Are there minimal criteria for the confident or unequivocal diagnosis of invasive carcinoma in the lamina propria both in Barrett's mucosa and in squamous mucosa?
H.D. Appelman (Ann Arbor)
The answer is yes.
The diagnosis of invasive carcinoma below the mucosa is straightforward, because it depends upon location; that is, dysplastic epithelium where it is not ordinarily found, in the submucosa and deeper. In contrast, for the diagnosis of the most incipient invasive carcinoma in the lamina propria, the criteria are more vague, so that the definition of this most superficial of invasion is more problematic. However a careful review of the significant publications in the field yields some interesting information about this problem. For instance, in the World Health Organization definitions of carcinomas of the esophagus, no mention is made of the criteria for this first level of invasion. Squamous carcinoma is defined as "a malignant tumor composed of squamous epithelium", while adenocarcinoma is defined as "a malignant tumor composed of glandular epithelium, with papillary and/or tubular structures" . There is no mention of minimal invasion or its histologica criteria. Why this ommission occurs is not clear. A possibility is that the framers of these definitions felt that the criteria for invasion were so clear-cut that they did not need to put them in the WHO syllabus.
The usual criterion for invasion is penetration of carcinoma through the basement membrane of pre-existing epithelial structures, be it a tubule or surface epithelium of Barrett's mucosa or the basal epithelium of squamous mucosa. With squamous mucosa, if we begin with a completely in situ lesion composed of high-grade dysplastic or carcinomatous epithelium, then simple expressions of this basement membrane penetration include poking of small clusters of epithelial cells or single cells through what seem to be an intact basal layer and thus, an intact basement membrane. Associated with this, quite often is a change in cell type from a predominantly basal cell to a cell with a more abundant, more clearly squamous cell cytoplasm.
Most recent attention has focused upon Barrett's mucosa and its associated adenocarcinomas, because Barrett's carcinomas are increasing in frequency in many parts of the world at the same time that squamous cancers are declining in frequency. For carcinoma in Barrett's mucosa, there is recent literature supporting the basement membrane penetration concept. For instance, in the multi-authored study by Reid et al., which looked at the interobserver and intraobserver variability in interpretation of Barrett's biopsies, the following statement was made: "Intramucosal carcinoma is defined as carcinoma that has penetrated through the basement membrane of the glands into the lamina propria" . This paper is one of the most frequently cited papers in all the pathology literature covering Barrett's mucosa. However, in that paper, no mention was made how this basement membrane penetration was identified, possibly because it was assumed by the authors of this paper that that determination was simple and something that all pathologists could make with little trouble.
A somewhat later publication, by McArdle et al., included a statement to the effect that high-grade dysplasia differs from intramucosal carcinoma "by the lack of invasion through the basement membrane" . As with the other references cited above, no hard and fast histologic rules were given for the determination of such basement membrane invasion. However, the authors stated that agreement as to "the presence of intramucosal carcinoma was achieved by a consensus of the reviewing authors." Therefore, this paper added another definitive criteria for determining invasion, namely the concept of consensus or agreement among a number of different pathologists.
Based upon this literature, we can state that in Barrett's mucosa, the determination of invasion of carcinoma into the lamina propria begins with established high-grade columnar dysplasia within the Barrett's mucosa penetrating through an intact tubular, or even surface epithelial, basement membrane. There are some helpful histologic hints that such penetration has occurred, including compromise of the lamina propria by crowded or back-to-back tubules or the finding within the lamina propria of strands of dysplastic or carcinoma-like cells sometimes without lumens or single cells of similar type. There are some modifications of this concept and of these criteria. For instance, Haggitt has defined three tiers of highly-dysplastic epithelium within Barrett's mucosae . At one end of the spectrum was high-grade dysplasia confined to the preexisting tubular contours of the Barrett's itself. At the other end was invasive carcinoma, identified as "when individual malignant-appearing cells infiltrate the lamina propria". In the middle was a category called "high-grade dysplasia with marked architectural distortion; invasive carcinoma cannot be excluded". This category included dysplastic tubules in a cribriform pattern that might have been nothing more than expansion of pre-existing tubules rather than invasion. However, also included in this category were dysplastic tubules in a back-to-back or crowded pattern, suggesting that the pre-existing Barrett's tubules might squeeze the lamina propria between them, and that might not indicate invasion. As mentioned above, such foci are likely to be considered evidence of invasion in the lamina propria by more aggressive morphologists. Haggitt had a third inclusion in this category, namely ill-defined abortive glands in the lamina propria, a concept that is somewhat difficult to define.
The finding of dysplastic tubules surrounded by fibers of the muscularis mucosae is not necessarily evidence of invasion, because in Barrett's mucosa, the muscularis mucosae is often disorganized. In addition, there is often an element of prolapse which commonly includes the presence of smooth muscle fibers from the muscularis mucosae extending perpendicularly into the mucosa.
Putting all these bits of literary information and support for this argument together, a final policy statement as follows is recommended: "Minimal criteria of invasion of carcinoma in the esophagus, both adenocarcinoma and squamous carcinoma include 1) penetration of dysplastic cells through the intact basement membrane, 2) more than "illdefined abortive glands" in the lamina propria, a Haggitt criterion, and 3) "consensus" by reviewing pathologists, a criterion from McArdle et al.
1. Watanabe H, Jass JR, Sobin LH. Histological typing of oesophageal and gastric tumors. Second edition. World health organization international histological classification of tumors. Berlin: Springer-Verlag, 1990.