gastric epithelial dysplasia
Monday 1 October 2012
gastric mucosal dysplasia
Definition: Gastric dysplasia is characterised microscopically by a set of histological alterations.
Phenotypic diversity of gastric epithelial dysplasia
The diagnosis relies on cytological (cytoplasmic mucin depletion, cellular crowding and pleomorphism, nuclear hyperchromatism, pleomorphism and stratification, increased nuclear:cytoplasmic ratio, and increased mitotic activity) and architectural abnormalities (glandular disarray or budding with irregular branching and dilatation, and intraluminal folding).
Several types of gastric dysplasia have been reported in the literature but what authors refer to most frequently is gastric adenomatous dysplasia, thought to be the precursor of intestinal (or tubular) gastric adenocarcinoma, the most common type of gastric cancer in populations at risk.
adenomatous gastric dysplasia
foveolar gastric dysplasia
pyloric gastric dysplasia
Grading of gastric epithelial dysplasia
low-grade of gastric mucosal dysplasia (type 1)
high-grade of gastric mucosal dysplasia (type 2)
According to the severity of histological abnormality gastric dysplasia has been graded using either a two tier system of low and high grade dysplasia or three tier system of mild, moderate or severe dysplasia.
Grading is easier and more reproducible in a two tier than in a three tier system. These inevitably become three or five tiered systems (e.g. mild to moderate dysplasia), although, surprisingly, the use of an intervening term for high and low grade dysplasia seems to have been largely avoided.
In 1984 Ming and an international panel recommended that moderate and severe dysplasia be grouped in a single category as they cannot be sharply distinguished and actually coexist.
However, the same can also be said of "mild and moderate dysplasia", at least when both are defined as above and exclude reactive lesions. The use of "low grade" instead of both "mild and moderate" permits a reasonable comparison between both.
Low grade dysplasia
In low grade dysplasia, the cells have closely packed basal nuclei with dense chromatin).
The nuclei are also elongated in shape and if pseudostratified retain their polarity and are confined to the basal half or two thirds of the cell.
Classic “moderate” dysplasia has nuclei that extend into the upper two thirds of the cell so that the broadening of low grade dysplasia to include this common morphological subgroup is appealing.
Low grade dysplasia may be difficult to differentiate accurately from atypical reactive/regenerative epithelial changes.
In atypical reactive/regenerative epithelial changes, the cells usually appear immature and may be cuboidal with basophilic cytoplasm, large but often widely opened and relatively widely spaced vesicular nuclei and reduced or absent mucus secretion. They may or may not be uniform in shape and size with basally or centrally located nuclei. They are also arranged in a row and if present the pseudostratification is considerably less than in adenomatous, but not necessarily type 2 dysplasia. Mitoses are often present but not on the surface and abnormal mitoses are absent. Increased cellular differentiation and maturation is usually seen toward the luminal surface.
The difficulty in differentiating reactive from dysplastic changes may account for reports of reversibility of low grade dysplasia.
In cases where there is a real interpretative problem, the term “indefinite for dysplasia” is sometimes used. However, operationally this is a diagnosis of exclusion obtained by getting a negative response to the two questions, “is this epithelium unequivocally negative for dysplasia?” (this including all reparative epithelium) and “is this epithelium unequivocally dysplastic?”. Epithelium that is not unequivocally negative or unequivocally dysplastic is, by definition, indefinite for dysplasia.
High grade dysplasia
In high grade dysplasia, the nuclei regularly extend into the luminal aspect of the cell in the adenomatous variant but in type 2 dysplasia are frequently oval, round or irregularly shaped, with more open and clumped chromatin confined to the lower half or two thirds of the cells.
Prominent nucleoli are often seen.
More often than not the nuclei reach the apical region of the cells and their polarity is partially or totally lost.
Because the cells are small and relatively cuboidal and the nuclei relatively large, it is easy for them to occupy most of the cell so that the distinction between low and high grade dysplasia can be hazy.
High grade dysplasia also includes the lesion referred to as "carcinoma in situ", which is a non-invasive lesion so called because virtually identical changes can be found in invasive carcinoma.
