Section 1 -

"Borderline" Pathology: Definitions and Diagnosis Carolyn Compton 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 (malignant) Borderline between grades: Dysplasia: high-grade vs. low-grade Cancer: well, moderately, poorly differentiated (or numerically assigned equivalent) Borderline between stages: Carcinoma in situ (pTis) vs. invasive carcinoma (pT1) anywhere in the GI tract Intraepithelial carcinoma vs. intramucosal carcinoma vs. invasive carcinoma in the colorectum 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: 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). Consensus Classifications 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 Normal Reactive foveolar hyperplasia Intestinal metaplasia Complete Incomplete 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) Dysplasia 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) High-grade adenoma/dysplasia (severe dysplasia) Non-invasive carcinoma (carcinoma in situ) Suspicious for invasive carcinoma Category 5: Invasive neoplasia 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 References 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; 91:864. 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 2001; 54:246. 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. 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