Management of Early Cancer of the Gastrointestinal Tract
Moderators: Robert H. Riddell and Elizabeth Montgomery
Section 1 -
"Borderline" Pathology: Definitions and Diagnosis
National Cancer Institute
Bethesda, MD, USA
What's a "Borderline" Lesion?
Lesions that challenge the pathologist's ability to render a definitive diagnosis are those that
straddle the border between two morphologic entities or between two stages or grades of the same entity.
They are common and represent the limits of certainty with which morphologic patterns of change predict
underlying biology and behavior. Frequently, they also correspond to branch points in the clinical
decision tree and impact patient care. Thus, they are frustrating for pathologist and clinician alike,
both of whom are seeking diagnostic clarity on which to base patient management. This is primary reason
they are of such intense interest and why such effort has been expended seeking molecular markers to more
sharply define the cut-point between these lesions. Common examples are listed below.
Borderline between entities:
- Reactive/reparative change in normal mucosa vs.
neoplastic change in genetically altered mucosa: dilemma posed as to whether or not the lesion poses a
risk of cancer and merits immediate ablative treatment or surveillance
- High-grade dysplasia (pre-malignant) vs. cancer
Borderline between grades:
- Dysplasia: high-grade vs. low-grade
- Cancer: well, moderately, poorly differentiated (or
numerically assigned equivalent)
Borderline between stages:
In anatomic pathology, areas of uncertainty are legitimate and may never be fully eliminated, even
with greater understanding of the biology underlying phenotypic change. For the pathologists, the
emphasis is rightly placed on three issues:
- Carcinoma in situ (pTis) vs. invasive carcinoma (pT1) anywhere in the
- Intraepithelial carcinoma vs. intramucosal carcinoma vs. invasive
carcinoma in the colorectum
- Familiarity with the spectrum of morphologic alterations that defy
certainty in interpretation (i.e., knowing when it is not only appropriate but part of good judgment to
be uncertain about the interpretation of the morphological appearance of a lesion).
- Consistency in defining and classifying them – all pathologists
should mean the same thing when they use terms of uncertainty
- Consistency in communicating them – all clinicians should understand
what the pathologist is saying (so that they know what action to take).
The globalization of medicine and science makes it more important than ever for pathologists worldwide
to be applying the same terms to the same morphologic lesions. Former international differences in
diagnostic criteria and terminology often lead to identical lesions being called by different names and
dissimilar lesions being called by the same names. Such discrepancies would logically lead to spurious
data on cancer incidence and treatment standards around the world. In particular, Eastern and Western
pathologists used terms as common as "carcinoma" in different ways. For Eastern pathologists,
"carcinoma" was diagnosed on the basis of cytological and structural features, but for Western
pathologists, evidence of stromal invasion was required before this term was applied. In short, lesions
that Western pathologists called "dysplasia" would be termed "adenocarcinoma" by Eastern pathologists.
In even a single hemisphere, many different terms have been used by pathologists to diagnose the same
lesion of early gastrointestinal cancer. These terms include dysplasia, atypical hyperplasia, in situ
carcinoma, preinvasive cancer, preinvasive lesion, cancer precursor, precancerous lesion, precancerous
state, premalignant lesion, premalignancy, and incipient neoplasia. Currently, the term "intraepithelial
neoplasia" is preferred, as discussed below.
In seeking international standardization of definitions and terminology for gastrointestinal lesions,
several important steps towards consensus have occurred. Landmark consensus classifications are shown
below. Most recently, the Vienna Classification, emanating from the World Congress of Gastroenterology
in Vienna in 1998, has been created with the goal of standardizing terminology and criteria for all
gastrointestinal lesions under one classification. It collapsed the diagnoses of high-grade dysplasia or
adenoma, non-invasive carcinoma (carcinoma in situ) and suspected invasive carcinoma into a single
category: "category 4 or non-invasive high-grade neoplasia". This particular change, based on
consensus, eliminated the major East-West discrepancy and corresponds to the treatment recommendation of
local ablation (endoscopic mucosal resection or surgical excision). However, the World Health
Organization subsequently published its classification of neoplasia of the gastrointestinal tract and has
replaced the term "dysplasia" with "intraepithelial neoplasia". It has been suggested, therefore, that
the Vienna classification be modified to this standard.
Padova Classification for Gastric Mucosa (1998)
- Negative for dysplasia
- Reactive foveolar hyperplasia
- Intestinal metaplasia
- Indefinite for dysplasia
- Foveolar hyperproliferation
- Hyperproliferative intestinal metaplasia
- Non-invasive neoplasia (flat = dysplasia; or elevated = adenoma)
- Low grade
- High grade
- Suspicious for carcinoma without invasion
- Including carcinoma without invasion
- Suspicious for invasive carcinoma
- Invasive carcinoma
Dysplasia in Inflammatory Bowel Disease (1983; modified 1992)
- Negative for dysplasia
- Indefinite for dysplasia (no longer subdivided)
- Low-grade dysplasia (LGD)
- High-grade dysplasia (HGD)
Vienna Classification of Gastrointestinal Neoplasia (1998)
Category 1: Negative for dysplasia/neoplasia (includes reactive changes)
Category 2: Indefinite for dysplasia/neoplasia
Category 3: Non-invasive neoplasia: low grade (=LGD)
Low-grade adenoma/dysplasia (includes mild and moderate dysplasia)
Category 4: Non-invasive neoplasia: high grade (=HGD)
Category 5: Invasive neoplasia
- High-grade adenoma/dysplasia (severe dysplasia)
- Non-invasive carcinoma (carcinoma in situ)
- Suspicious for invasive carcinoma
- Intramucosal carcinoma (invades lamina propria)
- Invasion into submucosa or beyond
Communicating Uncertainty to Other Physicians
These classifications represent powerful tools for universal pathology standardization, but
unfortunately, they are not universally applied. Problems exist in two major areas: interobserver
variation in diagnosis of a single category (of the Vienna Classification, for example) and use of
"ambiguous terminology" in reporting uncertainty for any category, especially if uncertainty as to
whether or not invasive carcinoma is present.
