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 WISCONSIN SOCIETY OF PATHOLOGISTS 2004 ANNUAL MEETING GASTROINTESTINAL PATHOLOGY AND Country Inn Resort UNKNOWN SLIDE CASES Robert E. Petras, M.D. Wisconsin Society of Pathologists UNKNOWN SLIDE SEMINAR Discussant: Robert E. Petras, M.D.
National Director for Gastrointestinal Pathology Services AmeriPath, Inc. Associate Professor of Pathology Northeastern Ohio Universities College of Medicine Case Histories
CASE 1: CASE 2: CASE 3: CASE 4: DISCUSSION FOR CASE 1 HISTOLOGIC DIFFERENTIAL DIAGNOSIS OF GASTROESOPHAGEAL REFLUX Robert E. Petras, M.D.
GASTROESOPHAGEAL REFLUX Introduction Gastroesophageal reflux disease (GERD) describes a symptomatic clinical condition related to reflux of gastric and/or duodenal contents into the tubular esophagus that usually presents with pyrosis (heartburn), acid regurgitation, and dysphagia. The term reflux esophagitis refers to a subset of patients, usually with symptoms of GERD, who show endoscopic and/or histological manifestations of inflammation within squamous and/or gastric cardia type mucosa (1). The etiology of GERD is multifactorial and clearly some degree of gastric/acid reflux occurs commonly in apparently normal asymptomatic individuals. Lesser degrees of gastric reflux can usually be handled by the normal clearance mechanisms (e.g., swallowed saliva, the peristaltic function of the esophagus) (2,3). Patients with more severe acid reflux associated with symptomatic GERD often demonstrate abnormalities of the lower esophageal sphincter such as abnormal transient relaxation, anatomic disruption of the gastroesophageal junction by a hiatal hernia or rarely, sustained hypotension of the lower esophageal sphincter (4-6). However, even some of these patients remain asymptomatic. Therefore, it appears that symptomatic GERD and the histologic changes of reflux occur when the forces of acid reflux and the potency of the refluxate overwhelm the esophageal acid clearance mechanisms and the inherent mucosal resistance. Many consider esophagoscopy (with biopsy when indicated) the prudent initial evaluation of patients with symptoms of GERD (1). It quickly excludes other conditions in the clinical differential such as gastritis, infective esophagitis, "pill esophagitis", and peptic ulcer disease. The endoscopic changes described with GERD are seen more often in severe cases and include erosions, ulcers, and stricture. Biopsy specimens are generally obtained to rule out infection and malignancy and to establish a diagnosis of Barrett's esophagus. Erosive lesions are often sampled to rule out Candida species and herpes virus infection. Approximately one-third of patients with reflux have endoscopically normal or only slightly hyperemic esophageal mucosa; however, endoscopic biopsy specimens will show characteristic histologic changes (see below) (7). Some investigators consider histologic evaluation of biopsy specimens the "gold standard" in the diagnosis of GERD and reflux esophagitis, whereas others believe that it is unreliable (8). Histologic Changes - Squamous Mucosa Well-oriented normal esophageal squamous mucosa demonstrates a basal cell layer that is usually 1-3 cells thick. These basal cells can be discerned by their smaller size and their more basophilic cytoplasm as compared to normal surface squamous cells. The cytoplasmic appearance of basal cells and their relative lack of glycogen can be highlighted with the PAS stain. Lamina propria papillae are present, but make up only one-half of the total epithelial thickness (9,10). Biopsy specimens from endoscopically demonstrable lesions in GERD (erosions, ulcers) show acute inflammation of the mucosa and submucosa. Exudates contain neutrophils and eosinophils often overlying an erosion or an ulcer with an inflamed granulation tissue base. Acute inflammation is fairly specific but insensitive for reflux esophagitis (10,11). Many patients with clinical symptoms and with the acid abnormalities of GERD as measured by intraesophageal pH probes have endoscopically normal appearing esophagi or only show minimal esophageal changes such as hyperemia and lack neutrophils in biopsy specimens. Often, these patients show characteristic squamous mucosal changes of reflux esophagitis consisting of hyperplasia (lamina propria papilla greater than 67% of the thickness of the squamous mucosa) and an increase in the basal cell layer (greater than 15% of the squamous mucosal thickness) (10-12). These abnormalities are often accompanied by increased numbers of intraepithelial eosinophils and lymphocytes (10,11,13-16). These milder changes are often present in the lower 3 cm of the esophagus in asymptomatic, apparently normal individuals. Therefore, the significance of these changes near the gastroesophageal junction requires clinical pathologic correlation. The squamous mucosa adjacent to ulcers and erosions can show striking regenerative features with basal cells occupying the full thickness of the squamous mucosa and papillomatosis that can mimic squamous carcinoma or dysplasia (see below). Histologic Changes - Glandular Mucosa Several investigators have suggested that the presence of gastric cardia-type mucosa in the esophagus at or near the squamocolumnar junction may be metaplastic and that inflammation of this metaplastic gastric cardia-type mucosa (so-called "carditis") is highly correlated with GERD (17,18). Oberg and colleagues, in an elegant study of 334 patients, convincingly linked inflammation and intestinal metaplasia of gastric cardia mucosa at the squamocolumnar junction to GERD (as documented by abnormal lower esophageal sphincter manometry and increased esophageal acid exposure measured by pH probe) and not to Helicobacter pylori infection (17). In stark contrast, several other investigators have concluded that this "carditis" is a manifestation of gastric Helicobacter pylori infection (19-21). After critical review, coupled with my own anecdotal observations, I have come to the conclusion that both schools of thought are probably correct. These apparent disparate viewpoints can be reconciled based on methodologic differences and inherent biases within these studies. For instance, Oberg et al. obtained biopsy specimens from the esophagus directly at the squamocolumnar junction. Furthermore, they performed fairly sophisticated tests (e.g. pH monitoring, esophageal manometry) to establish GERD (17). In contrast, Goldblum et al. obtained their biopsy specimens in the stomach 5 mm below the squamocolumnar junction and prospectively did more tests (e.g. special stains, serology) to establish a diagnosis of Helicobacter pylori infection. Furthermore, these authors based a diagnosis of GERD on symptoms alone. (19) I believe that biopsy specimens from the stomach even millimeters below the squamocolumnar junction reflect disease processes of the stomach. Therefore, inflammation and intestinal metaplasia in that area are highly correlated with Helicobacter pylori infection. Helicobacter pylori-associated pangastritis can effect the gastric cardia can also cause inflammation in the esophagus at the squamocolumnar junction. Although statistical correlation between this form of "carditis" and Helicobacter pylori exists, these studies also argue strongly for other causes of inflammation in gastric cardia-like mucosa at the esophagogastric/squamocolumnar junction that are not associated with Helicobacter pylori. For instance, over 70 percent of the "carditis" described by Spechler et al. were not associated with Helicobacter pylori infection (21) and approximately 12 percent of the intestinal metaplasia found at the gastric cardia by Goldblum et al. were not associated with Helicobacter pylori infection (19). In these studies, this non-Helicobacter pylori "carditis" did not necessarily correlate with symptoms of GERD because it may reflect the physiologic response of the region to low level reflux of gastric contents (a normal phenomenon). However, "carditis" at the esophagogastric junction or above is also characteristic of patients with more severe gastroesophageal reflux disease as demonstrated by symptoms, manometric and pH probe abnormalities. Similar to "carditis", the etiology and the significance of intestinal metaplasia at the gastroesophageal junction is the subject of considerable debate (22,23) that raises a number of interesting/important questions. Is intestinal metaplasia at the gastroesophageal junction caused by Helicobacter pylori or reflux? Can intestinal metaplasia in the gastric cardia be reliably distinguished from the specialized columnar epithelium of Barrett's esophagus? Is intestinal metaplasia at the gastroesophageal junction associated with an increased risk of adenocarcinoma? Although the answers to these questions remain unknown, there is some evidence that differential cytokeratin staining may be exploited in a classification system for intestinal metaplasia at the gastroesophageal junction. Ormsby and colleagues showed that superficial mucosal staining for cytokeratin 20 combined with strong cytokeratin 7 staining of both superficial epithelium and deep glands was virtually unique to specialized columnar epithelium of Barrett's esophagus (24,25). These observations have also been verified by others (26, 27). Differential staining for cytokeratins 7 and 20 may also help distinguish gastric carcinoma from adenocarcinoma arising in Barrett's esophagus (28, 29). DIFFERENTIAL DIAGNOSIS Infectious Esophagitis Herpetic esophagitis typically occurs in immunosuppressed (e.g. AIDS, chemotherapy, bone marrow transplant) patients (30). Endoscopically, ulcers occur and are typically described as shallow and "punched out" with adjacent normal-appearing squamous mucosa. Biopsy specimens demonstrate an ulcer base that is relatively bland in terms of acute inflammation but may have prominent aggregates of larger mononuclear cells (30). The diagnostic epithelial changes are found in the adjacent squamous mucosa with giant cell formation, ground-glass nuclei, and eosinophilic intranuclear (Cowdry type A) inclusions (31, 32). Occasional multinucleated epithelial giant cells without viral inclusion can happen as part of regeneration in esophagitis and should not be confused with herpetic infection (33). Inclusions of cytomegalovirus (CMV) can be seen in the base of some esophageal ulcers. The role CMV plays as a primary etiologic agent can be difficult to prove. CMV inclusions typically effect mesenchymal cells such as fibroblasts, smooth muscle, and endothelial cells, and usually spare the epithelium (34, 35). Candida species esophagitis usually presents endoscopically as brownish-white plaques with exudate that has been described as "cheesy." Candida esophagitis often occurs in patients with other debilitating illnesses, such as immunosuppression, diabetes mellitus, and long-term antibiotic therapy. The diagnosis of Candida esophagitis requires the identification of budding yeast and pseudohyphae, usually within the inflammatory exudate. Their identification is certainly enhanced by using special stains for fungi. I recommend routine use of the Alcian blue/PAS combination stain because it is a useful fungal stain, it highlights the basal cell layer, it vividly decorates signet ring cell adenocarcinoma making it easier to identify and can be used to verify the specialized columnar epithelium of Barrett's esophagus. Allergic (Eosinophilic) Esophagitis Symptomatic and histologic reflux esophagitis can certainly occur in children (36). One should however, be wary of diagnosing reflux esophagitis in the presence of large numbers of eosinophils because some of these cases could represent so-called "allergic (eosinophilic) esophagitis", a condition related to eosinophilic gastroenteritis (37-39). Children with allergic esophagitis usually present with dysphagia or "food-catching", and often have an "allergic history". Endoscopic erosions or ulcers are seldom seen but many patients exhibit esophageal furrows or rings (40). Esophageal pH probe studies have shown normal or borderline acid levels in these children and the symptoms of allergic esophagitis will typically not respond to acid suppression therapy. Walsh and colleagues have found that the most useful histologic criteria to differentiate allergic esophagitis from reflux esophagitis are; large numbers of intraepithelial eosinophils (greater than 5/HPF) intramucosal eosinophilic aggregates, and superficial eosinophils (37). Patients with allergic esophagitis may respond to drugs that stabilize mast cells and may require corticosteroids. Allergic (eosinophilic) esophagitis is not being increasingly recognized in adults in whom it is often associated with endoscopic abnormalities such as rings or