observations on the origin of adenomatous epithelium of the colon. serial section studies of minute...

OBSERVATIONS ON THE ORIGIN OF ADENOMATOUS EPITHELIUM OF T H E COLON

Serial Section Studies of Minu te Polyps in Familial Polyposis NATHAN LANE, M.D., AND ROBERT LEV, M.D.

ARCINOMA OF THE COLON AND RECTUM IS C one of the most common-some say the most common-type of visceral carcinoma. The precancerous significance of adenomatous lesions continues to be a subject of contro- versy.21 l2 However, many investigators feel that adenomatous lesions do play a highly significant precursor role, and they feel that the systematic detection and eradication of adenomatous lesions, within sensible limits of operative risk, will exert a substantial preven- tive effect.

The relation of tumors composed of adenomatous epithelium to carcinoma of the colon was the subject of an extensive study reported by this Laboratory several years ag0.7 Both the common adenomatous polyps and the less frequent papillary or villous adenomas were studied in this regard. Both of these are thought to be composed of benign but clearly neoplastic epithelium of distinctive appearance, for which the term “adenomatous epithelium” will be used herein.

In the aforementioned study,7 2 observations were presented that are pertinent to the origin of adenomatous epithelium and are worthy of brief mention. They are as follows.

There is little disagreement that in papillary adenomas, which when discovered are generally at least several centimeters in size, the likelihood of finding invasive carcinoma may be in the range of 30 to 50%. It has been our experience that in the large adenomatous polyps (about 2 cm. or more) one may encounter foci of invasive adenocarcinoma with a frequency of about 10%. However, in the smaller aggregates of adenomatous epithelium (e.g., adenomatous polyps less than 1 cm.), the likelihood of encountering foci of invasive carcinoma seems to be very low-perhaps 1% or less. Of course, these smaller polyps are far more numerous, and this “dilution” with

From the departments of Surgery and Pathology, the Laboratory of Surgical Pathology, Columbia Univer- sity College of Physicians and Surgeons, 630 W. 168th St., New York, N.Y.

Received for publication Oct. 5, 1962.

small polyps explains why, in any series of adenomatous lesions not subdivided according to size, the reported incidence of foci of invasive carcinoma is bound to be low.

From a practical point of view, the less frequent larger adenomatous lesions are the ones that deserve more attention. For the purpose of this paper, however, the point is that these clinically important larger adenomatous lesions must have grown from smaller aggregates of adenomatous epithelium.

It was also suggested that because of the failure to find microscopic or minute carcinoma (e.g., 3 mm. or less) surrounded by normal colonic mucosa, and the frequency with which this is found in adenomatous tissue, most, if not all, ordinary colonic carcinomas evolve from adenomatous epithelium. Special situations, such as that of carcinoma in ulcerative colitis, are not meant to be included in this statement.

If the 2 observations just presented are correct, the genesis of adenomatous epithelium is obviously a subject of great importance in the field of colonic neoplasia. For these reasons, in recent years this Laboratory has made a par- ticular effort to make histological sections from the most minute and barely visible mucosal elevations that could be discovered in our routine specimens. As every pathologist knows, a minute mucosal elevation occasionally proves to be a lymphoid follicle or some other nonepithelial process. In this report, however, we are concerned only with those minute mucosal elevations that prove to be the result of a proliferative epithelial process.

As might be expected, most of the colon resection specimens were of cases of carcinoma of the colon, and the minute, barely visible, mucosal elevations studied were from the mucous membrane of the specimens. We also studied many excision biopsy specimens of minute mucosal elevations obtained at sig- moidoscopy .

In addition to studies of minute polyps from the routine colon specimens coming to our Laboratory, we have included as the principal

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FIGS. 1 and 2. Cross and longitudinal sections of adenomatous glands in the right half of the figures and of normal glands in the left. There is an over-all basophilia. Extreme crowding of adenomatous cells, which are nevertheless maintaincd in an even row, contrasts with the pattern in hyperplastic polyps. The significance of the abrupt transition and interface angle between the adenomatons and the normal epithelium shown in Fig. 2 is discussed in text. ( ~ 1 9 0 & xl40.)

