RODGER C. HAGGITT MEMORIAL LECTURE Ulcerative Colitis: The Scope of Dysplasia
Mount Sinai Hospital
Toronto, ON, Canada
Ulcerative colitis (UC) is an inflammatory disease in which the risk of colorectal cancer
is increased. The risk increases with extent of disease, including backwash ileitis which indicates
total large bowel disease, length of history, early onset, activity of disease, family history of
colorectal cancer and sclerosing cholangitis; the risk may be reduced with anti-inflammatory therapy.
However, the problem that became apparent decades ago that patients with longstanding extensive disease
would present with advanced and sometimes multiple colorectal cancer: the prognosis was correspondingly
poor. Worse, the mean age of patients presenting with colitic cancers was in their early 40's, a time at
which many had relatively young families, were developing their careers, and had heavy fiscal
responsibilities. A major issue became how to prevent patients developing and dying from these
carcinomas. Initially the only recourse was "prophylactic" total proctocolectomy, with an unwanted
ileostomy or subsequently a pouch operation. A better marker of increased risk was required short of an
invasive carcinoma the stage of which could not be accurately assessed.
While the concept of a pre-invasive lesion in colorectal cancer had long been recognized, the notion that
adenomas preceded carcinomas was expounded in the 60's by Morson at St. Mark's Hospital in London
England, and it became a logical step to consider that a similar principle applied to UC. Indeed, in
patients undergoing resection for carcinoma in UC, widespread "dysplasia" (as it was called), was
frequently found in patients undergoing resection for colitic cancers. The fact that the dysplasia was
so widespread that the rectum was invariably involved led Morson and Pang  (1967) to suggest that
regular rectal biopsies might well be able to detect rectal dysplasia, which in turn would identify
patients at particularly high risk for the development of carcinoma. The era of trying to predict which
patients within a high risk group might be particularly at risk was born.
An initial series of issues developed very quickly. Some patients with carcinoma clearly
did not have widespread dysplasia (indeed, sometimes there was no dysplasia), nor did it involve the
rectum, so rectal biopsies alone were clearly inadequate. Fortunately, the flexible sigmoidoscope, and
then the full-length colonoscope were chronologically "just around the corner" so that it became possible
to examine patients regularly and to take multiple biopsies in an attempt to further refine patients at
risk. This solved the issue of accessibility to the proximal colon but a second series of issues
This became a major bone of contention, because there was no good agreement between pathologists as to
what constituted "dysplasia". It was recognized that in colectomy specimens and in biopsies, that
nuclear features were encountered that were not normal but it was unclear whether they were also risk
factors for carcinoma. Some were overtly occurring in inflamed mucosa. Because of the confusion that
clearly existed, a slide exchange was arranged in the early 1980s in which any pathologist that had
written about dysplasia in colitis was invited to participate. This resulted in the Human Pathology
paper in 1983 that tried to address many of these issues  . Issues that needed addressing urgently
- Some patients would be found with small (and sometimes large) tumors, occasionally when the previous colonoscopy had been negative. Thus the risk a lesion being invasive was quickly found to differ depending on whether it was found at the initial (screening) colonoscopy or a subsequent (surveillance) colonoscopy, a principle that still holds
- Because on follow-up (surveillance) colonoscopy, some patients actually had carcinomas, surveillance colonoscopy was also a method of detecting small carcinomas (not necessarily "early" pathologically). Surveillance carcinoma therefore became a screen for both dysplasia and carcinoma.
- Patients were found with endoscopic abnormalities varying from mucosal irregularities, plaques, nodules or polypoid lesions which were dysplastic / adenomatous on biopsy. However if colectomy was carried out on these patients the abnormality was often found to harbor an underlying invasive carcinoma that was not suspected clinically. Worse, sometimes these lesions were advanced, and patients still died of their carcinoma, although this seemed to occur much more frequently when the endoscopic abnormality was found on the initial screening colonoscopy. This gave rise to the concept of "dysplasia-associated lesions or masses" (DALMs - Blackstone), which therefore became an indication for proctocolectomy  .
- Patients with only dysplasia also had unexpected carcinomas found incidentally in colectomy specimens, especially if found on screening colonoscopy, so that the diagnosis of "dysplasia" became a potential indication for colectomy  .