corregation, proximal esophageal stenosis or small whitish vescicles (41). "Pill Esophagitis" Esophageal injury can occur with prolonged direct mucosal contact with medicinal tablets or capsules, even in therapeutic doses (42-46). Symptomatic "pill esophagitis" has been associated with odynophagia (pain on swallowing) or a feeling of a "lump in the throat". Lesions have been associated with various drugs including antibiotics, Alendronate, potassium chloride, ferrous sulfate, quinine and nonsteroidal anti-inflammatory drugs. Patients frequently give a history of taking pills "on the run" with little or no water (44). Endoscopic erosions and ulcers are found in more proximal locations of the esophagus (versus GERD), often in areas of external esophageal compression such as near the arch of the aorta or near the left atrial appendage especially in patients with cardiomegaly. The histology of "pill esophagitis" is nonspecific. Squamous Dysplasia/Squamous Carcinoma Regenerative epithelial changes of reflux esophagitis can be quite alarming and may mimic squamous dysplasia or carcinoma. In most pathology practices in the United States, esophageal squamous cell carcinoma is becoming quite rare and atypical squamous changes near the esophagogastric junction are much more likely to represent regenerative changes of reflux esophagitis. Histologic features that favor regeneration over squamous carcinoma include; uniform nuclear enlargement with hyperchromasia that maintains a relatively low nuclear to cytoplasmic size ratio; nuclei that are evenly distributed, smooth external nuclear membranes, nuclei that contain one or several chromocenters but have similar size and staining characteristics and look very similar, one to another. In my experience, squamous dysplasia/squamous carcinoma is often accompanied by a curious simplification of the epithelium (versus the papillomatosis more characteristically seen in reflux esophagitis) or a major alternation in mucosal architecture with an invasive pattern and tumor desmoplasia. The cytologic abnormalities must be quite severe before I call something squamous carcinoma. Squamous dysplasia/carcinoma typically shows irregular nuclear crowding with overlap, variable nuclear hyperchromasia, irregular nuclear contours, atypical mitoses, high nuclear to cytoplasmic size ratio, single cell necrosis, and a tendency toward paradoxical maturation (i.e. individual cell keratinization and squamous pearl formation). CLINICAL HISTORY CASE 1 35 year-old woman with dysphagia, distal esophageal web. DESCRIPTION OF SLIDE Sections show papillomatosis, an increased basal cell layer and numerous intraepithelial eosinophils. The number of eosinophils is more than is usually seen in gastroesophageal reflux. Superficial eosinophils and eosinophilic clustering also argue against reflux and in favor of eosinophilic esophagitis. DIAGNOSIS FOR CASE 1 Allergic (Eosinophilic) Esophagitis REFERENCES 1. Kahrilas PJ. Gastroesphageal reflux disease and its complications. 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Cytokeratin expression in adenocarcinomas of the esophagogastric junction: A comparative study of adenocarcinomas of the distal esophagus and of the proximal stomach. Am J Surg Pathol 26:1213-1221, 2002. 30. Greenson JK, Beschorner WE, Boitnott JK, Yardley JH. Prominent mononuclear cell infiltrate is characteristic of herpes esophagitis. Hum Pathol, 22:541-549, 1991. 31. Nash C, Ross JS. Herpetic esophagitis: A common cause of esophageal ulceration. Hum Pathol, 5:339-345, 1974. 32. McKay JS, Day DW. Herpes simplex oesophagitis. Histopathology, 7:409-420, 1983. 33. Singh SP, Odze RD. Multinucleated epithelial giant cell changes in esophagitis. Amer J Surg Pathol, 22:93-99, 1998. 34. Henson D. Cytomegalovirus inclusion bodies in the gastrointestinal tract. Arch Pathol, 93:477-482, 1972. 35. Wilcox CM, Diehl DL, Cello JP, Margaretten W, Jacobson MA. Cytomegalovirus esophagitis in patients with AIDS. A clinical, endoscopic and pathologic correlation. Annals of Internal Medicine, 113:589-593, 1990. 36. Black DD, Haggitt RC, Orenstein SR, Whitington PF. Esophagitis in infants. Morphometric histological diagnosis and correlation with measures of gastroesophageal reflux. Gastroenterology, 98:1408-1414, 1990. 37. Walsh SV, Antonioli DA, Goldman H, Fox VL, Bousvaros A, Leichtner AM, Furuta GT. Allergic esophagitis in children: A clinicopathological entity. Am J Surg Path 23:390-396,1999. 38. Mahajau L, Wyllie R, Petras R, Steffan R, Kay M. Idiopathic eosinophilic esophagitis with stricture formation in a patient with longstanding eosinophilic gastroenteritis. Gastrointestinal Endoscopy, 46:557-560, 1997. 39. Lee RG. Marked eosinophilia in esophageal mucosal biopsies. Amer J Surg Pathol, 9:475-479, 1985. 40. Orenstein SR, Shalaby TM, DiLorenzo C, Putnam PE, Sigurdson L, Kocoshis SA. The spectrum of pediatric eosinophilic esophagitis beyond infancy: A clinical series of 30 children. Am J Gastroenterol 95:1422-1430,2000. 41. Potter JW, Saeian K, Staff D, Massey BT, Komorowski RA, Shaker R, Hogan WJ. Eosinophilic esophagitis in adults: an emerging problem with unique esophageal features. Gastrointest Endosc 59:355-361, 2004. 42. Bott S, Prakash C, McCallum RW. Medication-induced esophageal injury: Survey of the literature. Am J Gastroenterol, 82:758-763, 1987. 43. Kikendall JW, Friedman AC, Oyewole MA, et al. Pill induced injury. Case report and review of the medical literature. Digestive Disease & Science, 28:174-182, 1983. 44. deGroen PC, Lubbe DF, Hirsch LJ, et al. Esophagitis associated with the use of alendronate. New Eng J Med, 335:1016-1021, 1996. 45. Oren R, Fich A. Oral contraceptive-induced esophageal ulcer. Two cases and literature review. Digestive Diseases and Sciences, 36:1489-1490, 1991. 46. Abraham SC, Cruz-Correa M, Lee LA, Yardley JH, Wu T. Alendronate-associated esophageal injury: Pathologic and endoscopic features. Mod Pathol 12(12):1152-1157, 1999. DISCUSSION FOR CASE 2 BARRETT'S ESOPHAGUS: DYSPLASIA AND CARCINOMA Barrett's esophagus, the eponym given to columnar epithelium-lined esophagus, is acquired through chronic gastroesophageal reflux (1-4). Traditionally, it was defined as the presence of columnar epithelium lining the tubular esophagus above the level of the LES (5). For purposes of cancer surveillance, the American College of Gastroenterology (ACG) defines Barrett's esophagus as an endoscopic change in esophageal epithelium of any length that contains intestinal metaplasia (6,7). Barrett's esophagus would be little more than a medical curiosity if not for its complications: ulcer, stricture, bleeding, and carcinoma (8). It is the association with carcinoma that has brought gastroesophageal reflux disease and Barrett's esophagus to so much attention (9). Although the exact magnitude of the cancer risk is unknown, the high prevalence and dismal outcome of carcinoma complicating Barrett's esophagus (10,11) have caused most gastroenterologists to investigate patients with reflux symptoms for the presence of Barrett's epithelium. The ACG recommends that patients with longstanding reflux symptoms have endoscopic examination to detect Barrett's esophagus (7). Once Barrett's esophagus is discovered, such patients should undergo endoscopic surveillance. DIAGNOSIS OF BARRETT'S ESOPHAGUS The Clinical Diagnosis of Barrett's Esophagus Endoscopy has become the mainstay in the diagnosis of Barrett's esophagus (12). In general, the color (orange-red) and appearance (velvety) of Barrett's epithelium as seen through the endoscope is similar to that of normal gastric mucosa. Barrett's epithelium can appear as circumferential or tongue-like extensions of orange-red mucosa into the tubular esophagus (13). Occasionally, Barrett's epithelium can present as an island of orange-red mucosa entirely surrounded by the more pale pink to gray-white squamous epithelium of the normal esophagus. Many endoscopists augment endoscopic visualization with the use of vital stains such as methylene blue (14,15). Since other conditions such as a hiatal hernia, especially one occurring in the setting of severe gastroesophageal reflux, can sometimes mimic Barrett's esophagus endoscopically, the endoscopist's impression of Barrett's epithelium must be confirmed histologically (6,7,16). The Histologic Diagnosis of Barrett's Esophagus Three epithelial types are found in traditionally defined Barrett's esophagus and include junctional epithelium (gastric cardia-like), gastric fundic-type epithelium, and specialized columnar epithelium (incomplete intestinal metaplasia) (17). The junctional epithelium is composed of glands and pits that resemble the gastric cardia except for some atrophy and inflammation. The glands are composed of mucus-secreting cells (5,12,17). Chief, parietal, Paneth, enterochromaffin, and goblet cells are not encountered in junctional epithelium. Gastric fundic-type epithelium, encountered in some cases of Barrett's esophagus, is virtually identical to that of the normal gastric body except that, again, there is usually some degree of inflammation and atrophy. Specialized columnar epithelium (incomplete intestinal metaplasia) is a distinctive epithelial type that is virtually unique to and considered diagnostic for Barrett's esophagus. Furthermore, this epithelial type (intestinal metaplasia) defines the cancer surveillance group (See below) (6,7). Specialized columnar epithelium can occur in a flat or villous configuration and consists of goblet cells and columnar cells. The goblet cells contain mucin that stains positively both with periodic acid-Schiff and with Alcian blue at pH 2.5. These mucins are most often a combination of sialomucins and sulfated mucins (18,19). The columnar cells between goblet cells most often resemble gastric foveolar epithelium or rarely intestinal absorptive cells. The cells lack absorptive capability or ultrastructural features of true intestinal absorptive cells and, therefore, the term "incomplete intestinal metaplasia" has been applied (20). Specialized columnar epithelium can also contain Paneth cells and enterochromaffin cells (5,12,17) and can occasionally overlie simple mucus-type glands, or even gastric body-like glands. The principal differential diagnostic considerations are gastric heterotopia and hiatal hernia. Endoscopists encounter patches of ectopic gastric tissue, appearing as orange-red islands of abnormal mucosa surrounded by normal pink to white squamous esophageal mucosa in approximately 4% to 10% of patients who undergo upper endoscopy (21-24). These foci of gastric tissue occur in the cervical esophagus, are often referred to as inlet patches, and are thought to represent embryonic rests. Histologically, they are similar to Barrett's epithelium and they are distinguished from Barrett's esophagus clinically by their cervical location, their separation from the stomach by intact esophageal squamous mucosa, and lack of association with reflux. Problems with the Histological Diagnosis of Barrett's Esophagus Intestinal metaplasia of the stomach can be histologically indistinguishable from specialized columnar epithelium of Barrett's esophagus (25). So-called "short-segment" Barrett's esophagus (intestinal metaplasia in the distal esophagus measuring <3 cm) can be difficult to distinguished from intestinal metaplasia of the cardia at the esophagogastric junction (6). The ACG suggests that this distinction be made at endoscopy because mere intestinal metaplasia at an otherwise normal gastroesophageal junction is not associated with an endoscopic abnormality of the esophagus. Although specialized columnar epithelium (intestinal metaplasia) at the esophagogastric junction may not technically be Barrett's esophagus (because it is not in the anatomic esophagus), it is possible that this epithelial type at that location increases the risk of developing adenocarcinoma of the gastric cardia or gastroesophageal junction (6,26). However, this requires more study. There are several lines of reasoning that potentially associate specialized columnar epithelium (intestinal metaplasia) at the gastroesophageal junction with carcinoma of the gastroesophageal junction, lower esophagus and gastric cardia including: a) the prevalence of specialized columnar epithelium at the gastroesophageal junction is proportional to the length of specialized columnar epithelium in Barrett's esophagus (27,28); b) carcinomas of the cardia and Barrett's associated carcinoma share common morphology, epidemiology, risk factors, frequency of gastroesophageal reflux and prognosis (see below), c) carcinoma of the cardia and Barrett's-associated carcinoma have shown a similar increased incidence (6,7,28-32). A proposed classification and clinical approach is outlined in Table 1.