No. 6 ORIGIN OF ADENOMA~OUS EPITHELIUM OF COLON Lane Q Lev 753 part of this paper a histological study of 2 cases of familial polyposis. In both of these cases, near-total colectomy specimens were available. In addition to dozens of grossly obvious adenomatous polyps ranging, upward, from 3 to 20 mm. in size, there were literally hundreds of minute sessile discrete mucosal elevations ranging, downward, from 2 mm. to a fraction of a millimeter in size. In the first of the 2 cases, we prepared carefully oriented but purely routine sections of several dozen of the minute polyps. In addition to this type of study, in the second case we prepared serial sections from 8 of the minute lesions. The findings in these serial sections proved to be of great interest to us because they appeared to constitute a direct anatomic demonstration of the site of origin of adenomatous epithelium as seen in familial polyposis, and it may well be that a similar morphogenesis exists in the case of ordinary adenomatous lesions.

As a result of our studies of minute polyps in routine cases and in the 2 cases of familial polyposis, a number of findings emerged that can be roughly grouped into 3 general areas: (1) the existence of 2 readily separable microscopic types of minute polyps-the hyperplastic and the adenomatous; (2) the probable lack of a sequential relationship between hyperplastic and adenomatous polyps in ordinary cases as well as in familial polyposis; and (3) conversely, the probable de novo origin of adenomatous epithelium in “normal” mucosa -specifically, from the germinative epithelium in the deep portion of the colonic crypts.

Two MICROSCOPIC TYPES OF MINUTE POLYPS

It has been our experience that after microscopic study of minute colonic polyps (2 mm. or less), the observer can readily classify almost all of them into 2 apparently distinct and readily separable types-adenomatous and hyperplastic. In the size range of these minute polyps, it has not been possible to predict from the color or other gross characteristics what the microscopic epithelial type of any given minute polyp would finally prove to be. In the fresh state, the minute pdyps of the type we are discussing are glistening and the same color as the surrounding glistening mucosa. When closely viewed from above, these minute polyps are circular and very sharply outlined; when viewed in profile, they are dome-shaped, the height of the dome increasing with the size of the polyp. While there are many reports on

the epidemiology of “polyps,” one cannot eval- uate accurately the incidence in the popula- tion or the precancerous significance unless the 2 types of polyps are classified separately.

On the one hand, there is the minute edi- tion of the true adenomatous polyp. Like the larger typical adenomatous polyp, this is composed of a characteristic “race” of true adenomatous epithelium that has a distinctive cytological appearance and gives a characteristic appearance to the truly adenomatous gland.

More frequently, in the ordinary specimen, one will observe a minute polyp to be a lo- calized area of epithelial proliferation for which, in our Laboratory, we use the term “hyperplastic polyp.” The epithelium and glandular patterns in this lesion are obviously different in appearance from those of the true adenomatous polyp. The clearness of this distinction has only rarely been noted in the literature.15

What is here referred to as a hyperplastic polyp is a discrete, generally minute mucosal elevation found against a background of surrounding normal mucosa and should not be confused with inflammatory tags, juvenile polyps, pseudopolyps of ulcerative colitis, or ex- crescences of this sort.

A number of microscopic features are note- worthy. Figures I and 2 show cross and longitudinal sections of typical adenomatous glands with adjacent normal glands for comparison. Such appearances are commonly encountered in random sections of minute but truly adenomatous lesions. The adenomatous epithelial cells are extraordinarily crowded, often to the point of appearing superimposed on one another. Perhaps as a result of this extreme crowding, the cells (and their nuclei) are markedly narrowed and elongated into pencil- shaped units. However, in spite of the obvious extreme crowding, in a typical adenomatous gland in either cross or longitudinal section, the adenomatous cells appear lined up in a remarkably even row, apparently not “reliev- ing” their crowding by papillary infolding into the glandular lumen. Not only because of the large number of prominent elongated nuclei present, but also because of the staining reac- tion of the cytoplasm, the usual appearance of a group of adenomatous glands gives the over- all impression of basophilia.