Less publicised is the fact that any dysplastic lesion can give rise directly to invasive carcinoma of identical morphology, but this is a much less frequent occurrence from low grade dysplasia.
There is also no agreement on whether the changes known as carcinoma in situ should be architectural, cytological, either or both.
Furthermore, in the Japanese system, many lesions called high grade dysplasia are also called carcinoma, especially those of type 2 dysplasia. This can result in overdiagnosis of cancer by Western standards by Japanese pathologists, or underdiagnosis by Japanese standards by Western pathologists. The implication of these differences is that data generated from these two systems are usually not directly comparable.
It can sometimes be very difficult to separate high grade dysplasia from intramucosal carcinoma. Numerous small glands budding out of the lamina propria can be difficult to distinguished from invasion. Previously held concepts such as breaching the basement membrane sound good in theory but are difficult or impossible to apply on haematoxylin and eosin sections, in which it is not visible. Irregularity of pit outlines with irregular infiltration into the lamina propria is what is used operationally.
Interobserver variability in diagnosing dysplasia in the gastrointestinal tract is inevitable whenever a continuous spectrum is subjectively divided, as has been previously reported, particularly in Barrett’s oesophagus and ulcerative colitis.
Whenever a group of pathologists examine the same biopsy sample, the result is inevitably a distribution curve around a mean. The issue becomes the width of the curve. Usually this is about half a grade, although when the extremes of the spectrum (no dysplasia, high grade dysplasia) are used the variation can only go in one direction and therefore is inevitably less. The corollary is that it is also possible to select biopsy samples that are literally on the borderline between two categories, e.g. low and high grade dysplasia, so that one would expect that there will always be 50% of observers calling it low grade and 50% calling it high grade. Nevertheless, with severe reactive changes the alternative diagnosis may be high grade (type II) dysplasia.
Similar problems have been found in the stomach. The problem may also be partly related to the relative lack of experience of some histopathologists in diagnosing gastric dysplasia.
Differentiating reactive changes such as foveolar hyperplasia and metaplastic changes from low grade/moderate dysplasia is a challenge for many.
In one series 51% of cases diagnosed as hyperplastic or metaplastic lesions by specialists were initially diagnosed as moderate dysplasia by general histopathologists.
Less variation is usually noted for higher grade lesions. In the same series 65% of the original diagnoses of severe dysplasia were confirmed whereas 10% were downgraded to moderate dysplasia and 6% diagnosed as carcinoma.
Variations also exist among pathologists with an interest in gastrointestinal pathology. Inherent difficulties in agreeing upon the definitions of mild to moderate and high grade dysplasia are translated by moderate sensitivities of 82 and 83% in diagnosing these lesions whereas higher specificities (92.8 and 92.3% respectively) indicate agreement on the minimal diagnostic criteria.
In the same series, when all dysplasias are included in a single category, a mean κ of 0.7, indicative of moderate agreement, was calculated.
As major therapeutic decisions may be taken after a diagnosis of dysplasia, it has been suggested that such a diagnosis be confirmed by seeking a second opinion from a gastrointestinal pathologist.
To the gastroenterologists this may appear as incompetence on the part of the histopathologists. However, it is worth pointing out that histopathologists are medical consultants rendering their diagnostic opinion based both on morphological grounds and also on their understanding of the biology of the lesions. Similarly, it is neither expected nor observed that a patient will always receive the same medical treatment for the same disease in different institutions.
The chronology of the progression from one dysplastic grade to a higher grade or adenocarcinoma is critical in order to recommend appropriate treatment.
In several series the time frame between a diagnosis of severe/high grade dysplasia and the identification of gastric cancer was between less than one month to 39 months with a mean between four and 23 months.
Clearly the possibility that some of these lesions were already carcinomatous but the invasive element was not included in the original biopsy sample cannot be excluded.
Following a diagnosis of moderate/low grade dysplasia, cancer was found during a mean follow up of 10–30 months with extremes of one and 39 months.
Finally, although most cases of mild dysplasia are believed to regress, rare cases with a diagnosis of carcinoma after a median follow up of 34.5 months and 41.5 months have been reported, suggesting that either some of these lesions were unequivocally neoplastic or that they were not included in the original biopsy specimen.