CARCINOMA AND CANCER SURVEILLANCE IN BARRETT'S ESOPHAGUS Cancer Risk and Surveillance Patients with Barrett's esophagus are at increased risk for esophageal adenocarcinoma (5-7,33). The exact magnitude of the risk is unknown and recent studies suggest that the risk could be overestimated because of publication bias (34). Most prevalence rates for carcinoma complicating Barrett's esophagus range from 10%-15% (10,11,35). Cancer prevalence represents patients in a population already with carcinoma. The true problem in assessing the need for cancer surveillance involves patients with Barrett's esophagus who do not yet have carcinoma. What is their risk of developing carcinoma (incidence) and does that risk justify the cost of a cancer surveillance program? Three retrospective studies address this issue (10,11,35). Of 105 patients followed by Spechler et al (10), two developed carcinoma, one after six years and the other after eight years. The mean length of follow-up in this study was only 3.3 years. Cameron et al (11) found that two of their 104 patients developed carcinoma during the follow-up period (one at 11 years and one at 20 years). The mean follow-up here was 8.5 years. Achkar and Carey reported the occurrence of carcinoma in one of 62 patients who were followed on average 2.6 years (35). This cancer developed five years after the discovery of Barrett's epithelium. Outwardly, these incidence rates seem low, but they are estimated to be 30-40 times higher than the rate of esophageal carcinoma found in the general population. In prospective studies, Robertson et al reported an incidence of 1786 cases of Barrett's associated carcinoma per 100,000 population per year (36) and Hameeteman et al reported 1920 cases per 100,000 per year (37), rates that are 350 times and 125 times the rate of esophageal carcinoma in the general population respectively. To put these figures into perspective, these rates are approximately triple the incidence of lung cancer in males over 65 years of age (38). Though most agree that Barrett's esophagus places patients at risk for esophageal adenocarcinoma, no consensus has emerged as to whether the increased risk justifies the cost of a cancer surveillance program. Van der Veen et al concluded that systematic endoscopic surveillance was not indicated in patients with Barrett's epithelium, citing that there was no difference in survival between patients with Barrett's esophagus and a control population (39). In a subsequent study of the same cohort with eight additional years of follow-up, eight additional patients had developed esophageal adenocarcinoma (40). This represented 1 carcinoma per 180 patient years or a forty-fold increased risk. Despite this fact and the 50% greater death rate in the Barrett's esophagus group vs. controls, the authors concluded that too few patients actually died of Barrett's esophagus-associated carcinoma (only two deaths), and therefore, formal surveillance would have been of little benefit. Though controversial, we think that in the absence of a definitive study to the contrary, it is prudent to place all patients with Barrett's esophagus into a cancer surveillance program. The American College of Gastroenterology recommends surveillance for Barrett's esophagus (7). The surveillance goal is either prevention of carcinoma or the detection of carcinoma in an early and potentially curable phase. The marker used as the end point for cancer surveillance programs is identification of epithelial dysplasia in a biopsy specimen. Dysplasia, the presumed precancerous epithelial lesion, has been regularly recognized in esophageal specimens adjacent to and distant from Barrett's-associated adenocarcinomas (5,33). Circumstantial evidence suggests that dysplasia may not only be a marker for carcinoma, but may itself be the early carcinomatous change that can progress to invasive carcinoma (33). All grades of dysplasia appear to have the potential to give rise to invasive carcinoma and epithelial changes need not go through a recognizable carcinoma in situ phase before being associated with invasion (6,41). Although the circumstantial evidence for the dysplasia-carcinoma sequence is compelling, the progression of dysplasia to carcinoma is still largely unproven and the time course unknown. The potential benefits (largely unknown) of removing a dysplastic esophagus must be weighed against the relatively high mortality associated with esophagectomy (estimated to be 5-15%) and the dismal outcome in patients who present with invasive adenocarcinoma of the esophagus (34% survival at two years and 14.5% survival at five years) (42). Dysplasia in Barrett's Esophagus: Histopathologic Diagnosis, Significance, and Proposed Patient Management Dysplasia is recognized histologically and criteria for identifying these changes in ulcerative colitis (33,41) are applied in studying Barrett's epithelium. A reaffirmation of criteria with numerous illustrations has recently been published (43). The term dysplasia in Barrett's epithelium should only be used to describe a change that is unequivocally neoplastic. As with inflammatory bowel disease, dysplasia in Barrett's epithelium can be closely mimicked by reparative epithelial changes associated with active inflammation and ulcer. Dysplasia and repair are associated with nuclear enlargement and hyperchromasia, increased mitotic figures, and decreased intracellular mucin. However, some histologic features favor repair over dysplasia. The nuclei of repair are often round to oval with smooth external contours, are evenly spaced, do not overlap, contain granular chromatin with single or multiple chromocenters/nucleoli, and are remarkably similar to one another in both size and appearance. In contrast to dysplasia, the nuclear to cytoplasmic size ratio of reparative cells is often decreased, especially in cells adjacent to ulcerated areas. Nearby active inflammation helps to confirm a diagnosis of repair. Features that favor dysplasia over repair are: a) variable nuclear hyperchromasia associated with pleomorphism, b) irregular nuclear contours, c) marked nuclear stratification with crowding and overlap, d) loss of nuclear polarity, e) nuclear and architectural abnormalities that are visible at low magnification (44), and involvement of the surface epithelium. Some Barrett's-associated dysplasias can look similar to colonic or small intestinal adenomas (43-45), however, in my experience the majority do not. Dysplasia has been reported to occur in all three types of Barrett's epithelia. However, it is certainly more frequently seen in areas of specialized columnar epithelium (44,46) and it is unlikely that cancer ever occurs except in patients with specialized columnar epithelium (6,7,28). It is frequently difficult or impossible to ascertain epithelial types in mucosa totally replaced by dysplasia or carcinoma (44). Riddell has proposed, and we currently use, a modification of the Inflammatory Bowel Disease-Dysplasia Morphology Study Group Classification in Barrett's epithelium (12,41,47). Under this three-tiered system, biopsy findings are classified as negative for dysplasia, positive for dysplasia, or indefinite for dysplasia. Biopsy specimens interpreted as positive for dysplasia are further subdivided as low-grade or high-grade dysplasia based upon the degree of cytologic change present. In low-grade epithelial dysplasia, the abnormal nuclei are limited to the basal half of the cells. In high-grade dysplasia, more severe cytologic and architectural alterations are present. Hyperchromasia and pleomorphism are more marked. Nuclear crowding and stratification are often present. Nuclei may be found in the luminal half of the cells. No distinction is made between high-grade dysplasia and carcinoma in situ in this system. If equivocal changes are present, they are usually due to epithelial repair associated with active inflammation. In this setting the specimen is best classified as indefinite for dysplasia. We think that high-grade dysplasia can be reliably detected by an experienced surgical pathologist, but because of the marked interobserver variation reported in diagnosing low grade dysplasia and indefinite for dysplasia (43,48,49), and similar outcome (6,50) we follow the guidelines of Reid et al (48) and have adopted similar management for either diagnosis. Our current management plan (12) based upon this histologic classification which is a modification of other proposed plans, is outlined in Table 2. The histologic grade of dysplasia appears to have clinical significance (6,50). Infiltrating carcinoma is a rare event in patients with Barrett's esophagus initially negative for dysplasia (0-3%). In contrast, 60% of patients with initial HGD have developed or already have infiltrating carcinoma. The results are intermediate for LGD and indefinite for dysplasia (14-18% for each). During surveillance endoscopy, four quadrant biopsy specimens at 2-cm increments are obtained throughout the entire extent of the Barrett's epithelium (6,7,51,52). Patients negative for dysplasia can safely continue regular surveillance (q 1-2 years). Some advocate that the surveillance interval can be increased to 3 or even 5 years in this group (16). The ACG suggests that after 2 negative surveillance endoscopies, that the interval can be increased to 3 years (7). Investigators recommend shorter term follow-up for "indefinite" and "low-grade" dysplasia. The ACG suggests 1 year. Management of high-grade dysplasia remains controversial. Some recommend continued surveillance (6,7,) whereas the majority recommend esophagectomy for the surgically fit candidate. Since the operative mortality and morbidity of esophagectomy is high, we think it prudent to confirm a diagnosis of high-grade dysplasia before moving on to esophagectomy. Immediate re-endoscopy with multiple biopsies (12,52) should be performed. If high-grade dysplasia is again encountered, this is considered adequate confirmation. This re-biopsy approach has the added advantage that intramucosal or invasive carcinoma may be detected with careful endoscopic re-examination and extensive re-biopsy, thus making the decision for esophagectomy easier. If after an original diagnosis of high grade dysplasia the follow-up endoscopy with biopsy is negative, then the original specimens should be re-reviewed and confirmed ideally with the aid of another experienced pathologist. If high grade dysplasia is again confirmed in the original specimen, we recommend esophagectomy. Dysplasia can be focal (12,52). Since dysplasia is considered neoplastic, it is unlikely that it ever resolves spontaneously. Therefore, gastroenterologists and surgeons must never be lulled into a false sense of security by negative follow-up examinations once true dysplasia has been identified, as follow-up negatives are likely the result of sampling error. TABLE 2 DYSPLASIA IN BARRETT'S EPITHELIUM: MANAGEMENT PLAN BASED UPON
*Modified from other proposed management plans,
