Chapter 11, Page 5 
Chapter 11, Page 5
CARCINOMA OF THE STOMACHGASTRIC DYSPLASIAThe diagnosis of carcinoma in situ of the stomach and its differentiation from high-grade dysplasia is often difficult, if not impossible, and therefore we have combined the two categories under high-grade dysplasia. The behavior and management of both lesions is similar. Another designation used by some for these high-grade dysplasias and carcinomas in situ is "possible cancer." In Japan, possible cancer, as the name implies, is not a definitive diagnosis and is understood by the clinician to be a temporary designation until the issue can be resolved by urgent rebiopsy. High-grade dysplasia is a noninvasive neoplastic lesion. In contrast, early gastric cancer is an invasive lesion traversing the lamina propria or submucosa, and often eliciting a desmoplastic response as a result. Grading. Dysplasia is graded according to the degree of histologic abnormality as low grade or high grade, or mild, moderate, or severe dysplasia (48, 66, 102, 125, 153, 156, 163, 164, 171, 206, 270). As is true for other sites, low-grade dysplasia may be difficult to differentiate from epithelial atypia associated with inflammation and regeneration. This difficulty in interpretation may account for reports on the reversibility of low-grade dysplasia (3, 27, 154, 184, 211). The Pathology Panel of the International Study Group on Gastric Cancer has recommended that regenerative and mild dysplastic changes be grouped under hyperplasia, whereas moderate and severe dysplasia be grouped into one category of dysplasia because they cannot be sharply separated and often coexist (156). In addition, the degree of interobserver agreement for high-grade dysplasia is much higher than for the other categories (125, 153). In keeping with the current nomenclature of dysplasia for ulcerative colitis (200) and Barrett's esophagus (198), we prefer to use low and high grades for dysplasia. For those cases in which there is difficulty in differentiating between reactive change and dysplasia the term "indefinite for dysplasia" is recommended. Clinical Significance of Dysplasia. Data on the prevalence of gastric dysplasia and the progression of low-grade dysplasia to high-grade dysplasia and carcinoma are scant and not always consistent. Furthermore, the definitions of carcinoma vary as well: in some studies carcinoma denotes invasive lesions (206) whereas in others it is not always clear and may include in situ lesions, which we regard as high-grade dysplasia. In addition, all studies on dysplasia are based on symptomatic patients and its true incidence in the general population is unclear (206, 227). Despite these limitations, a number of important factors regarding gastric dysplasia are becoming apparent. Gastric dysplasia appears to be an important marker for carcinoma risk and is almost certainly a precursor lesion for gastric carcinoma, primarily for the intestinal type. In retrospective studies of gastric resection specimens, dysplasia adjacent to early gastric cancers occurred in 50 to 100 percent of cases and in up to 80 percent of advanced cancers (90, 146, 185, 270). In another study (206) in which 134 cases of gastric dysplasia were followed prospectively, it was found that there was progression of the degree of dysplasia and the development of gastric carcinoma in many: mild dysplasia appeared to regress in 66 percent, persist in 15 percent, and progress in 19 percent (3 cases to moderate dysplasia, 1 to severe dysplasia, and 5 to invasive carcinoma); moderate dysplasia persisted in 30 percent of cases and progressed in 40 percent (1 case to severe dysplasia and 7 to invasive carcinoma); severe dysplasia appeared to regress in 12.5 percent of cases, persist in 12.5 percent, and progress to invasive carcinoma in 75 percent. These findings support the notion that a significant proportion of high-grade dysplasias progress to carcinoma. The time frame for the transformation of dysplastic lesions into carcinoma is not clear because detailed information is lacking, particular for diminutive flat lesions (less than 5 mm in diameter). It probably varies from case to case depending on the severity of the dysplasia. However, high-grade dysplasia is highly predictive for gastric carcinoma. In fact, a high proportion of cases already have coexisting carcinoma or it develops within months of diagnosis (206, 227). It is unclear whether all grades of gastric