Interobserver variation has been the subject of numerous studies, and although the degree of variation
differs from study to study, all studies document inconsistencies in interpretation among pathologists.
Variation is more marked at some cut-points than others and may never be eliminated altogether. The
overall agreement in among pathologists assessing dysplasia in inflammatory bowel disease is notoriously
poor (less than 2/3 of pathologists agreeing with one another). Agreement in recognizing the presence or
absence of dysplasia is higher (about 70-85%), but it is not perfect. This has lead to practice
recommendations that surveillance biopsies in chronic inflammatory conditions that predispose to cancer
risk be assessed by more than one observer.
The classifications above allow for a category of "indefinite for dysplasia" that addresses
uncertainty at the cut-point between reactive/reparative and neoplastic. However, uncertainty may exist
at other cut-points, especially at the level of diagnosing carcinoma. When abnormal histology or
cytology is present but uncertainty exists as to whether or not it sufficient to make a definitive
diagnosis of cancer, pathologists use a plethora of different terms to communicate the dilemma. The
problem of "ambiguous terminology" continues to plague borderline diagnosis. It is a major contributor
to poor interdisciplinary communication, which is the major cause of low satisfaction among "customers"
of Pathology departments (surgeons, internists, specialists, tumor registrars, cancer epidemiology
organizations, etc). It also contributes heavily to misinterpretation of pathology reports, which in
turn, can lead to mistreatment or mismanagement of patients or skewing of cancer statistics or both.
It is unsurprising that users of pathology reports interpret "ambiguous terminology" variably, since
pathologists do not agree among themselves what they mean when they use these terms. It has been
documented repeatedly that the phraseology used in pathology reports is the subject to wide variation in
interpretation among both clinicians and other pathologists. A recent study from the USA showed that
surgeons misunderstood pathologists' reports 30% of the time. This compromises the quality of patient
care and can be the source of medical errors. Among the major groups that track cancer incidence in the
USA including the Commission on Cancer of the American College of Surgeons, the Food and Drug
Administration, the Centers for Disease Control, and the California Cancer Registry, ambiguous terms are
variably interpreted as indicating new cancer cases, and there is no consistency among the groups as to
how an individual term is interpreted. This compromises the quality of cancer statistics and the
tracking of medical progress and economics. The adoption of a limited number of phrases acceptable to
and understood by both groups has been recommended but still goes unrealized. This year, the College of
American Pathologists has convened a task group to address the issue of ambiguous terminology since it so
clearly compromises the quality of pathology consultation services and the quality of medical care.
Common Examples of Ambiguous Terminology
(Used in the diagnosis line of a pathology report as per this example: "Funny-looking cells, ______
(insert ambiguous term here) carcinoma")
|Consistent with ||Rule out ||Suspicious of|
|With the appearance of ||Apparently ||Reminiscent of|
|In keeping with ||Likely ||Questionably|
|Indicative of ||With features of ||May be|
|Compatible with ||Looks like ||Possible|
|Most likely ||Presumed ||Not excluding|
|Appears to be ||Suspected ||Presumed|
|Highly suspicious of ||Suggestive of ||Appearance approaching|
|Moderately suspicious for ||Favours/favors ||Not ruling out|
|Somewhat suspicious of ||Suggests ||Worrisome for|
|Typical of ||Probable ||Could be|
| ||Seems to be ||Equivocal for|
- Attanoos RL, Bull AD, Douglas-Jones AG, Fligelstone LJ,
Semararo D. Phraseology in pathology reports. A comparative study of interpretation among pathologists
and surgeons. J Clin Pathol 1996; 49:79.
- Powsner SM, Costa J, Homer RJ. Clinicians are from Mars
and pathologists are from Venus. Arch Pathol Lab Med 2000; 124:1040.
- Riddell RH. Pre-malignant and early malignant lesions of
the gastrointestinal tract: definitions, terminology and problems. Amer J Gastroenterology 1996;
- Riddell RH, Goldman H, Ransohoff DF, et al. Dysplasia in
inflammatory bowel disease: standardized classification with provisional clinical applications. Hum
Pathol 1983; 14:931.
- Rugge M, Correa P, Dixon MF, et al. Gastric dysplasia:
the Padova international classification. Am J Surg Pathol 2000; 24:167.
- Schlemper RJ, Riddell RH, Kato Y, et al. The Vienna
classification of gastrointestinal neoplasia. Gut 2000; 47:251.
- Silcocks P, Page M. What constitutes a histological
confirmation of cancer? A survey of terminology interpretation in two English regions. J Clin Pathol
- Stolte M. The new Vienna classification of epithelial
neoplasia of the gastrointestinal tract: advantages and disadvantages. Virchows Arch 2003; 442:99.
- Zarbo RJ. Determining customer satisfaction in anatomic
pathology. Arch Pathol Lab Med 2006; 130:645.