In contrast, the cells in the gland of a hyperplastic polyp are strongly eosinophilic, except only for the sharply outlined distended goblet

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cells. The cells, as shown in Figs. 3 to 7, although greatly increased in number, are not unduly crowcled because they are thrown into papillary infoldings into the glandular lumens. This produces a saw-toothed appearance on longitudinal section and a typical stellate appearance on cross section. The similarity to hyperplasia elsewhere in the body, such as in the endometrial glands, mammary ducts, or thyroid follicles, is interesting to note. Usually there is no great change in the size, shape, or prominence of the nuclei.

The sum of these characteristic features of hyperplastic and adenomatous epithelium im- parts to each variety of polyp its own over-all distinctive appearance, arid only rarely will there be difficulty on microscopic grounds in designating a minute colcinic polyp as either typically adenomatous or hyperplastic in type. We believe that this distinction should be made and will assist in gathering useful in- formation regarding the incidence and neoplastic significance of “polyps” according to type.

RELATIONSHIP BETWEEN ADENOMATOUS AND HYPERPLASTIC POLYPS

A fundamental statistical observation is the fact that among minute colonic polyps the hyperplastic type is by far the more common.1l With increasing size, the proportion changes, and just the reverse is true among larger colonic polyps. Our experience is in agreement with this observation. Therefore, as a work- ing hypothesis, it would seem very reasonable to suggest that the hyperplastic polyp is the precursor of the true adenomatous polyp.

However, our current anatomic studies have suggested alternatives. We think that the hyperplastic polyp need not always be the precursor of the adenomatous polyp. We think it possible that the hyperplastic polyp may not even usually be the precursor or the adcnoma- tous polyp and that, morcover, as will be ex- plained subsequently, the adenomatous polyp can arise de novo from the “normal” mucosa, at least in familial polyposis. We would like to present in detail severxl anatomic reasons for suggesting these points.

Just as foci of microscopic carcinoma are found much more frequently in the adenomatous epithelium than in 1 he normal mucosa, thereby justifying the regirding of adenomatow epithelium as precancerous, so should microscopic foci of adenomatous glands be found

more frequently in hyperplastic polyps than in normal mucosa if we are to verify the hypothesis that hyperplastic polyps are “preadenoma- tous” lesions.

Considering the grear frequency of both types of polyps, focal adenomatous changes in hyperplastic polyps or other evidence of transition should be easy to find if the hypothesis is correct. We have purposefully searched through sections of many minute polyps in ordinary specimens hoping to find support for the hypothesis that a polyp progresses from the normal to the hyperplastic to the adenomatous stage. Thus far we have been unable to find satisfactory anatomic evidence for this assumption, i.e., such changes have not been encountered with the frequency one would expect.

However, as a very rare finding we have encountered the reverse situation in at least 2 specimens. That is to say, microscopically minute foci of hyperplastic glands were found in moderate-size typical adenomatous polyps. This is illustrated in Fig. 8. Of course, it is possible that the hyperplastic glands may have preceded the adenomatous component. How- ever, considering the far larger number of adenomatous glands than hyperplastic glands in these specimens, one might even suggest from this evidence alone that the hyperplastic glands have developed in residual normal glands, as shown in Fig. 9, in response to the proliferation of the adenomatous tubules.

Our second reason for doubting this sequence is the following. While it is true that most sporadically encountered minute polyps prove to be of the hyperplastic variety, this is by no means always the case. Occasionally we have found that even the most minute polyp microscopically proves to be typically adenomatous. In such an instance, because of the minute size, it seems hardly necessary to postulate a precursor lesion, hyperplastic or otherwise.

These 2 observations alone, based on purely routine cases, have always raised doubts in our minds about a normal to hyperplastic to adenomatous sequence.

Thirdly, these doubts were amplified by our study of 2 near-total colectomy specimens re- moved for familial polyposis. With their hundreds oi minute polyps, these 2 specimens seemed :in ideal testing ground for the hypothesis under consideration. MJe anticipated that among the great number of minute polyps present a majority or a substantial frac-

No. 6 ORIGIN OF ADENOMATOUS EPITHELIUM OF COLON Lane & Lev 755

FIGS. 3 and 4. Scanning-power views of hyperplastic poIyps. Epithelial hyperplasia is moderate in Fig. 3 and marked in Fig. 4. In sections, there is an over-all eosinophilia. The stellate and saw-toothed lumens contrast with adenomatous polyps and make for easy recognition even at very low magnification. (x65 & x53.)