20 years ago the solutions to some of these were somewhat revolutionary. We were so uncertain about
where reactive changes stopped and which were likely dysplastic that there was not only a "don't know"
category in the grading system – itself revolutionary – the acknowledgment that pathologists might "not
know" was, at the time, one that pathologists (and the clinicians with whom they interacted), had
problems accepting, as pathology was always taught to be "the final arbiter", and were therefore not
allowed "not to know". There were also 3 grades of don't know – which were more grades than there were
for dysplasia itself. And just to rub it in, if you had any doubt about the ability of any specific type
of epithelium to give rise directly to an invasive carcinoma, it could not be called dysplastic. The
diagnosis of "indefinite for dysplasia' was therefore arrived at by asking 2 simple questions:
- the spectrum of reactive changes and their separation from dysplasia
- a definition of dysplasia
- a grading system for dysplasia
- implications of each of these "grades"
|Is this epithelium unequivocally negative for dysplasia?|
|Is this epithelium unequivocally positive for dysplasia?|
If the answer to both of these questions was "no" then one was dealing with "indefinite for
The grading system: Although "mild, moderate and severe" was the grading system in common
parlance at the time, a mere glance at the kappa values in the interobserver variability study made it
clear that 2 were preferable, not only to improve kappa values, but because management could readily be
tied in with a 2-grade system. Low and high grade dysplasia were thus introduced along with no
dysplasia and indefinite for dysplasia. However, within the study, and not reflected by kappa values,
were that pathologists clearly stratified themselves into a spectrum regarding interpretation of the same
slide with a malignant group (who tended to err on the high side, a benign group, that were on average
about a full grade below the malignant group, and an intermediate group, who tended to be in between both
of the other groups. It became very easy to predict who would call what, once one had made up ones own
mind and then titrated oneself against everyone else. However it was also clear that while the
"adenomatous" pathway appeared the best recognized, that there were other variants/pathways that were
only recognized as neoplastic because carcinomas were overtly falling off of them. One of these we would
now call "serrated".
"Implications" also created a dilemma. The association of HGD with an associated invasive
carcinoma was already apparent, but it was also clear that some carcinomas arose directly from LGD (or
less). Yet given the interobserver agreement that we knew to be present, it was difficult to give an
unequivocal recommendation to carry out "prophylactic" colectomy for LGD, especially as it overlapped
with IFD, the natural history of which was unclear. Further, it also became clear that even amongst this
group of interested pathologists, was the potential necessity for confirming a diagnosis of dysplasia.
This was a tough one to swallow, but thought necessary – if the experts were having such a tough time
agreeing, one could only imagine what might be called HGD, and therefore an implication of colectomy, at
the more grass roots level. However, it had also become apparent that some crypts that fed into actively
regenerating mucosa could mimic HGD very closely.
In the 20years that have passed, some of this has been seriously (and rightly questioned)
while new problems and concepts have emerged:
The Definition of Dysplasia
(An unequivocally neoplastic
proliferation). The notion that we actually know what is neoplastic initially sounds pretty arrogant,
although most of the time with the adenomatous type of dysplasia, we are confident because we have seen
carcinomas fall off of it directly. But if there is identical epithelium without carcinoma falling off
of it, why does some have carcinoma falling off of it and others not? They must surely be different? We
could interpret this in terms of molecular differences yet to be defined – the "invasion genes".
Nevertheless it remains subjective and really only applies satisfactorily to the adenomatous pathway.
One of the problems is that there clearly are other pathways which may or may not use the traditional
adenomatous pathway including those involving mismatch repair genes and serrations, in which traditional
dysplasia may be only one option. Sometimes, invasive carcinomas appear to arise from epithelium that is
not dysplastic in the conventional adenomatous sense; indeed sometimes there is very little nuclear
atypicality. Such "minimal deviation" carcinomas are always problematic in trying to reconcile very
bland morphology with the paradoxical invasive pattern, which can be highly aggressive. There will
always be the need for "better markers" of neoplasia, but it may be some time before we arrive at a the
molecular diagnosis that must necessarily involve not only the epithelium but the host reactions
including inflammatory and desmoplastic responses and the interchange of growth and suppression factors,
some of which may be mutant, that occur between them.
The Vienna Classification for Dysplasia
system for dysplasia has remained virtually unchanged for since 1983, In 1998 an upgraded system was
developed that it was hoped would help resolve international differences in terminology  . It utilized
the term "non-invasive neoplasia" – both low grade and high grade, and also borrowed the term "suspicious
of invasive carcinoma for those tumors that have all of the hallmarks of invasion except that the
invasive component cannot be demonstrated unequivocally. The re-introduction of the term carcinoma in
situ was more for molecular work, as increasingly molecular work needs something between usual high grade
dysplasia as defined by marked nuclear stratification and the architectural abnormalities that tend to be
involved in carcinoma in situ. It is now used widely in Europe and frequently when those in other
non-English speaking countries such as Japan publish in English journals. Like the original
classification it also has management implications.
Reproducibility and Need for a Second Opinion
All of the studies with
dysplasia show a considerable and disturbing interobserver variability. Given that potential colectomy
with its morbidity and even mortality are on the line on one side, and possibly dying from a carcinoma if
colectomy is not carried out in a timely manner, "getting it right" is important. Surprisingly, the
impetus for suggesting a second opinion came from some of the comments made regarding how one arrived at
a diagnosis of dysplasia, which were at times little more than tossing a coin. This has evolved to the
point that the adenomatous pattern of dysplasia is fairly easy to diagnose in the absence of
inflammation, although when maturation is present it can cause problems (in Barrett's the existence of
bottom up dysplasia is pretty well denied in one paper as it is a criterion for "indefinite for
dysplasia"  . While most dysplasia is maximal at the surface (top down dysplasia}, a small
proportion is maximal at the base with some degree of maturation (bottom up dysplasia). Because
maturation is a feature of regeneration the differential diagnosis of maturation include both
regeneration and bottom-up dysplasia. If maturation is used as the sine que non of regenerative changes,
it follows that the existence of bottom up dysplasia is called into question, and virtually cannot exist,
even though in some patients maturing dysplasia has infiltration from the base, as seen in for example,
in a villous adenoma in the large bowel with invasive carcinoma, and also the superficial dysplastic
component of many colloid cancers.
