in the rigid segment of the gastric wall. A polygram of the peristaltic waves by repeated roentgenographic views of several phases of a peristaltic movement may be informative in these cases. In view of the fact that the contour of the organ is not changed either by the formation of an ulcer crater or by endo- phytic growth, only the most careful fluoroscopic examination of the condition of the gastric wall or a series of spot films or a videofluoroscopy will permit one to show this type of gastric carcinoma.
From the histopathologic point of view, the most frequent malignant growth in the stomach is adenocarcinoma. Its macroscopic appearance, as the surgeon or the pathologist sees it, depends essentially upon the time or the developmental stage at which it happens to be recognized. It its early stages, it may be a relatively small, cauliflowerlike mass only a few centimeters in diameter, which projects into the lumen. Unfortunately, however, it reaches far larger dimensions (though still being well circumscribed) before causing local symptoms and before having metastasized to more distant structures. In any event, the size of the tumor alone is not indicative of the spread to neighboring organs. If it grows in the prepyloric area, as do about two thirds of gastric cancers, it may bring about early signs of obstruction, gastric enlargement, and disturbances of the motoric function of the stomach, which lead to its discovery. Macroscopically visible invasion of the pylorus proper or of the duodenum by a gastric adeno- carcinoma is an extreme rarity.
Gastric adenocarcinoma usually arises from a broad base. Less frequently, a papillary adenocarcinoma arises from a polyp or pedunculated adenoma and invades the gastric wall through the stalk. Some adenocarcinomas assume on their surface a polypoid or fungating appearance, with necrotic and ulcerating foci. On the cut section, this “vegetative” type of carcinoma, as it has been called, presents a yellowish, solid mass in a gray fibrillar stroma. The histologic architecture of the adenocarcinoma may sometimes exhibit the typical columnar cell arrangement, with formation of glandular spaces, but it is usually more complicated and varies considerably. Atypical tubular glands may replace the normal mucosal pattern, penetrating into the muscularis mucosae or spreading from the submucosa as far as the serosal coat. The nuclei of the tumor cells stain distinctly darker than do those of the normal surrounding glands. At times, the tumor consists only of closely grouped alveoli with cylindrical and cuboidal cells and hyperchromatic nuclei. The cells lining these alveoli may, in some cases, contain substantial amounts of mucus, and, occasionally, the entire tumor may be replaced by gelatinous or slimy colloid material, in which only a few embedded cancer cells may be found. In such instances, the displaced nuclei and overextended, ruptured, or disintegrated cells in this mucinous matrix may create a most complex histologic picture.
Linitis plastica, also known as Brinton disease, scirrhous carcinoma, or leather bottle stomach, is a morphologic variant of gastric cancer with a diffuse and infiltrating form. This rare type of stomach cancer begins in the lining of the stomach and spreads to the muscles of the stomach wall. This causes the wall to become thick, hard, and rubbery, which leads to trouble in digesting food. Another cause of linitis plastica is metastatic infiltration of the stomach, particularly by breast or lung carcinoma.
Linitis plastica produces a diffuse thickening of all layers and involves a large part of the gastric wall (sometimes, the entire wall), which becomes contracted and rigid. The scirrhous malignant lesion usually begins in the pyloric canal and may, in some cases, remain limited to this region, where it may soon cause signs of obstruction, because the profuse growth of its fibrotic components markedly reduces the lumen. The same phenomenon takes place over the whole gastric cavity, when the scirrhous growth has expanded extensively over the entire lining. The mucosal folds become immobile and inflexible, while simultaneously, as a result of the abundant formation of fibrous tissue, the whole organ shrinks, assuming a shape that has been described as the leather bottle stomach.
Histologically, nests of epithelial cells are scattered in dense fibrous tissue, which leaves nothing of the normal gastric structures. The number of recognizable malignant cells is gradually reduced, and, in the advanced stages, it is difficult to demonstrate their presence except by the most painstaking microscopic study. In some cases the fibrotic reaction has gone so far as to make recognition of the original nature of the process practically impossible. In view of such proliferation of connective tissue, it is not surprising that the primary cause was formerly considered to be a chronic reactive inflammatory process and received, accordingly, the designation linitis plastica.
The roentgenographic appearance of linitis plastica, or scirrhous carcinoma, varies, of course, depending upon the extent to which the gastric wall has become involved. If limited to the pyloric region, a localized area of narrowing, distinct irregularities of the contour, and the disappearance of the normal mucosal markings leave no doubt as to the diagnosis. With the fibrotic process sufficiently advanced at the pyloric canal to cause a more or less complete obstruction and the more proximal parts of the wall still maintaining their normal structure and extensibility, the stomach is markedly dilated and can retain food ingested during the previous 24 hours or even over a longer period of time. If, however, the neoplasm has spread over a larger segment or, as happens not infrequently, over the entire inner aspect of the stomach, the cavity of the stomach presents itself as a narrow tube with no mucous membrane pattern visible. The contour in such cases may be erratically distorted, and the barium meal rushes through the organ because of the rigidity of the pylorus, which, under these circumstances, is permanently opened. Gastric peristalsis in these patients is conspicuously absent. Because the obstruction in advanced linitis plastica is located at the cardia, it is the esophagus that eventually becomes dilated.