FIG. 5. Portion of the polyp shown in Fig. 3. Note the stellate luinens arid the beginning of papillary infolding. (XSOO.)

tion of those less than 2 mm. would prove to be of the hyperplastic type. We also hoped to encounter some minute polyps in which some microscopic evidence of transition from the hyperplastic to the adenomatous form might be recognized. To our surprise, of the many minute polyps sectioned,, including 8 polyps that were serially sectioned, not a single one proved to be a polyp of t.he hyperplastic type, nor were any glands of the hyperplastic type in them. Every one of. the minute polyps studied proved to be typically and completely adenomatous. This strongly suggested a normal to adenomatous sequence without pas- sage through a hyperplastic stage in both of the familial polyposis specimens. Obviously, these findings may, but not necessarily, apply to the evolution of the ordinary adenomatous polyp. They are cited, however, to supplement the first 2 reasons given.

Two other observations based on routine specimens have some bearing on this subject:

Exceptionally, a polyp 1 cm. or larger will be typically and entirely hyperplastic in type. This proves that it is possible for a hyperplastic polyp to grow to this size and that when

it does so it is not ineluctable that it undergo adenomatous transformation.

It is our experience that groups of typical adenomatous glands are almost never found except in characteristic adenomatous polyps or papillary adenomas. This impIies that adenomatous change yields a specific "race" of epithelium of characteristic appearance. On the other hand, glands resembling those seen in hyperplastic polyps can on occasion be observed in some areas of the inflammatory pseudopolyps of ulcerative colitis, in inflammatory and edematous mucosal folds, and in juvenile polyps. This hint of nonspecificity and similarity to some non-neoplastic lesions suggests that the hyperplastic polyp may not be a step in a sequence of neoplastic changes. The spon- taneous reversibility and disappearance6 of minute colonic polyps, most of which because of their size must have been hyperplastic in type, is consistent with this line of thinking.

Thus, considering all of the anatomic observations, we feel that the assumption that the usual sequence for polyps is the normal pass- ing through the hyperplastic to the adenomatous, since it is based only on statistical evi-

FIGS. 6 and 7. Portion of middle and superficial zones of the polyp shown in Fig. 4. Note the marked papillary infolding with stellate lumens in Fig. 6 and the resulting saw-toothed appearance when glands of this type are cut longitudinally in Fig. 7. (X140.)

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No. 6 ORIGIN OF ADENOMATOW EPITHELIUM OF COLON - Lane 6. Lev 759 dence relating to size, may be a misleading one.

I t is true that hyperplastic polyps are frequent in colons containing carcinoma and adenomatous polyps. However, they may ex- ist without being otherwise related. Of course, even if hyperplastic polyps are not particularly predisposed to adenomatous change, this does not mean that their epithelium, in common with that of the rest of the colon, may not occasionally undergo adenomatous change. Therefore, an occasional specimen appearing to show such a change may be expected to be found.

kfUC0SAL ORIGIN OF ADENOMATOUS EPITHELIUM

An interesting question that we studied con- cerns the site (or level) of origin of adenomatous epithelium within the colonic mucosa. The literature contains conflicting views on

Microscopically, the normal colonic mucosa is relatively flat, without villi, and with numerous simple test-tube-shaped glandular crypts “coming down” from the surface. These are lined by a single row of columnar epithelium. As confirmed in recent studies in which tritiated thymidine and radioautography were used,’. *a 10 it is known that cells in the superficial one third of the mucosa are approach- ing senility and exfoliation. They will be replaced by cells moving up from the deeper portions of the glands. I t is the cells in the deep one third of the glandular crypts that are the mitotically active, germinative ele- ments undergoing frequent divisions. The question, then, of the level of origin of rapidly dividing neoplastic adenomatous epithelium becomes one of interest in relation to our knowledge regarding the deep, mitotically active zone and the upward migration, aging process, senility, and exfoliation of the cells of the colon.