References 5, 12, 41, 48, and 51 Investigators at the University of Washington favor intense endoscopic surveillance for high-grade dysplasia and recommend esophagectomy only when intramucosal adenocarcinoma has been detected (53). The operative mortality for esophagectomy in their series was relatively high. Although the results of their surveillance are quite acceptable, the biopsy protocol is so demanding and expensive that many believe that it can not be applied outside of a research setting. Dysplasia is relatively rare in patients with Barrett's esophagus but data suggest that when biopsy specimens are positive for high-grade dysplasia, there is considerable risk that infiltrating carcinoma is already present. We reported our experience with esophagectomy for high grade dysplasia without endoscopic abnormality. We discovered a 40% prevalence of intramucosal adenocarcinoma in the resection specimens. This fact along with our relatively low mortality rate for esophagectomy allow us to recommend esophagectomy for high grade dysplasia in patients physically sound enough to survive such an operation (47). Others have made similar conclusions (16,54). While it is tempting to conclude that patients with early carcinoma detected by surveillance endoscopy have benefited from early resection, initial enthusiasm at these apparent successes must be tempered by the realization that in at least one series the operative-related death rate was 25% (53). In addition, one must critically consider the patients who underwent surgery for high-grade dysplasia in whom only high-grade dysplasia was identified in the resection specimens. There is currently no conclusive evidence that they would have ever developed invasive carcinoma and if they did, the time course from dysplasia to carcinoma is unknown. Prelimnary data suggest that there is a more favorable survival in patients participating in surveillance endoscopy programs than in those patients who are not (6,7). Other options for treatment of dysplasia and early cancer in Barrett's esophagus often used in high surgical risk patients include photodynamic therapy, endoscopic ablation, and endoscopic mucosal resection (7,16,55). Management recommendations for indefinite or low grade dysplasia must be considered preliminary as there are no long-term follow-up studies available for a guide. We currently repeat endoscopy at three to six months. If two consecutive negative follow-up studies occur, we return to yearly endoscopic surveillance. If low-grade dysplasia or indefinite changes persist, then we continue three to six month surveillance until dysplasia progresses. Restoration of squamous mucosa after laser (or other) ablation of Barrett's epithelium in an achlorhydic environment has been described (16,56-58). This type of treatment for Barrett's esophagus could obviate the need for surveillance by eliminating the cancer risk. However, long term follow up studies are required to detect any effect on the incidence of carcinoma. Furthermore, lifelong therapy with proton pump inhibitors such as omeprazole may be required to prevent regrowth of Barrett's epithelium. The long-term side-effects of this drug in humans (e.g., development of gastric carcinoids) are unknown but appears to be minimal. Dysplasia in Barrett's Esophagus: The Role of Other Pathological Techniques Mucin histochemistry has been extensively investigated in Barrett's esophagus and dysplasia (18,20,33,59,60). Some retrospective analyses have shown an association between adenocarcinoma and the presence of sulfated acid mucins in the non-goblet cells of the specialized columnar epithelium (18). However, others have concluded that the presence of sulfated mucins in these cells is so common that it is of no predictive value as a marker for dysplasia or carcinoma (20,33,60). Similarly, immunocytochemical detection of carcinoembryonic antigen seemed to have little value in "predicting" malignant change. Heightened cancer risk has also been described with loss of o-acetylated mucin, aberrant expression of blood group antigens, and abnormalities of sucrase - isomaltose, but these associations require more study (33,61-65). Reid et al have reported their experience with deoxyribonucleic acid (DNA) analysis by flow cytometry in patients with Barrett's esophagus (66-68). In these studies, carcinoma and dysplasia in biopsy specimens were highly correlated DNA cell cycle abnormalities. Furthermore, there appeared to be progression of DNA abnormalities with increasing epithelial dysplasia. Investigators from this same institution have also demonstrated a strong association between multiple different DNA aneuploid cell populations and adenocarcinoma in Barrett's esophagus. Others, however, (69) have demonstrated discordance between DNA aneuploidy, dysplasia, and carcinoma. It is possible that flow cytometry could be a useful adjunct to standard histologic assessment in cancer surveillance of patients with Barrett's esophagus, but more study is needed. Since some examples of Barrett's associated adenocarcinoma and dysplasia lack DNA abnormalities by flow cytometry (67,68) it is clear that this technique could not be used alone in a cancer surveillance program. The role of DNA analysis could be in the identification of a subgroup of Barrett's patients requiring less frequent surveillance (68). Few, if any, patients with histology negative for dysplasia and normal DNA content have progressed to adenocarcinoma . In these patients, one could argue that surveillance intervals could be expanded to up to 5 years. At the moment, DNA content analysis must be considered as a research tool. Chromosomal imbalances by comparative genomic hybridization (70) and abnormalities of various genes have been described in Barrett's associated adenocarcinoma including p53, APC, DCC, and Rb (71-75). p53 is one of the more commonly studied gene loci because abnormalities of p53 gene usually produce an altered protein that can be studied using immunocytochemistry (75). Abnormal p53 protein has been found in few or no specimens classified as negative or indefinite/low grade dysplasia. In contrast, abnormal p53 expression has been identified in approximately two thirds of the high grade dysplasias and carcinomas examined. This suggests that the p53 mutation is a relatively late event. Although aberrant p53 expression may be an objective marker for neoplastic progression, it cannot be used alone in a surveillance program and the current clinical utility is unknown. Similarly, abnormal expression of C-erbB2, H-ras, C-myc, TGF , EGF, EGFr, have been reported, however, their role in clinical management if any, is yet to be determined (33). Brush cytology can also be useful in diagnosis and management of patients with Barrett's epithelium by recognizing specialized columnar epithelium or carcinoma (76,77). Since brush cytology is done via the endoscope, biopsy is performed as well and cytology has played a complimentary role. Recently, non-endoscopically directed balloon cytology for cancer surveillance in Barrett's esophagus has been described (77). The role of cytology in diagnosis and surveillance and its relative merits compared to endoscopic biopsy are yet to be determined (33). The ACG states that dysplasia is the best current indication of the risk of cancer in Barrett's esophagus. The ACG also concludes that a marker other than dysplasia in identifying a high risk group on which to perform surveillance has not yet been established (6). CLINICAL HISTORY FOR CASE 2 67 year-old woman with Barrett's esophagus. R/O dysplasia. DESCRIPTION OF SLIDEThe number of mitoses figures are more than is usually encountered in Barrett's esophagus even those examples of Barrett's esophagus with ulceration, active inflammation and marked regeneration. Many of the mitoses figures are arrested in metaphase, characterized by the "ring" morphology. These are characteristic changes associated with colchicine (78). Upon questioning the gastroenterologist, this patient was receiving colchicine as therapy for primary biliary cirrhosis. 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Reid BJ, Levine DS, Longton G, Blount PL, Rabinovitch PS. Predictors of progression to cancer in Barrett's esophagus: Baseline histology and flow cytometry identify low- and high-risk patient subsets. Am J Gastroentrol 95:1669-1676, 2000. 69. Fennerty MB, Sampliner RE, Way D, Riddell R, Steinbronn K, Garewal HS. Discordance between flow cytometric abnormalities and dysplasia in Barrett's esophagus. Gastroenterology 97:815-820, 1989. 70. Walch AK, Zitzelsberger HF, Bruch J, Keller G, Angermeir D, Aubele MM, Mueller J, Stein H, Braselmann H, Siewert JR, Höfler H, Werner M. Chromosomal imbalances in Barrett's adenocarcinoma and the metaplasia-dysplasia-carcinoma sequence. Am J Pathol 156:555-566, 2000. 71. Blount PL, Ramel S, Raskind WH, et al.17p allelic deletions and p53 protein over expression in Barrett's adenocarcinoma. Cancer Research 51:5482-5486, 1991. 72. Boynton RF, Blount PL, Yin J, et al. Loss of heterozygosity involving the APC and MCC genetic loci occurs in the majority of human esophageal cancers. Proceedings of National Academy Sci USA. 89:3385-3388, 1992. 73. Boynton RF, Huang Y, Blount PL, et al. Frequent loss of heterozygosity at the retinoblastoma locus in human esophageal cancers. Cancer Research 51:5766-5769, 1991. 74. Huang Y, Boynton RF, Blount PL, et al. Loss of heterozygosity involves multiple tumor suppressor genes in human esophageal cancers. Cancer Research 52:6525-6530, 1992. 75. Rice TW, Goldblum JR, Falk GW, Tubbs RR, Kirby TJ, Casey G. P53 immunoreactivity in Barrett's metaplasia, dysplasia, and carcinoma. J. Thoracic Cardiovasc Surg 108:1132-1137,1994. 76. Geisinger KR, Teot LA, Richter JE. A comparative cytopathologic, histologic study of atypia, dysplasia, and adenocarcinoma in Barrett's esophagus. Cancer 69:8-16, 1992. 77. Falk GW, Chittajallo R, Goldblum JR, Biscotti CV, Geisinger KR, Petras R, Birgisson S, Rice TW, Richter JF. Surveillance of Barrett's esophagus for dysplasia and carcinoma with balloon cytology. Gastroenterology 112:1787-1797,1997. 78. Iacobuzio-Donahue CA, Lee EL, Abraham SC, et al. Colchicine Toxicity: Distinct morphologic findings in gastrointestinal biopsies. Amer J Surg Path 25:1067-1073, 2001. 