dysplasia can transform directly into carcinoma or whether there is a stepwise progression from low-grade through high-grade dysplasia before carcinoma can develop. However, in general it has been found that low-grade dysplastic lesions remain stable for many years, in contrast to those of high grade, which are frequently associated with carcinoma (from 30 to 80 percent of cases) either at the time of diagnosis of dysplasia or within 1 or 2 years (27, 43, 55, 57, 206, 211). The size of the adenoma appears to be an important indicator of the likelihood of malignant change. The incidence of malignant change is low in small lesions but rises with increasing size. The reported incidence of malignant change for small adenomas is 6 to 18 percent, compared to around 35 percent for the larger lesions (174, 240). However, the incidence figures reported in the literature vary greatly, from a low of 6 percent to a high of 76 percent (155). Independent coexisting carcinomas are common in patients with gastric dysplasia. In one study of 121 cases of gastric adenoma, there were 55 concomitant early gastric carcinomas and 29 advanced carcinomas (90). Microscopic Findings. The dysplastic epithelium has either a tubular, villous, or mixed tubular villous configuration (11-6, 11-7a, 11-7b). In tubular lesions, there are two types of dysplastic cells which have been designated by some as adenomatous dysplasia and hyperplastic dysplasia. Because the latter term may cast doubt about the neoplastic nature of dysplasia, we prefer not to use these qualifiers and just refer to dysplasia generically, while recognizing that there may be several patterns and that these may occur together (39, 102). One type of dysplasia, which is commonly associated with intestinal metaplasia, is characterized by cells that are crowded together and pseudostratified with cigar-shaped nuclei, inconspicuous nucleoli, and abundant amphophilic cytoplasm (11-7a, 11-7b, 11-8). The nuclei occupy the basal half of each cell and mitoses may be prominent. As the severity of dysplasia increases the nuclei become less hyperchromatic and more vesicular, and the number of mitoses increases. The cell cytoplasm frequently contains mucin which may be neutral (periodic acid-Schiff [PAS] positive) or acidic (Alcian blue positive at pH 2.5). Enterochromaffin and Paneth cells are common. The second histologic pattern is often found in the setting of chronic atrophic gastritis and immature or incomplete intestinal metaplasia. This type of dysplasia sometimes resembles, and is confused with, regenerative change. There are architectural derangements of the mucosa consisting of abnormal glands with budding, irregular branching, and crowding. Both goblet cells and columnar cells may be present. There is variation in size and shape of the cells and an increased nuclear/ cytoplasmic ratio. The cytoplasm of the dysplastic cells is pale and sparse; the nuclei show loss of polarity, and are enlarged, rounded, and vesicular with enlarged single nucleoli. In high-grade dysplasia the cells are round and have large vesicular nuclei, a prominent nucleolus, and many mitoses (fig. 11-9). A number of Japanese pathologists consider the latter cytologic features to be diagnostic of gastric carcinoma irrespective of whether there is invasion into the lamina propria. The histologic features of the different grades of dysplasia depend upon the architectural complexity and the degree of cytologic atypia. The two components however do not always go hand in hand. Low-Grade Dysplasia. This lesion usually occupies the superficial portion of the mucosa, and is characterized by simple dysplastic tubules with little branching, connecting to the underlying normal foveolar epithelium (fig. 11-6). Some dysplasias involve the full thickness of the mucosa. The dysplastic cells may be of the different types described above but they tend to retain their basal nuclear polarity and have small indistinct nucleoli. Mitoses are present but usually sparse, increasing in number with progressive dysplasia. High-Grade Dysplasia. The dysplastic tubules often show pronounced architectural changes, with elongation and complex budding producing a cribriform pattern in the most extreme cases. The dysplastic cells show marked variation in size and shape and loss of basal nuclear polarity. The nuclei are large, often vesicular, with irregularly clumped chromatin and large nucleoli (fig. 11-9). Mitoses