Theoretically, one might expect the active germinative zone, with its many “young” dividing cells, to give rise to the adenomatous epithelium. Paradoxically, most random sec-

this point.3, 5, %13, 14

tions of minute, truly adenomatous polyps show cross sections of adenomatous tubules in the superficial (senile) portion of the mucous membrane and cross sections of normal tubules in the deeper portion (Fig. 11). This was illustrated by Sunderland and Binkleyls and led these authors to the conclusion that the adenomatous epithelium arises in the superficial portion of the mucosa. Another pho- tograph illustrating this phenomenon in a small adenomatous lesion is shown by Acker- man.1 We believe that our serial section studies of the minute polyps in familial polyposis may explain this apparent paradox of a vigorous new “race” of neoplastic epithelium seeming to arise in the zone of relatively senile cells.

Eight of the minute polyps from one of the cases of familial polyposis were used for serial section study. Trimming of the blocks bearing these minute polyps was done after fixation; embedding was done in such a way that the serial sections would be oriented perpendicularly to the mucosal surface. The serial sections proceeded from the normal mucosa im- mediately peripheral to the polyp, through the periphery of the polyp, and then through the central zone of the polyp and finally emerged through the opposite periphery of the

The appearance at the extreme periphery is shown in Fig. 10. The normal epithelium in the mouth of a single gland is replaced by adenomatous epithelium. As shown in Fig. 11, somewhat deeper sections, but still not near the center, show normal and adenomatous tubules cut in cross section. I t is the tubules in the upper portion of the m u m a that are typically adenomatous and those in the deeper portion that are normal. We have not encountered the reverse situation, i.e., a zone of adenomatous tubules cut in cross section in the deep portion of the mucosa surmounted by a zone of normal tubules cut in cross section in the superficial portion of the mucosa.

The fact that the adenomatous and normal glandular tubules away from the center of the polyp are likely to be cut in cross section proved to be a clue in reconstructing the over-

P01Y P.

FIG. 8. A minute focus of hyperplastic glands in a moderate-sized adenomatous polyp. Note the side-by-side contrast between the papillary infoldhgs and stellate lumens of the hyperplastic glands on the right and the men row of adenomatous epithelium and round lumens of the adenomatous glands to the left. A small group of residual normal cells (arrow) are present in the obliquely cut adenomatous gland at the left. (~8 .5 . )

FIG. 9. Portion of the specimen shown in Fig. 8. In the right half of the figure, there is a focus of residual normal glands not yet replaced by adenomatous epithelium, (X90.)

FIG. 10. Adenomatous epithelium filling the mouth of a single gland. This was noted in serial sections from the extreme periphery of minute adenomatous polyps. (x70.)

FIG. 11. This specimen is frotn a set of serial sections, but it is not yet near the center of the adenomatous polyp. In our experience, this superficial position of adenomatous tubules cut in cross section is typical of what IS encountered in random sections. (~90 . )

No. 6 ORIGIN OF ADENOMATOUS EPITHELIUM OF COLON Lane 6. Lev 761

all architecture of the polyp. Ordinarily, sections taken through normal colonic mucosa, more or less perpendicular to the mucosal surface, will generally show the colonic glands cut longitudinally or nearly so.

In the peripheral portions of a minute adenomatous polyp, one may encounter an obliquely cut gland lined in its superficial portion by a characteristic row of adenomatous epithelium and in its deeper portion by normal epithelium. In such a gland from the peripheral portion of a polyp, there is typically a very abrupt transition between the 2 types of epithelium. This is shown in Fig. 2. Thus situated, at the periphery of the polyp, this phenomenon suggests replacement of normal epithelium rather than the origin of adenomatous epithelium. Finding a sharp division between normal and adenomatous epithelium is commonly observed at the periphery of larger adenomatous polyps as well. The interface between the adenomatous and normal epithelial cells (Fig. 2) is characteristically not perpendicular to the basement membrane but is angled back toward the adenomatous epithelium, suggesting that it is “undermining” the normal epithelium.