With x-ray findings as clear as those described above, the diagnosis of scirrhous carcinoma presents no difficulties, and laboratory data, such as achlorhydria, hypo- chromic or hyperchromic macrocytic anemia, or occult blood resulting from the destruction of the glands or from erosions, provide little more than mere additional supporting or confirming information. Upper endos- copy, at times difficult to perform because of the rigidity and lack of air in the stomach, may help establish the diagnosis, although the endoscopic picture of an infiltrating carcinoma may now and then resemble that of a lymphoma or hypertrophic gastritis, necessitating a biopsy for differentiation. The unfortunate feature of the situation, however, is that these characteristic x-ray pictures are seen only in a late stage of the disease when the presence of lymph node metastases can be expected. Symptoms develop rather insidiously, and patients come for medical care at a time when total gastrectomy, the only sensible treatment for this condition, can scarcely be more than palliative. The prognosis may become more favorable for the infiltrating type of carcinoma, as for other types of cancer of the stomach, when the methods for early recognition improve and when institutions such as cancer prevention clinics are more widely used.
Many pathologists separate ulcerative cancer as a special type and consider it the most common form of early detectable gastric carcinoma. Though all forms of cancer of the stomach may become necrotic in parts and undergo ulcerative degeneration, it is particularly adenocarcinoma and its papillary and polypoid varieties that tend to ulcerate while still relatively small. Necroses and loss of substance on the surface of a diffuse, infiltrating, scirrhous carcinoma are relatively rare and only superficial, whereas the funguslike, proliferating, and more circumscribed (but still broadly infiltrating) neoplasms tend often to become deeply ulcerated by the sloughing of substantial parts of their central segments, probably because their blood supply cannot keep pace with their rapid growth. In such cases, especially with the early superficially spreading type, it may be extremely difficult, if not impossible, to separate the ulcerating carcinoma diagnostically from a benign chronic, callous, and penetrating peptic ulcer. The issue is further complicated by the fact that a not negligible percentage of ulcers that we e originally benign may undergo malignant alteration.
The functional disturbances brought about by cancer of the stomach depend essentially on the tumor’s location and size. The great majority of patients feel no discomfort or pain in the early stages and report to their physician only when the neoplasm has reached dimensions that cause obstruction of the pylorus or cardiac orifice or reduction of the entire gastric lumen or secreting surface. At this time a gamut of manifestations, from vague epigastric discomfort, nausea, and anorexia to weight loss and cachexia, may be present, pointing to a serious digestive dysfunction. If the tumor happens to invade the nerves, pain may become one of the early or actually the earliest symptom. In such cases, as well as with manifestations of an ulcerating tumor, the physician faces the most difficult problem of differentiation between a cancer and a benign ulcer. In any event, whatever the symptoms and whenever they appear, it has been estimated that at least half of the patients with gastric carcinoma do not seek medical attention until the tumor has extended beyond the stomach.
All types of carcinoma of the stomach either spread by direct extension to neighboring organs or metastasize by means of the lymphatics or bloodstream. Some types have a greater tendency and some (e.g., scirrhous carcinoma) a lesser tendency to produce metastases. The regional lymph nodes become involved, sometimes very early and usually, though by no means always, in a definite sequence. With the lesser curvature being, to a certain degree, the preferred site, the lymph nodes of the upper left, anterior, and posterior walls of the stomach and their drainage system along the left gastric artery and the coronary vein are those first and most frequently affected. A rather serious prognostic significance must be attached to an early involvement of the nodes in the pyloric area, including the suprapancreatic nodes and those near the hilus of the liver, which excludes any possibility of radical removal of the malignancy. Secondary growth of malignant tumor cells in the lymph nodes of the prepyloric, pyloric, and pancreatic regions and in the hepatoduodenal ligament may be accompanied clinically by icterus, as a result of an obstruction of the common bile duct, subsequent biliary stasis, and dilatation of the gallbladder (Courvoisier law or sign). The liver is held as a site of predilection for metastases of gastric cancer, either by direct spread or through the lymphatic routes just mentioned. It is possible, but probably not common, for cancer cells to enter the liver by way of the portal circulation. Similarly, though less frequently, metastases develop in the lower part of the esophagus, colon, pancreas, and gallbladder.
Metastatic involvement of the lymph nodes along the greater curvature, in the gastrocolic ligament, and in the omentum majus occurs less regularly than in those structures along the lesser curvature. Occasionally, the cancer cells are carried via celiac lymph nodes to the thoracic duct and the mediastinal and supraclavicular lymph nodes (Virchow node).
Hematogenic metastases in lung, bone, and brain (in that order of frequency) are relatively rare and are encountered, of course, only in far-advanced cases.
The direct transplantation of aberrant cancer cells upon the peritoneum represents a special type of spread. It requires complete penetration of the stomach wall and, thus, is again a phenomenon of an advanced stage of gastric cancer. Once the serosa has become involved, cancer cells may be set free and may settle on the surface of any organ within the peritoneal cavity. The ovaries seem to be the most frequent site, sometimes the only site of such implanted metastases, which, in this organ, develop into a histologically rather characteristic secondary neoplasm known as Krukenberg tumor. If conditions permit, the simultaneous resection of the primary tumor and the ovarian metastases seems justified and worth serious consideration.
Another, certainly not infrequent, site of metastases is the pelvic peritoneum, where they may project into the rectum as a shelflike structure (rectal shelf of Blumer) and can be felt on rectal examination.