are common and often atypical (fig. 11-9). The extreme form of high-grade dysplasia, which is considered carcinoma in situ by some, is characterized by marked cytologic atypia, with or without architectural complexity of the glands. The glands proliferate and bud, resulting in an abnormal network of loop-shaped glands with anastomoses producing a cribriform pattern. The cytologic atypia is characterized by round cells with large, spherical, vesicular nuclei; irregularly clumped chromatin; and numerous large distinct and irregular nucleoli, considered by some as the hallmark of carcinoma (fig. 11-11). Mitoses, which often are atypical, are frequently prominent. Lesions Indefinite for Dysplasia. Reactive and regenerative epithelium in gastric mucosa may sometimes be difficult to differentiate from adenoma (11-12a, 11-12b). The nuclei may be larger and denser than those normally seen in regenerative epithelium and may have bigger and more prominent nucleoli. In addition, there is often increased cytoplasmic basophilia (11-12a, 11-12b). Those lesions in which the distinction between regenerative and dysplastic epithelium is not clear have been called indefinite for dysplasia. Dysplasia Involving Nonmetaplastic Mucosa. The precursor lesion of the diffuse type of gastric carcinoma is much more subtle than that occurring in intestinal mucosa. This is because tumor cells, such as those from signet ring carcinoma, frequently appear to extrude from gastric pits that look virtually normal morphologically. Careful examination of many of these pits reveals that the nuclei vary slightly in size and shape. In one study the dysplasia was characterized by cytologic atypia in the absence of architectural glandular derangement and replacement of the differentiated cells lining the glands by cells with varying degrees of cytologic abnormalities (crowding, loss of nuclear polarity, and nuclear pleomorphism) (66). The nuclei are enlarged, vesicular or hyperchromatic, with numerous nucleoli and the cytoplasm is frequently scant (fig. 11-13). The severity of the changes can be graded by the degree of involvement of the gland as measured from the proliferative zone (situated in the lower third of the gastric pit and the isthmus) and by the degree of cytologic abnormality. By analogy with dysplasia in inflammatory bowel disease, the authors of this study found that in a number of cases the histologic changes were equivocal and were categorized as indefinite for dysplasia (66). A second change that is frequently observed at the edge of the carcinoma is markedly thickened, distorted, hyperplastic foveolar epithelium which may be the gastric equivalent of the transitional mucosa seen in the large bowel rather than a genuine precancerous lesion. It occurs with both intestinal and diffuse carcinomas. Differential Diagnosis. The major histologic differences between dysplastic, and reactive and regenerative gastric epithelia are listed in Table 11-3. The regenerative changes are characterized by a gradual transition of the normal surrounding epithelium to reactive epithelium; regular arrangement of tubules; uniform enlargement of nuclei, with homogeneous basophilia; and small, frequently multiple nucleoli (11-12a, 11-12b). Other changes are syncytial epithelial cells with red cytoplasm and inflamed vascular stroma. However, occasionally, the epithelial nuclear changes are almost identical to those seen in gastric dysplasia and cannot be relied upon to separate the two. Treatment. There is no agreement on the management of gastric dysplasia. Some clinicians believe that this is a neoplastic lesion and should be managed by surgical resection, especially high-grade lesions (19, 50, 105, 146, 153, 163, 171, 211, 221). Others argue that since dysplastic lesions of the stomach are frequently multifocal, unpredictable in location, and sometimes regress, low-grade dysplasias are best handled conservatively with regular follow-up endoscopy (3). In Japan, where most cases are seen, the consensus is for the conservative approach. However, as already noted, since coincident gastric carcinoma may already be present at the time of diagnosis of gastric dysplasia, it is imperative to examine the stomach meticulously by biopsies if the conservative approach to management is undertaken. In contrast to gastric dysplasia, most authorities recommend excision of pedunculated and sessile adenomas because of their well-circumscribed nature. |