As one follows the serial sections from the peripheral portion of the adenomatous polyp to the central portion, the glands are sectioned progressively less in cross section and more obliquely. I n the center of the polyp, they are Cut longitudinally or very nearly so. Figures 12 and 13 are representative of the picture one observes in sections through the central portion of one of these minute lesions. The typically adenomatous appearance of the epithelium in the upper half of the central glands is obvious. There is, however, no abrupt transition to normal epithelium as one traces this epithelium downward. On the contrary, one gains the impression of a gradual insensi- ble transition from the tall, hyperchromic, obviously adenomatous epithelium in the upper portions of the gland to a definitely shorter but still hyperchromic epithelium in the deep one third of the gland. The latter epithelium either closely resembles or is identical with the epithelium found in the germinative deep one third of normal glands. The graduaI transition suggests that these deep cells are the ones that give rise to adenomatous epithelium.

It is of interest that in the 8 minute adene matous polyps studied with serial sections, we have not been able to trace the apparent origin of the adenomatous epithelium to the deep

portion of a single central crypt but, rather, to a central group of crypts.

Putting these observations from many slides into a single picture, we would like to suggest the concept diagrammed in Fig. 14. It seems that there is a central group of colonic crypts, whose relatively normal-appearing germinative epithelium in the deep one third is in continuity with and gives rise, by gradual transition, to the typical adenomatous epithelium as it proceeds “upward.” Thus, the deep portion of the central glands would appear to be the site of origin.

This adenomatous epithelium seems to emerge superficially from these central glands and “flow” peripherally over the surface in an irregular manner displacing the normal epithelium. It seems to permeate downward from the surface into some of the adjacent, more peripheral glands. It is at these points that the adenomatous and normal epithelium appear in abrupt transition.

This rapidly dividing, tall adenomatous epithelium causes elongation and widening of the upper portions of the involved crypts. Thus, the adenomatous glands tend to flare out (as flowers in a vase), tilting and even overhanging into the adjacent nonadenoma- tous glands. This flaring effect of the adenomatous glands and tilting of the adjacent normal glands (Figs. 12 and IS) readily explains how a section taken through the periphery of such a lesion (Fig. 11) or a section not taken perpendicularly to the mucosal surface will show adenomatous tubules cut in cross section in the superficial portion of the mucosa and normal tubules Cut in cross section in the deep portion of the mucosa. Most random sections, especially from sigmoidoscopic biopsies of minute polyps, will be of this type. This explains what we believe to be a false impression likely to be gained from random sections, viz., that the adenomatous cytological alteration originates in the superficial zone of the mucosa.

This serial section study, suggesting a deep origin, seems to bring into harmony the high- growth potential and high mitotic activity of the adenomatous epithelium and that mucosal level that is normally the zone of greatest mitotic activity. In addition, the serial section studies appear to demonstrate the de novo origin of the adenomatous epithelium from a normal epithelium without transition through a stage of hyperplasia, at least in the minute polyps occurring in familial polyposis. Re- cently, in multiple-level sections, we have

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No. 6 ORIGIN OF ADENOMATOUS EPITHELIUM OF COLON - Lane & Lev 763

FIG. 14. The diagram represents a central perpendicular section comparable to Figs. 12 and 13. The dark and lighter-shaded bands represent adenomatous and normal epithelium. Three points are illustrated: (1) Normal- appearing germinative epithelium in the depths of the central crypts appears to give rise directly to adenomatous epithelium by a process involving gradual transition: abrupt .transition between adenomatous and normal

glands, explains how peripheral or oblique sections (as shown by the dotted lines) will result in an appearance such as that in Fig. 11. From such a section it might be falsely concluded that the adenomatous tubules have arisen in a superficial mucosal zone.

epithelium is noted at the periphery of the polyp: an %’ (3) the flaring effect, with tilting of adjacent normal

noted the same findings at the center and periphery of a minute, truly adenomatous polyp in a routine colon resection specimen. This suggests the expected, viz., the same mucosal level of origin for the ordinary adenomatous poIyp as in familial polyposis. We antici- pate doing multiple level or serial sections on minute p d y p ~ in routine specimens to study this point further.