Analysis of several Western series revealed that 57% of cancers discovered during follow up were early gastric cancer, a figure out of line with prevalence in the population at large, but which underscores the importance of following patients closely in order to detect these lesions early.
Practically, several conclusions can be drawn:
(a) gastric dysplasia, as defined earlier, should be regarded as an important marker of cancer risk;
(b) the higher the grade of dysplasia the greater the risk of developing invasive gastric cancer;
(c) surveillance leads to detection of “early”, potentially curable adenocarcinoma;
(d) a period of few months for high grade dysplasia and longer for moderate and mild dysplasia is usually available to plan an adequate therapeutic strategy.
Although gastric dysplasia is usually described as a dynamic process, with a reported possibility of progressing/regressing, limited evidence of transformation exists. The actual progression of repeatedly biopsied, flat dysplasias has never been shown. Evidently, one limitation is the difficulty in sampling identical mucosal areas during endoscopic follow up.
Series focusing on adenomas observed malignant foci in 5.9% of flat (tubular) adenomas and up to 33% of large villous and tubulovillous adenomas.
However these figures might be inflated as malignancy in that article was established both when invasion was seen and also when severe architectural and cytological atypia were noted in the absence of invasion.
Others reported malignant transformation in 11% of 85 cases examined and sequentially biopsied during an average follow up of 49 months.
Alternatively, the frequent demonstration of the multifocal neoplastic process would indicate the presence of diffuse mucosal instability which is prone to malignant transformation.
Thus, the various dysplastic grades could be viewed as representing independent distinct end points of epithelial transformation in a genetically unstable gastric mucosa likely to develop an adenocarcinoma eventually.
Factors to be considered when designing therapeutic guidelines include understanding of the biological process and current technical capability.
With regard to the biology, recent molecular studies have supported the histological assessment that gastric dysplasia is a neoplastic lesion.
In addition, follow up studies, as discussed earlier, have clearly established risks and time frames for the development of gastric cancer.
However, in spite of abundant literature it was shown that most gastroenterologists do not equate "epithelial dysplasia" to a neoplastic process.
Yet, when confronted with a diagnosis of "high grade dysplasia" most of these same clinicians recommend surgical treatment.
Neoplasia means tumour to most, and the concept of adenomas and areas of flat dysplasia being non-invasive neoplasia still requires considerable education.
Given this information and with the knowledge of notable interobserver variability in the pathological diagnosis, different recommendations have been drafted.
Many of the Western publications to date call for close endoscopic follow up of patients with "moderate/low grade gastric epithelial dysplasia".
The frequency of the follow up is variable but given the risk of malignant transformation endoscopy has been recommended every three to 12 months at least during the first year.
An open question is how long the follow up should be maintained when no progression has been detected. Some suggest suspending surveillance when two endoscopies with multiple biopsy samples are negative at the six month interval.
Provided that a diagnosis of "high grade dysplasia" has been confirmed, many authors suggest surgical resection because of the intimate association with invasive gastric adenocarcinoma.
However, others argue that endoscopic follow up might be sufficient.
Increasingly, endoscopic mucosal resection has a place in the management of these lesions, although it is a skill to which relatively few hospitals in the West have access compared particularly with Japan where it is the standard practice for most centres.
Although with some merit, once a synchronous carcinoma has been excluded, this conservative therapy is not immune to criticism.
Dysplastic lesions are not free of the risk of malignant transformation and non-surgical resection can be curative.
Another issue to enter into the equation is the patient’s compliance with protracted and costly follow up.
With advances in endoscopic localisation (chromoscopy) and staging techniques (endoscopic ultrasound), endoscopic mucosal resection can offer non-surgical cure for intramucosal adenocarcinoma.
However, these modern interventional endoscopic procedures are not widely available outside of the specialist centres and their place in treatment needs to be defined and made more widely available.
Furthermore, the issue of protracted follow up in these patients at high risk of developing metachronous adenocarcinoma has still to be settled.
Gastric epithelial dysplasia, Gut 1999;45:784.
The Vienna classification of gastrointestinal epithelial neoplasia. Gut 2000 Aug;47 (2):251-5