79.Torbenson M, Montgomery EA, Iacobuzio-Donahue C, et al. Colchicine effect in a colonic hyperplastic polyp: A lesion mimicking serrated adenoma. Arch Pathol Lab Med 126:615-617, 2002. DISCUSSION FOR CASE 3SMALL BOWEL BIOPSY: INTERPRETATION AND SPECIMEN HANDLING Robert E. Petras, M.D. AmeriPath, Inc. Oakwood Village, Ohio Specimen Procurement and Processing Small-bowel mucosal biopsy examination remains one of the most important steps in the evaluation of patients with malabsorption (1). A standard gastroscope is used to obtain duodenal biopsy specimens as distally in the small bowel as possible (2,3). The specimens are adequate to evaluate mucosal disease, and because the biopsy is performed under direct vision, many more specimens can safely be obtained. The most critical part of small bowel biopsy and interpretation is the proper orientation of the specimen. Ideally, specimens are immediately mounted, mucosa side up, on a solid substance such as filter paper, and then placed into fixative. After processing, the histotechnologist embeds the tissue perpendicular to the mounting material. Proper specimen evaluation requires examination of optimally oriented intestinal villi obtained from the central region of the biopsy specimen. Although serial sectioning is advocated by some (4), step sectioning (obtaining ribbons of sections from at least three levels) is a reasonable alternative (5). Our standard small-bowel biopsy procedure consists of obtaining 4-6 endoscopic biopsy specimens. The samples are fixed and routinely processed. Three to four step-sectioned slides are obtained; three are stained with hematoxylin and eosin, and one with Alcian blue/periodic acid-Schiff (PAS) combination stain. The Alcian blue/PAS stain is a useful screen for Whipple's disease, foveolar metaplasia in chronic duodenitis, and Mycobacterium avium-intracellulare infection. A trichrome stain can be useful for confirming collagen deposits in ischemia or collagenous sprue. In addition, the iron hematoxylin counterstain used in the trichrome technique facilitates identification of Giardia lamblia (5). Normal Small-Intestinal Histology The normal villus to crypt length ratio approximates 3:1 to 5:1 (6). Inflammatory cells, including plasma cells, are normally present in the lamina propria. Intraepithelial lymphocytes occur in a ratio of approximately 1 lymphocyte per 5 enterocytes (4,6). A brush border is often discernable on the enterocyte. The enterocyte nuclei should be basilar in location and evenly aligned. Brunner's glands in proximal duodenal specimens have an inconsistent effect on villus architecture (6). In some circumstances, normal-length villi may be encountered overlying Brunner's glands, but usually the villi are shorter and somewhat distorted. Similarly, villi are often short and distorted next to or overlying lymphoid aggregates. Such shortened villi should not be misinterpreted as evidence of celiac sprue. In general, we subscribe to the philosophy that identification of four normal villi in a row indicates that the villus architecture of the whole biopsy specimen is probably normal (4). This does not mean that biopsy specimens with less than four aligned normal villi should be considered inadequate for evaluation, because even one normal villus in a proximal small-bowel biopsy specimen rules out celiac sprue. Conversely, finding four normal villi in a row does not necessarily rule out focal lesions, although it almost always does (5). Patterns of Abnormal Small-Bowel Architecture The small-bowel mucosal responses to injury are limited and recognition of a response pattern can be useful in differential diagnosis (Table 1). I use the term "severe villus abnormality" to describe a flat intestinal mucosa lacking villi. Usually this change is diffuse, accompanied by intraepithelial lymphocytosis (more than 40 intrepithelial lymphocytes per 100 enterocytes) (7), and associated with crypt hyperplasia, evidenced by numerous mitoses. The terms "severe villus abnormality" or "flat intestinal mucosa" are preferred to "villus atrophy" because the mucosa in the forms associated with crypt hyperplasia is actually of normal thickness. I use the term "variable villus abnormality" to describe specimens in which the villi are either only focally flat or are less than flat (mild or moderate villus shortening) (4). Many specimens in this category will also show increased numbers of intraepithelial lymphocytes (more than 40 per 100 enterocytes) (7). These changes may be associated with features that suggest a specific diagnosis (e.g., numerous eosinophils, granulomas, parasites) or may be non-specific. Entities Associated with a Diffuse Severe Villus Abnormality and Crypt Hyperplasia Celiac Sprue Celiac sprue (gluten induced enteropathy, gluten sensitive enteropathy, non-tropical sprue) is a major cause of malabsorption (8). Almost all adult patients in North America with a severe villus abnormality and crypt hyperplasia have celiac sprue (4). The pathogenesis of celiac sprue involves immunologic injury to the enterocyte associated with gluten ingestion, which is a protein found in cereal grains such as wheat, rye, and barley. Celiac sprue is associated with the major histocompatibility alleles DQA1*0501 and DQB1*0201. This HLA-DQ2 combination is found in 98% of patients (8). Patients with celiac sprue usually show a quick and dramatic clinical and histologic improvement following removal of gluten from the diet and quickly relapse following its reintroduction (9). The flat mucosa of CS is associated with increased lymphocytes and plasma cells in the lamina propria and increased intraepithelial lymphocytes. The enterocyte nuclei lose their basilar alignment and become stratified. Neutrophils may be present but are usually not prominent. The histologic abnormality is most severe in the proximal intestinal mucosa and gradually lessens distally. With gluten withdrawal, the abnormalities recede from distal to cephalad in the small intestinal mucosa. Thus, proximal small bowel biopsy specimens may remain abnormal for quite some time, even in patients showing marked clinical improvement (10). Remember, a pathologist does not make the diagnosis of CS. All that can be said is that the specimen contained a severe villus abnormality that is consistent with CS. Definitive diagnosis depends upon demonstration of a suitable clinical presentation, compatible serologic tests (11,12) (e.g., IgA endomesial antibodies, antibodies to TTG, IgG and IgA - antigliadin antibodies) and small bowel histology (13), clinical and, ideally, histologic response to a gluten-free diet, and relapse following gluten challenge. Mucosal lesions can be classified into five types (8,14). (The Marsh classification which is more popular in Europe than North America). Type 0, the preinfiltrative lesion, is essentially normal. Type 1, the infiltrative lesion, is characterized by intraepithelial lymphocytosis (at least 40 per 100 enterocytes). The type 2 lesion, which is also known as the hyperplastic lesion, shows a variable villous abnormality with epithelial lymphocytosis. The type 3 destructive lesion represents the classic CS lesion described earlier. The hypoplastic type 4 lesion is considered an atrophic end-stage lesion that is seen in a minority of patients unresponsive to gluten withdrawal; it includes the lesion of collagenous sprue. The histologic differential diagnosis includes all entities that may cause at least a focal severe villus abnormality (5): common variable immune deficiency, protein allergies other than gluten, some cases of infectious gastroenteritis (15), rare cases of tropical sprue (16), stasis (17), the Zollinger-Ellison syndrome (4,18), Crohn's disease, and nonspecific duodenitis. Clinicopathologic correlation is essential for proper diagnosis. All biopsy specimens should be carefully evaluated for plasma cells, since their absence in common variable immunodeficiency syndrome is easy to overlook. Numerous neutrophils, cryptitis, and crypt abscess formation are usually not part of CS, and entities such as infectious gastroenteritis, Zollinger-Ellison syndrome, Crohn's disease, nonspecific duodenitis, and stasis syndromes, therefore, should be considered. Refractory Sprue If there is no clinical response to a gluten-free diet, before changing your diagnosis, remember the most common cause of unresponsiveness is that the diet is not really gluten free (18). Furthermore, wheat is commonly used as an extender in processed foods and can occasionally be present in seemingly non-cereal-grain products, such as ice-cream, cocoa mixes, instant coffee, and salad dressings. Medications, vitamins and mineral supplements may also contain gluten. If dietary indiscretions are ruled out, patients may have refractory or unclassified sprue (4) which may respond to the administration of corticosteroids. Many demonstrate collagenous sprue in their small bowel biopsy specimen (19) (see below). A minority have some unusual histologic features (e.g., thin mucosa or subcryptal inflammatory infiltrate). Refractory sprue can also be associated with cavitation of mesenteric lymph nodes and hyposplenism (20). Lymphoma must be considered in non-responsive patients (10) and should prompt re-review of biopsy specimens or re‑biopsy. Furthermore, there is increasing evidence that some refractory sprue cases may actually be low-grade intraepithelial T-cell lymphomas that cannot be recognized without molecular techniques (21-24). Other Protein Allergies Allergic reactions to chicken, soy protein, milk, eggs, and tuna fish have been reported to show a flat mucosa similar to celiac sprue (5). Definitive diagnosis depends upon identifying the offending protein, showing a response to withdrawal from the diet and demonstration of recrudescence of symptoms and pathology with its reintroduction. Lymphocytic enterocolitis Celiac sprue and other "sprue-like" lesions may be associated with a colonic epithelial lymphocytosis similar to what has been described in lymphocytic colitis (25-27). It is possible that in some patients with true celiac sprue (responsive to gluten withdrawal), occult dietary gluten actually reaches the colon and induces the histologic changes of "lymphocytic colitis". However, approximately 1/2 of the patients with "sprue-like" small bowel lesions and "lymphocytic colitis" have not responded to gluten withdrawal. The term "lymphocytic enterocolitis" has been coined to describe this refractory sprue-like condition associated with colonic epithelial lymphocytosis. Entities Associated with a Variable Villus Abnormality and Crypt Hypoplasia This type of biopsy specimen has been described in malnourished patients with marasmus and kwashiorkor, in patients with megaloblastic anemia and as a sequelae of radiation and chemotherapy. Microvillus inclusion disease also typically causes a variable villus abnormality with crypt hypoplasia. This is an inherited autosomal recessive condition that causes intractable diarrhea in infants. Diarrhea persists despite total parental nutrition and patients rarely survive beyond the age of 2 years. The disease should be recognized so that genetic counselling can be offered. Small bowel biopsy specimens usually show a severe villus abnormality with shortened and hypoplastic crypts. Intraepithelial lymphocytes are usually not increased. Transmission electron microscopy establishes the diagnosis by identifying abnormal microvillus structures at the luminal border of the enterocyte and intracytoplasmic inclusions lined by microvilli in the same cells (28,29). Microvillus inclusion disease can sometimes be suspected based on light microscopic findings because the abnormal microvillus inclusions will be highlighted as PAS positive inclusions. The inclusions can also be recognized with carcinoembryonic antigen immunostaining. Prominent surface enterocyte CD10 immunoreactivity has also been described in microvillous inclusion disease (30). Entities Associated with a Non-Specific Variable Villus Abnormality Many diseases are associated with non-specific variable villus abnormalities that are usually not flat (see Table 1). Although some (10%) mucosal biopsy specimens showing this change will be from patients with partially treated or clinically latent celiac sprue, other conditions enter into the differential diagnosis including dermatitis herpetiformis, tropical sprue, infectious gastroenteritis, stasis syndromes, Zollinger‑Ellison syndrome, systemic mastocytosis, duodenitis with peptic ulcer disease, autoimmune enteropathy, autoimmune disorders and NSAIDs. Clinical correlation is required (5,31). Entities Associated with Variable Villus Abnormalities Illustrating Specific Diagnostic Changes The specific diagnostic features seen in this group of conditions are outlined in Table 2. TABLE 1 PATTERNS OF ABNORMAL SMALL BOWEL ARCHITECTURE A. Celiac sprue II. Variable villus abnormality and crypt hypoplasia:
III. Nonspecific variable villus abnormality, usually not flat:
IV. Variable villus abnormality with specific diagnostic changes:
TABLE 2 ENTITIES ASSOCIATED WITH VARIABLE VILLUS ABNORMALITIES ILLUSTRATING SPECIFIC DIAGNOSTIC CHANGES
CLINICAL HISTORY FOR CASE 3 42 year-old woman, small bowel biopsy. DESCRIPTION OF SLIDESections show a moderate villous abnormality with increased intraepithelial lymphocytes. The lengthy differential diagnosis includes all conditions that can cause a variable or diffuse severe villous abnormality. Further history revealed that the patient was positive for IgA-antiendomesial antibody and circulating antibodies against tissue transglutaminase. The patient had been on a gluten-free diet at the time of the biopsy. DIAGNOSIS FOR CASE 3 Partially treated celiac sprue. REFERENCES1. Trier JS. Diagnostic value of per oral biopsy of the proximal small intestine. New England Journal of Medicine 285:1470-1473, 1971. 2. Achkar E, Carey WD, Petras RE, Sivak MV, Revta R. Comparison of suction capsule and eoscopic biopsy of small bowel mucosa. Gastrointestinal Endoscopy 32:278-281, 1986. 3. Dandalides WM, Carey WD, Petras RE, Achkar E. Endoscopic small bowel mucosal biopsy: A controlled trial evaluating forceps size and biopsy location in the diagnosis of normal and abnormal architecture. Gastrointestinal Endoscopy 35:197-200, 1989. 4. Dobbins WO III. Small bowel biopsy in malabsorption states in Norris HT editor. Pathology of the Colon, Small Intestine, and Anus, New York, Churchill Livingstone 1991 pp 137-188. 5. Petras RE. Non-neoplastic intestinal diseases. In Mills SE editor. Sternberg's Diagnostic Surgical Pathology 4th edition. Lippincott, Williams, and Wilkins, New York, 2004 pp 1475-1485. 6. Segal GH, Petras RE. The small intestine. In Sternberg SS editor. Histology for Pathologists 2nd edition. Lippincott-Raven, Philadelphia, 1997, pp 495-518. 7. Oberhuber NS, Granditsch G, Vogelsang H. The histopathology of celiac disease: time for a standardized report scheme for pathologists. Eur J Gastroenterol Hepatol 11:1185-1194, 1999. 8. Ciclitira PJ, DeMaertelaer V, LeMoine O, Deviere J. AGA technical review on celiac sprue. Gastroenterology 120:1526-1540, 2001. 9. Walker-Smith JA, Guardlini S, Schmitz J, Shmerling PH, Visakorpi JK. Revised criteria for diagnosis of Coeliac Disease. Archives Diseases of Children 65:909-911, 1990. 10. Wahab PJ, Meijer JWR, Mulder CJJ. Histologic follow-up of people with celiac disease on a gluten-free diet: Slow and Incomplete Recovery. Am J Clin Pathol 118:459-463, 2002. 11. Vogelsang H, Genser O, Wyatt J, et al. Screening for celiac disease: a prospective study on the value of noninvasive tests. Amer J Gastroenterol 1995;90:394-398. 12. Fasano A, Catassi C. Current approaches to diagnosis and treatment of celiac disease: an evolving spectrum. Gastroenterology 120:636-651, 2001. 13. Valdimarsson T, Fransen L, Grodzinsky E, Skogh T, Strom M. Is small biopsy necessary in adults with suspected celiac disease and IgA anti-endomesial antibodies? 100% positive predictive value for celiac disease in adults. Dig Dis Sc 1996;41:83-87. 14. Marsh MN. Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiological approach to the spectrum of gluten sensitivity ("celiac sprue"). Gastroenterology 102:330-354, 1992. 15 Barnes GL, Townley RRW. Duodenal mucosal damage in 31 infants with gastroenteritis. Arch Dis Child 48:343-349, 1973. 16. Swanson VL, Thomasson RW. Pathology of the jejunal mucosa in tropical sprue. Am J Pathol 46:511-551, 1965. 17. Ament ME, Shimoda SS, Saunders DR, Rubin CE. Pathogenesis for steatorrhea in three cases of small intestinal stasis syndrome. Gastroenterology 63:728-747, 1972. 18. Perera DR, Weinstein WM, Rubin CE. Small intestinal biopsy. Human Pathology 6:157-217, 1975. 19. Robert ME, Ament ME, Weinstein WM. The histologic spectrum and clinical outcome of refractory and unclassified sprue. Am J Surg Path 24:676-687, 2000. 20. Maturcharski C, Colin R, Hemet J, et al. Cavitation of mesenteric lymph nodes, splenic atrophy, and a flat small intestinal mucosa. Gastroenterology 87:606-614, 1984. 21. Carbonnel F, Grollet-Bioul L, Brouet JC, Teilhac MF, Cosnes J, Angonin R, Deschaseaux M, Chatelet FP, Gendre JP, Sigaux F. Are complicated forms of celiac disease cryptic T-cell lymphomas? Blood 92:3879, 1998. 22. Cellier C, Patey N, Mauvieux L, Jabri B, Delabesse E, Cervoni JP, Burtin ML, Guy-Grand D, Bouhnik Y, Modigliani R, Barbier JP, Macintyre E, Brousse N, Cerf-Bensussan N. Abnormal intestinal intraepithelial lymphocytes in refractory sprue. Gastroenterology 114:471, 1998. 23. Cellier C, Delabesse E, Helmer C, Patey N, Matuchansky C, Jabri B, Macintyre E, Cerf-Bensussan N, Brousse N. Refractory sprue, coeliac disease, and enteropathy-associated T-cell lymphoma. French Coeliac Disease Study Group. Lancet 356:178-179, 2000. 24. Daum S, Weiss D, Hummel M, Ullrich R, Heise W, Stein H, Riecken EO, Foss HD; Intestinal Lymphoma Study Group. Frequency of clonal intraepithelial T lymphocyte proliferations in enteropathy-type intestinal T cell lymphoma, coeliac disease, and refractory sprue. Gut 49:804-812, 2001. 25. DuBois RN, Lazenby AJ, Yardley JH, Hendrix TR, Bayless TM, Giardiello FM. Lymphocytic enterocolitis in patients with "refractory sprue". JAMA 262:935-937, 1989. 26. Wolber R, Owen D, Freeman H. Colonic lymphocytosis in patients with celiac sprue. Human Pathology 21:1092-1096, 1990. 27. Fine KD, Lee EL, Meyer RL. Colonic histopathology in untreated celiac sprue or refractory sprue: Is it lymphocytic colitis or colonic lymphocytosis? Hum Pathol 29:1433-1440, 1998. 28. Bell SW, Kerner JA Jr., Sibley RK. Microvillus inclusion disease. The importance of electron microscopy for diagnosis. American Journal of Surgical Pathology 15:1157-1164, 1991. 29. Cutz E, Rhoades JM, Drumm B, Sherman PN, Durie PR, Forstner GG. Microvillus inclusion disease; an inherited defect of brused border assembly and differentiation. New England Journal of Medicine 320:646-651, 1989. 30. Groisman GM, Amar M, Livne E. CD10: a valuable tool for the light microscopic diagnosis of microvillous inclusion disease (familial microvillous atrophy). Am J Surg Pathol 26:902-907, 2002. 31. Kakar S, Nehra V, Murray JA, Dayharsh GA, Burgart LJ. Significance of intraepithelial lymphocytosis in small bowel biopsy samples with normal mucosal architecture. Am J Gastroenterol 98:2027-2033, 2003. DISCUSSION FOR CASE 4 GASTROINTESTINAL POLYPS AND POLYPOSIS SYNDROMES Robert E. Petras, M.D. Non-Adenomatous Epithelial Polyps of the Small Bowel Gastric Heterotopia and Hyperplastic Polyp of Gastric Type Gastric type mucosa occurs quite commonly in the proximal small bowel and can result from metaplasia associated with Helicobacter pylori-induced peptic duodenitis (1, 2) or may also represent a true heterotopia (3, 4). Histologic distinction between gastric metaplasia and heterotopia, though arbitrary, is usually made by the recognition of specialized gastric glands in the latter. Gastric heterotopia is usually asymptomatic but it can form a mural nodule or mucosal polyp that will be seen on endoscopy (3, 4). Once gastric mucosa has set up anywhere in the gastrointestinal tract, it may, under inflammatory influences, develop into a hyperplastic polyp of gastric type with edematous expansion of the lamina propria and foveolar epithelial cysts (5). Ectopic gastric mucosa can be found throughout the gastrointestinal tract including the rectum (6). Pancreatic Heterotopia, Adenomyoma and Myoepithelial Hamartoma I consider pancreatic heterotopia, adenomyoma and myoepithelial hamartoma variants of the same process. Pancreatic heterotopia is characterized by the presence of pancreatic acinar, islet, and/or ductular elements, usually associated with smooth-muscle proliferation, outside the topographic boundaries of the pancreas. Adenomyoma and myoepithelial hamartoma are synonymous terms and differ from pancreatic heterotopia in that acinar elements and islet-like tissue are not present. In my experience, the distribution of acinar and islet elements in heterotopic pancreas has been quite variable, and some areas of a pancreatic heterotopia may be indistinguishable from adenomyoma. The prevalence of heterotopic pancreas in different series has varied from 0.55% to 13.7% (7, 8). The common sites are the stomach, duodenum, and jejunum, but ectopic pancreatic tissue may also be encountered in Meckel's diverticulum, the ampulla of Vater, gallbladder, umbilicus, fallopian tube, and mediastinum (9). Most examples are encountered incidentally at surgery, and the pathologist is often asked to identify these lesions on a frozen section. On rare occasions, epigastric pain, weight loss, hemorrhage, gastric outlet obstruction, and intussusception have been attributable directly to the presence of the heterotopic pancreas (7, 8). Malignancy arising in association with pancreatic heterotopia has been reported (9). Pancreatic heterotopia presents grossly as a submucosal nodule, as an intramural mass, or as a nodular lesion involving the serosa. The color is typically yellow or yellow-white; on cut section, the surface is lobulated. Size has ranged from 0.2 to 4.0 cm (8, 9). Occasionally, it will contain a central mucosal dimple, which is an important diagnostic clue radiologically, endoscopically, and grossly (9-11). Histologically, those cases of pancreatic heterotopia associated with acinar elements or islet cells pose little problem in differential diagnosis. Those composed purely of ducts and smooth muscle may be difficult to diagnose and are often confused with metastatic adenocarcinoma. However, the adenomyomatous pattern shows an orderly arrangement or lobular pattern of benign ducts set in a background of proliferation smooth muscle. In those cases showing a gross central mucosal dimple, the pattern of ducts recapitulates the major duodenal papilla. Hyperplasia of Brunner's Glands/Brunner's Gland Nodules Brunner's glands are