Vienna classification of GI epithelial neoplasia
| Category || Diagnosis || Management|
| Category 1 ||Negative for neoplasia/dysplasia || Optional Follow-up|
| Category 2 ||Indefinite for neoplasia/dysplasia || Follow-up|
| Category 3 ||Non-invasive low grade neoplasia || Local Rx or Follow-up|
| (low grade adenoma/dysplasia) |
| Category 4 ||Non-invasive high grade neoplasia || Local Rx|
| 4.1 High grade adenoma/dysplasia |
| 4.2 Non-invasive carcinoma (carcinoma in situ)* |
| 4.3 Suspicion of invasive carcinoma |
| Category 5 ||Invasive neoplasia || Needs Rx|
| 5.1 Intramucosal carcinoma |
| 5.2 Submucosal carcinoma or beyond |
* Non-invasive indicates absence of evident invasion. Intramucosal indicates invasion into the lamina propria or muscularis mucosae.
There is increasing evidence that indefinite for dysplasia (IFD) in ulcerative colitis is at increased
risk of developing subsequent invasive carcinoma than patients without dysplasia, and is may approximate
that of LGD
. As such it is important to appreciate that, while currently IFD is not an indication
for endoscopic or surgical therapy, that it warrants careful follow up to ensure that LGD (or worse) is
not present while follow-up should be ensured.
Dysplastic Polyps in UC
This is the single most common problem in the
management of colitics and our clinical colleagues (and some pathologists) seem to spend a lot of
unnecessary time worrying about the ability to reliably distinguish apparently sporadic adenomas from
dysplasia-associated lesions or masses (DALMs). As there is no reliable way to do this there are
numerous algorithms available for managing this problem. However, the easiest guidelines are
simplistically stated as follows
- Adenoma-like masses (ALMs) above the upper limit of disease can be regarded as sporadic adenomas and treated as such.
- Dysplastic lesions within colitic mucosa can also be treated as sporadic adenomas provided they (i) can be demonstrably completely excised endoscopically (this means demonstrating a dysplasia free margin and no dysplasia in the immediately surrounding mucosa, (ii) can be shown to be unassociated with dysplasia elsewhere in the bowel (iii) the patient is in the adenoma bearing age range (often regarded to be <40 although these are not uncommon in the colitic population. If any of these provisos cannot be satisfied, serious consideration must be given to proctocolectomy. In practice, if the endoscopic appearance is suspicious of an invasive neoplasm some surgeons will proceed directly to proctocolectomy. Fears that one is dealing with an invasive lesion are often well founded.
Advances in Detection of Dysplasia
The answer therefore also has to involve advances in colonoscopic techniques. It is increasingly
apparent that most dysplasia does have an endoscopic abnormality of some sort,  although the
introduction of magnification endoscopy and chromoscopy increasingly allows identification of pit
patterns that may indicate dysplasia, apart from just exaggerating lesions detected colonoscopically.
. The addition of additional endoscopic techniques such as narrow band imaging and high
resolution colonoscopes accompanied by high resolution monitors are likely to make recognition of small
areas of dysplasia very feasible given the huge increase in resolution that these scopes produce.
There have been numerous attempts to find a gold standard to replace light microscopy. These have involved detection of aneuploidy, p53, oncogenes such as K-ras, mismatch repair genes and increasingly other cell cycle markers, telomere length and also the whole notion that the mucosa in which dysplasia arises is not normal but has abnormalities that are detectable
Attention has also shifted from detecting changes in dysplastic mucosa to the surrounding non-neoplastic mucosa, which are clearly demonstrable particularly when looking at chromosomal instability including telomere shortening. Indeed in one study loss of 4 genes in non-dysplastic mucosa were shown to accurately predict which patients had carcinoma. It seems a matter of time before better predictors are found, but we have been saying that for a long time
- Endoscopy and Biopsies
There hasbeen a lot of attention to the number of biopsies that are required, and looking for small areas of dysplasia is like looking for a needle in the proverbial haystack. Further, if it is found, the notion of then trying to confirm it seems farcical. Detecting a 2cm patch of dysplasia (radius 1cm) means it has an area of 3.142cm2 so that in a colon 100cm long and 10cm wide (1000cm2) would require 1000/3.142 biopsies (318!!!) while a33 are required to provide about a 90% chance of picking it up experimentally  . Random biopsies will therefore always cause problems while even getting many endoscopists to take 30+ biopsies, and telling them that less than this is an inadequate series is a major problem.
In summary, the whole story of evolution in colitis continues to evolve, and the pessimism that
surveillance is expensive, does not work, and neither prevents the development of carcinoma or improves
life expectancy can be seriously challenged.
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