SUMMARY

In an earlier study, it was suggested that most, if not all, ordinary colonic carcinomas originate in adenomatous epitheIium. This was based primarily on the failure to find minute (3 mm. or less) or microscopic carci-

noma surrounded by normal colonic mumsa and on the frequency with which this is found in the adenomatous epithelium, especially in larger adenomatous lesions. Should this be mr- rect, the genesis of adenomatous epithelium represents an early step in colonic neoplasia and is obviously a subject of major importance.

In this study, an attempt has been made to contribute observations concerning the origin of the adenomatous epithelium. This has been done by histological examination of human material, specifically, the study of a large number of minute colonic polyps, including 8 serial section studies of minute polyps in a case of familial polyposis.

The following impressions were gained from this study:

FIGS. 12 and 13. These perpendicularly oriented central sections show adenomatous epithelium in central tubules in gradual transition with the deep germinative zone. The latter resembles the deep germinative zone of normal crypts. This contrasts with the abrupt epithelial transition seen in peripheral sections. Note the flaring “vase of flowers’’ effect with peripheral overhanging of adenomatous glands and tilting of adjacent normal glands. Sections through these zones or nonperpendicular sections produce the appearance shown in Fig. 11. (XSO & XSO.)


1. .4t our present level of uncertain knowledge, we feel that pathologists can easily and should distinguish diagnostically between hyperplastic and truly adenomatous polyps. Es- pecially for those interested in colonic neoplasia, polyp detection, and the significance of truly adenomatous lesions, this distinction will assist in gathering more meaningful in- formation regarding the incidence and neoplastic significance of polyps according to type.

2. From our serial section studies we have offered a 3-dimensional concept of the architecture of minute, truly adenomatous polyps. Also, based on the serial sections, we believe we have offered an anatomic explanation of why random sections through minute adenomatous polyps so frequently show adenomatous tubules cut in cross section near the surface of the mucosa and normal tubules cut in cross section in the deeper portion. This appearance has led some observers to what we believe is a false impression, namely, that the adenomatous epithelium originates in the superficial and relatively senile one third of the colonic mucosa.

3. While acknowledging the statistical suggestion, based on size, that the hyperplastic

polyp is the precursor of the adenomatous polyp, a number of anatomic approaches to this problem, based on cases of both ordinary and familial polyposis, suggest that this may not be the case. 4. Conversely, our serial section studies in

the familial polyposis specimens appear to show that the adenomatous epithelium can arise de novo from normal mucosa and does so by a process involving gradual anatomic transition from the germinative epithelium in the deep portion of the colonic crypts. This apparent demonstration of a deep origin seems to bring into harmony the high-growth potential and high mitotic activity of the adenomatous epithelium and that mucosal level that is normally the zone of greatest mitotic activity.

Although there has been speculative interest in the site of origin of the adenomatous epithelium within the colonic mucosa, to our knowledge this is the first systematic serial section study of this problem. If future studies validate our suggestion that the origin of adenomatous epithelium can be pinpointed to the germinative zone of the colonic mucosa, this would represent another step in our attempts to trace the origin of colonic neoplasia.

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5. DUNPHY, J. E.; PATIERSON, W. B., and LECC, M. A.: Etiologic factors in polyposis and carcinoma of colon. Ann. Surg. 150: 488-499, 1959.

6. ENQUIST, I. F.: Incidence and significance of polyps of colon and rectum. Surgery 42: 681-688, 1957.

7. GRINNELL, R. S., and LANE, N.: Benign and malig- nant adenomatous polyps and papillary adenomas of colon and rectum; analysis of 1,856 tumors in 1,335 patients. Internat. Abstr. Surg. 106: 519-538, 1958.

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Thymidine-H8 as tool for investigation of renewal of cell populations. Lab. Invest. 8: 296-308, 1959.

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10. MESSIER, B.: Renewal of colonic epithelium of

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13. SUNDERLAND, D. A.. and BINKLEY, G. E.: Papillary adenomas of large intestine; clinical and morphological study of 48 cases. Cancer 1: 184-207, 1948.

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