branched tubuloalveolar glands confined predominantly to the duodenum in humans. The bulk of Brunner's glands is submucosal, but one-third of their volume can be found above the muscularis mucosae, where the glands empty into the crypts of Lieberkuhn (12). Hyperlasias of Brunner's glands exist in three forms (12-16): 1) diffuse glandular proliferation, imparting a coarse nodularity to most of the duodenum; 2) limited discrete nodules in the proximal duodenum; and 3) a solitary nodule, often referred to as "adenoma" of Brunner's glands. Most are encountered as incidental findings during investigation of the upper gastrointestinal tract. Histologically, these Brunner gland proliferations suggest a hamartoma or reactive hyperplasia in that they consist of increase numbers of normal-appearing Brunner's glands accompanied by variable proliferations of smooth muscle. Inflammatory cells are often present, and some larger lesions may ulcerate. Differentiating normal Brunner's glands from hyperplasia is difficult. If a gross nodule or polyp is present and is composed solely of Brunner's-type glands, then it is probably correct to refer to it as a hyperplasia. The distinction between adenoma and hyperplasia is arbitrary, and no substantial evidence exists to suggest that any of these proliferations are truly neoplastic (13); thus, the term "Brunner's gland nodule" is preferred. There is no convincing evidence of carcinoma having arisen either from normal Brunner's glands or Brunner's gland nodules. Non-Adenomatous Epithelial Polyps of the Colon Colonic Hyperplastic Polyps and Hyperplastic Polyposis Hyperplastic polyp is the most common benign polyp of the large intestine (17). These polyps are usually small (less than 5 mm), sessile and often about the same color as the surrounding colonic mucosa. Histologically, absorptive and goblet line crypts that are elongate and dilated. Since there are more epithelial cells per unit area than normal, the cells tend to pseudostratify, imparting a serrated or micropapillary appearance. Characteristically, the basement membrane under the surface epithelium is thickened and hyalinized. Regenerative epithelial changes are mitoses can be quite prominent at the crypt bases. This regenerative area can occasionally cause diagnostic confusion with carcinoma, especially in a variant referred to as inverted hyperplastic polyp (18, 19). In the inverted variety, the regenerative epithelium of the crypt base of the hyperplastic polyp is misplaced into or beneath the muscularis mucosae. This variant is easily recognized if one is cognizant of its existence and also notes the overall architecture and cytology of a hyperplastic polyp. The entity is distinguished from invasive adenocarcinoma by the lack of infiltration and tumor desmoplasia. The differential diagnosis between hyperplastic polyp and tubular adenoma can also be difficult, especially in a diminutive polyp that has been treated by hot biopsy (so-called "Thermal Polyp"). The features that I find useful in the differential are found in the table. TABLE HYPERPLASTIC POLYP VS. TUBULAR ADENOMA
In a "tight call", as long as an adenoma diagnosis is not going to result in a surgical resection (e.g. right colonic adenoma incompletely excised), I tend to error on the side of the adenoma since the patient will receive more frequent and careful surveillance. Mixtures of hyperplastic polyp and adenoma do exist (20, 21). Many cases illustrated as "serrated adenoma", I would consider variants of villous adenoma. Hyperplastic Polyposis Rare examples of patients with colons carpeted by hyperplastic polyps (so-called hyperplastic polyposis) have been described. Hyperplastic polyposis is probably a heterogeneous disorder with some forms associated with high microsatellite instability (MSI-H) cancers in which there is methylation with loss of expression of hMLH1 (22, 23). Therefore, hyperplastic polyposis may be a marker for the so-called "methylator phenotype". These patients may be prone to colorectal carcinoma. Some cases have shown evidence of inheritance presumably caused by a genetic predisposition to methylation. The type and order of methylated genes varies and may account for the microsatellite stable (MSS), low microsatellite instability (MSI-L) and MSI-H cancers described. When several cancers in hyperplastic polyposis families are MSI-H, the distinction from hereditary non-polyposis colon cancer syndrome can be difficult. Features that favor hyperplastic polyposis include; background serrated adenomas, presence of some MSS or MSI-L cancers in the kindred, older age at onset of cancer, limited numbers of affected family members, methylation of hMLH1 and failure to detect germline mutation of mismatch repair genes. Gastrointestinal Polyposis Syndromes Familial Adenomatous Polyposis Familial adenomatous polyposis (FAP) is inherited as an autosomal dominant trait. HJR Bussey recognized that 100 or more colonic adenomas (recognized grossly) phenotypically identified patients with FAP and distinguished them from patients with multiple adenomas in whom inheritance was not seen (24, 25). In typical FAP, hundreds to thousands of adenomas develop within the colon. The adenomas begin to appear in the second or third decades of life and are surprisingly asymptomatic considering their usually large numbers. Symptomatic patients present with signs and symptoms of increased bowel motility and the passage of blood and/or mucus, which often heralds the onset of carcinoma. Two-thirds of these so-called propositus cases present with carcinoma and nearly one-half of them will have more than one carcinoma in the colon. This high risk of invasive cancer in symptomatic patients forms the basis for polyposis registries and the extensive screening of asymptomatic kindred at risk for FAP. Screening recommendations have evolved with increased genetic information. Screening of primary relatives of affected individuals should begin at age 10 usually with the truncated protein assay (PTT) (26). In the absence of genetic testing, endoscopic screening is still useful to detect FAP. All effected patients have adenomas within the range of the sigmoidoscope. It is therefore recommended that screening sigmoidoscopy begin at age fourteen with reexamination every two years. The diagnosis of FAP must be confirmed with biopsy because lymphoid polyposis and hyperplastic polyposis can mimic FAP grossly and endoscopically. Once a diagnosis of FAP has been established, prophylactic proctocolectomy is recommended. Most investigators recommend sigmoidoscopy for mutation negative kindred at age 12 just in case the genetic test is erroneous. Thyroid examination and serum alphafetoprotein determination to screen for hepatoblastoma are recommended. Regular upper endoscopy should be done. Gastric and duodenal polyps develop in 30%-90% of FAP patients (27, 28). The gastric lesions are usually fundic gland polyposis whereas the duodenal polyps are usually adenomas. The fundic gland polyps can develop a peculiar atypia called foveolar dysplasia (29). The incidence of duodenal adenomas and FAP increases with increasing age. There is a propensity for these to develop in the periampullary region. Adenomas everywhere are prone to the dysplasia-carcinoma sequence. The relative risk of duodenal/periampullary carcinoma is approximately 125-350 times that seen in the general population and duodenal/periampullary carcinoma has become a major cause of morbidity and mortality in FAP patients in the post prophylactic colectomy era (30). Familial Adenomatous Polyposis Variants Gardner's and some Turcot's syndromes are variants of FAP. In Gardner's variant, in addition to colonic adenomas and upper GI polyps, patients can exhibit a number of extraintestinal manifestation such as osteomas, epidermal inclusion cysts, other benign skin tumors, desmoid tumors of the abdomen/abdominal wall, fibrosis of mesentery, dental abnormalities, carcinoma of the periampullary region/duodenum and carcinoma of the thyroid. Turcot's syndrome describes the association of FAP with tumors of the central nervous system (see below). Genetics of Familial Adenomatous Polyposis and Related Syndromes The gene responsible for familial adenomatous polyposis (APC gene) has been localized to the long arm of chromosome 5 (5q21-q22) and has been cloned (31-35). Mutation in most patients with FAP and its variants creates a stop codon resulting in a truncated protein product. The exact function of the APC protein is unknown, but it appears to have important tumor suppressor properties (36). Linkage analysis for diagnosis can be done in some affected families and is estimated to have a diagnostic accuracy of 98% (37). Linkage analysis requires that several family members have FAP. Unfortunately, 20% of patients appear to be new gene mutations, a phenomenon that can be explained by the relatively large size of the APC gene. Most patients are now diagnosed using an assay to detect the truncated APC protein (PTT). The conversion variant of this test in which each strand of the DNA is examined separately may be able to detect over 96% of mutations (26). Direct mutational analysis of the APC gene can be performed (38). Localization of gene mutations within the APC gene locus correlates with phenotype. For example, germline mutations between codon 1250-1464 are associated with very large numbers of colonic adenomas, whereas, mutations elsewhere, especially near the 5' end or the 3' end of APC, yield lesser numbers of colonic adenomas (see Attenuated Familial Adenomatous Polyposis below) (26, 39, 40). Patients with Gardner's Syndrome also have APC gene mutations; however, no particular APC mutation distinguishes FAP from Gardner's variant. Even within a "Gardner's family", Gardner's stigmata can be variably expressed and even skip generations (35). Obviously, some unknown disease-modifying factors are required for phenotypic expression of the extra-intestinal manifestations. Turcot's syndrome has been the subject of some controversy. In many investigators' zeal to publish, the phenotypic spectrum has been unduly broad with colonic manifestations ranging from a single adenoma to a virtual carpeting of the colonic mucosa with polyps. Furthermore, the brain tumors have comprised almost every conceivable histologic type. Molecular studies done on fourteen Turcot's Syndrome families have clarified the situation somewhat (41). Turcot's Syndrome families with germline mutations of the APC gene tend to develop a typical FAP colonic phenotype and often develop medulloblastomas. Other patients originally thought to have Turcot's Syndrome have mutations in DNA mismatch repair genes that are characteristic of the hereditary non-polyposis colon cancer syndrome families. The brain tumors in this group has varied with many reported as gliobastoma multiforme. Mutations of the APC gene near the 5' end and 3' end may have fewer adenomas (fewer than 100), a tendency for the adenomas to be macroscopically flat, and a propensity for these adenomas to cluster in the right colon. Originally reported as hereditary flat adenoma syndrome, this form is now more accurately referred to as attenuated familial adenomatous polyposis (26, 40). Like typical FAP, these patients can develop fundic gland polyposis, duodenal adenomas and periampullary carcinoma. The risk of colorectal carcinoma is increased in these patients albeit to a lesser degree than in other forms of FAP and the cancers tend to occur later in life. Recently, inherited variants of MYH have been associated with colorectal polyposis with an autosomal recessive mode of inheritance (41a, 41b). Some cases phenotypically resemble FAP or attenuated FAP and are referred to as "MYH polyposis" (41c). Juvenile Polyps and Juvenile Polyposis Syndrome Juvenile polyps can occur in a sporadic form or can be part of juvenile polyposis as a syndrome. In the sporadic form, juvenile polyps have their peak prevalence in children between ages 1 and 7. There is some evidence that juvenile polyps can regress, but they can certainly be seen in adults. Sporadic juvenile polyps typically occur singly but patients can have up to 5 usually in the rectum. Juvenile polyps typically range in size from millimeters to 2 centimeters, and can be associated with overt prolapse (42). Since they are often attached only by a small pedicle, they are particularly prone to auto-amputation. Histologically, typical juvenile polyps consists of a hamartomatous overgrowth of the lamina propria accompanied by elongation and cystic dilatation of crypts lined by non-dysplastic colonic epithelium (43). Osseous and cartilaginous stromal metaplasia can occur. The inflammatory component of juvenile polyps can be quite prominent with neutrophils and lymphoid follicles in the lamina propria. Frequently, the distinction between juvenile polyps and inflammatory polyps of primary inflammatory bowel disease cannot be made on histology alone, and requires clinical correlation. Solitary juvenile polyps appear to have no malignant potential (43). Juvenile polyposis syndromes can be familial or non-familial and usually becomes clinically apparent within the first decade of life with painless rectal bleeding, prolapse, iron deficiency anemia or by passing an auto-amputated polyp (24). The following diagnostic criteria have been applied. A patient is considered to have juvenile polyposis syndrome if they have 6 or more juvenile polyps in the colon and rectum, have juvenile polyp through the GI tract, or have any number of juvenile polyps in association with a positive family history (42, 44). In non-familial form of juvenile polyposis syndrome (approximately 30% of the total), patients frequently have associated abnormalities, such as cardiac defects, hydrocephalus, malrotation, undescended testes, and skull abnormalities. The familial form usually lacks these extraintestinal manifestations. Inheritance has varied although almost all are autosomal dominant with variable penetrance. Familial forms of juvenile polyposis syndrome appear to be associated with an increased risk of colorectal carcinoma (44); prophylactic colectomy may be prudent in juvenile polyposis syndrome. The number of polyps in juvenile polyposis syndrome typically range from a few dozen to several hundred. Phenotypically, juvenile polyposis syndrome appears to occur in three varieties: a) polyps limited to the colon; b) polyps limited to the stomach; and, c) polyps throughout the entire gastrointestinal tract (45-47). The mucosal polyps found in the context of juvenile polyposis syndromes are often unusual histologically. In addition to typical juvenile polyps (described above), one can find juvenile polyps with atypical features in which there is much more mucosa than lamina propria. In addition, mixture polyps (juvenile polyps with areas of adenoma/dysplasia) are quite frequent (44). A family showing an autosomal dominant inheritance of atypical juvenile polyps, adenomas, hyperplastic polyps and polyps showing a mixture of all three types (Hereditary Mixed Polyposis Syndrome) (48) may be variant of juvenile polyposis (49). Two genes have been identified to cause familial juvenile polyposis syndrome, SMAD-4 (18q21.1) and BMPR1A (10q22.3) (50-52). Juvenile polyps can be found in patients with other hamartomatous syndromes of the colon, such as intestinal ganglioneuromatosis/ganglioneuro-fibromatosis (see below) (53-55). Patients can sometimes be managed with endoscopy and polypectomy (q1-3 years), however, colectomy must be considered for patients with large numbers of polyps, polyps with dysplasia or complications (e.g., bleeding) (50). Upper endoscopy is also recommended in patients with juvenile polyposis syndrome. Ruvalcabas-Myhe-Smith Syndrome (Bannayan-Riley-Ruvalcabas Syndrome) The Ruvalcabas-Myhe-Smith syndrome consists of macrocephaly, mental deficiency, unusual craniofacial appearance, pigmented macules on the penis and hamartomatous polyps in the gastrointestinal tract. The syndrome may be passed on as an autosomal dominant although there are too few cases to be sure (56). The gastrointestinal polyps have been indistinguishable from juvenile polyps and in rare instances, intestinal ganglioneuromatosis has also been described. The syndrome has been linked to mutations in the PTEN gene (10q23.3) (46, 50, 57). Peutz-Jeghers Syndrome Peutz-Jeghers polyps can be found throughout the gastrointestinal tract and are most commonly seen as part of the Peutz-Jeghers syndrome (58). The polyp itself is characterized by fairly normal epithelium and lamina propria lining an abnormal arborising network of smooth muscle that represents hamartomatous overgrowth of the muscularis mucosae (58, 59). Peutz-Jeghers syndrome, usually inherited as an autosomal dominant trait, is the combination of skin hyperpigmentation and Peutz-Jeghers polyps in the gastrointestinal tract. The pigmentation consists of clusters of black/brown freckles about lips of buccal mucosa, perianal and genital area. Pigmented areas can occasionally be seen on the fingers and toes. The spots appear in the first year of life and tend to fade toward middle age. The polyps usually number only in the dozens and can be found throughout the gastrointestinal tract. However, there is a propensity for these polyps to form in the small intestine when they often cause intussusception. There are rare kindred in which Peutz-Jeghers polyps have been limited to the large bowel. Cases of complicating gastrointestinal carcinoma have been reported (60, 61). Approximately 5% of females with Peutz-Jeghers syndrome have a peculiar ovarian tumor, namely, sex cord tumor with annular tubules (SCTAT) (62). The rate of detection may go up if the ovaries are carefully examined (62, 63) and some tumors may be associated with sexual precosity (64). Males with Peutz-Jeghers syndrome occasionally have unilateral or bilateral Sertoli cell tumors of the testes (65, 66). Adenoma malignum and pancreaticobiliary tract carcinomas are reported to occur at increased rates (67-69). The gene for Peutz-Jeghers syndrome has been linked to the SKT 11 gene on chromosome 19 (70-73). Esophagogastroduodenoscopy, colonoscopy, upper GI series with small bowel followthrough are recommended in Peutz-Jeghers patients at age 10 and every two years thereafter. Testicular examination at age 10, pelvic examination by age 20, mammographic exam by age 25 and endoscopic ultrasound of the pancreas by age 30 have been recommended (74). Intestinal Ganglioneuromatosis Intestinal ganglioneuromatosis is defined as proliferation of ganglion cells, neurites, and supporting cells that can affect any layer of the gastrointestinal wall (56). These proliferations often present as mucosal polyps. Although these lesions can occur as an isolated phenomenon, the importance of intestinal polypoid ganglioneuromatosis is in recognizing the other settings in which it occurs such as vonRecklinghausen's disease (NF-1 mutation), MEN type 2b (RET gene mutation), Cowden's Syndrome (PTEN mutation) and Tuberous Sclerosis (TSC1 [9q34] or TSC2 [16p13] mutation) (75-78). Intestinal ganglioneuromatosis can coexist with juvenile polyps (53-55). Cowden's Syndrome Cowden's syndrome describes a multiple hamartoma syndrome in which patients have multiple orocutaneous hamartomas (e.g. facial trichilemmomas, mucosal papillomas), fibrocystic disease of the breast, an increased risk of breast carcinoma, thyroid abnormalities and hamartomatous polyps in the stomach, small intestine and colon. Polyps of the gastrointestinal tract, when described, have often demonstrated an abnormal proliferation of the smooth muscle lamina propria and have generally resembled the polypoid variant of solitary rectal ulcer syndrome (79). Intestinal ganglioneuromatosis has also been described (61). The gene (PTEN) for Cowden's disease has been mapped to chromosome 10 (10q22-23) (51, 80, 81). Cronkhite-Canada Syndrome Cronkhite-Canada syndrome is an acquired non-familial syndrome characterized by intestinal polyposis, dystrophic changes of the fingernails, alopecia and cutaneous hyperpigmentation (82, 83). Patients first present with diarrhea, abdominal pain and anorexia that progresses to weight loss and protein losing enteropathy. Many patients complain of loss of taste (hypogeusia) and loss of smell. As a rule, the ectodermal changes occur weeks to months after the other symptoms. The nail dystrophy consists of thinning, splitting and separation from the nail bed (onycholysis). Onychomadesis (complete loss) can also occur. The hair loss is rapid and may be seen in the scalp, eyebrow, face, axilla or pubic region. The cutaneous hyperpigmentation range from small macules to confluent areas of hyperpigmentation that can be 10 cm or more. Histologically, the pigmented macules are due to increased melanin in the basal layer. Cronkhite-Canada polyps are found throughout the gastrointestinal tract and are most commonly seen in the stomach and large bowel. Grossly, they are sessile; a few are pedunculated. The polyps tend to occur on a background of diffuse mucosal thickening. Histologically, the polyps are identical to juvenile polyps. However, the mucosa between polyps is abnormal showing edema, congestion and inflammation of the lamina propria coupled with glandular ectasia. Carcinomas of the colon and stomach have been rarely described in Cronkhite-Canada syndrome patients. The malabsorption in this syndrome is progressive and with no specific therapy available, the prognosis is poor. Death usually results from anemia, septic shock, bleeding or post-operative complications. Treatment consists of supportive therapy, antibiotics, corticosteroids and surgery. Some long term remissions have been described (84,85). Within the stomach, Cronkhite-Canada syndrome closely mimics Menetrier's disease. Menetrier's disease, however, is confined to the stomach and has no associated ectodermal changes. CLINICAL HISTORY FOR CASE 4 53 year-old woman with abdominal distress and pain with stools positive for occult blood. 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