Mucosal biopsy of theesophagus, stomach, and proximal duodenum

Progress in Pathology M U C O S A L BIOPSY OF T H E ESOPHAGUS, STOMACH, AND PROXIMAL D U O D E N U M Harvey Goldman, MD, and Donald A. Antonioli, MD The past decade has occasioned the development and extensive use of flexible endoscopes for visualization of large areas of the alimentary tract. Numerous small grasp biopsies are now performed to determine the diagnosis and epurse of a large variety of inflammatory and neoplastic disorders. In this review, the authors have concentrated on the uses and interpretation of endoscopy and biopsy of the upper alimentary tract including the esophagus, stomach, and proximal duodenum. They have also commented on the limitations of endoscopic biopsy with respect to its size, superficial nature, and imperfect orientation in the evaluation of some disorders. Hum Pathol 13:423-448, 1982.

The development of flexible endoscopes has ied to a marked increase in procedures involving visualization and biopsy of the upper and lower portions of the alimentary tract. ~-3 In the past, when such examinations r e q u i r e d rigid endoscopes, biopsy specimens were larger but few in number and their use was limited mostly to the detection of neoplasms, often at late stages. The biopsy specimens provided by flexible endoscopes are smaller but typically multiple, and they are obtained at earlier stages and at more frequent intervals in the course of a disease. Pathologists are now required to evaluate less well oriented specimens and, more importantly, to appreciate the subtle histologic features of a wide variety of inflammatory conditions and of earlier stages of neoplasms. Particularly with inflammatory lesions, the biopsy specimen may yield a pattern of iniury rather than a specific lfistologic diagnosis, and proper interpretation requires carefill consideration of clinical and other functional data. With selective biopsies the opportunity arises for improved correlation of the lfistologic features with the gross features o f disease at both advanced and early pllases. In addition, the relative ease of repeat endoscopy has made it possible for the natural tfistory of several pathologic conditions to be determined by serial biopsies. The major uses of mucosal biopsies include 1) diagnosis, either specific or in the form of an injury patteI:n or stage; 2) determination of the extent or severity o f lesions; 3) monitoring o f the clinical course Accepted for publication December 24, 1981. Received from the Departments of Pathology, Beth Israel Hospital and ttarvard Medical School, and from the Charles A. Dana Research Institute, Beth Israel Hospital, Boston, Mass. Address correspondence and reprint requests to Dr. Goldman, Department of l'athology, Beth Israel Hospital, 330 Brookline Ave, Boston, MA 02215.

of disease states with particular reference to effects of therapy; and 4) detection of complications. It is exceedingly important that the particular information sought in the biopsy be included in the clinical summary and that this be specifically addressed in the pathologic report. This review will concentrate on the uses o f e n d o s c o p y a n d mucosal b i o p s y o f the esophagus, stomach, and proximal duodenum. To clarify the interpretation o f mucosal biopsy results, we include a general discussion of the disease entities and clinical situations that are submitted" most often for endoscopic examination, with a selective bibliography. In a subsequent review we will consider mucosal biopsies of the distal ileum, colon, and rectum. The interested reader is referred to'several articles and books on mucosal biopsies of die jejunum. 4-7 TECHNICAL ASPECTS

The grasp biopsy specimens obtained at flexible endoscopy typically consist only of the mucosa; in regions of tile gut with thicker mucosa, such as the esopbagus and stomach, these biopsies usually contain only the snperficial portion. Suction or aspiration-type biopsy specimens containing the full mucosa and part of the submucosa are available when a larger sample or more exact orientation is required, as is essential for the proper evaluation of jejunal mucosal biopsies. Tile choice of fixative is usually not critical, although Bouin and related solutions may interfere with tile staining o f the characteristic granules of eosinophils and Paneth cells. It is most important, however, that multiple sections be obtained from each mucosal biopsy specimen to improve ttle chance o f detecting any focal or subtle changes. For routine analysis we recommend that there be at least three levels of a biopsy specimen, each with five or more sections; wben a focal lesion is not identified on the initial sections, additional levels should be obtaine.d. In contrast to musocal biopsies of the small intestine, mucosal biopsies o f the esophagus and stomach need not be precisely oriented for most diagnostic determinations. Furthermore, some welloriented sections are usually revealed in the numerous levels of each biopsy specimen. Therefore, no s.pecial preparatory effort is reqtfired, and it is sufficmnt that tile technical staff be familiar with the t o pography and dimensions of the biopsy specimen.

0046-817718210500/0423$5.20 O W. B. Saunders Co.

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HUMAN PATHOLOGY--VOLUME 1~. NUMBER 5 May 1982 The utility of various special stains a n d immuuocytologic techniques is discussed u n d e r tile specific diseases. Cytologic preparations are a useful diagnostic adjunct for the detection of neoplasms and some infectious agents. 8-~~They are best obtained under direct visualization, by abrasion of the lesion surface by a brush passed through a separate channel of the end o s c o p e . T h e cytologic smears contain a large n u m b e r o f p r e s e r v e d cells from specific areas; examination of these smears is most useful if biopsy results are equivocal owing to small size, distortion, excessive inflammation, or tissue necrosis. Cytologic preparations may also be taken from strictures from which it may be impossible to obtain direct biopsy specimens. M U C O S A L B I O P S Y OF T H E E S O P H A G U S

T h e normal mucosa of the esophagus consists of a stratified squamous epithelium without keratinization, a variable amount of lamina pr0pria, and a thick d o u b l e s m o o t h - m u s c l e layer o f muscularis mucosae? H2 The epithelium contains a basal proliferative zone, which usually does not exceed 5 to 10 per cent of the thickness (except in the distal 5 cm of the esophagus of an adult, where it may reach 20 per cent), a prominent glycogen-rich intermediate zone, and a superficial layer with shedding cells (fig. 1). W i t h i n ' t h e epithelium are scattered irregularlyshaped mononuclear cells but no other inflammatory cells. Clusters of inflammatory cells of all types, including occasional lymphoid nodules, and focal mucous glands are present in the lamina propria. Numerous papillary extensions of the lamina propria with small venules may extend to 50 per cent of the total epithelial thickness. In the more superficial endoscopic grasp biopsies, typically only the epithelium is obtained and the height of basal cells and the papillary length often can not be appreciated because o f imperfect orientation. Mucosal biopsies of the esophagus are generally obtained for the evaluation o f esophagitis and, in conjunction with cytologic preparations, for the detection and histologic typing of mass lesions. It is important to recognize that the bowel preparation and the e n d o s c o p i c p r o c e d u r e itself may affect the mucosal structure, resuhing in edema, focal fresh hemorrhage, and venular dilatation in the lamina propria and its papillae. ESOPtlAGITIS

T h e principal causes of esophagitis are infectious agents, especially certain viruses and fungi; ingestion of corrosive substances such as lye; and, most commonly, the reflux of gastric contents.

Infectious Esophagitis T h e infectious agents chiefly responsible for esophagitis are fimgi and viruses. A search for these organisms is indicated particularly when esophagitis develops in an immtmosuppressed patient, a diabetic

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patient, or a person in whom antibiotic therapy has caused suppression of normal flora? 3 In these persons, otherwise saprophytic organisms may become pathogenic, resulting in localized or systemic sepsis. Tile symptoms of esophageal involvement by these organisms are dysphagia and pain on swallowing, but many cases are asymptomatic and are detected at endoscopy p e r f o r m e d for o t h e r indications ~4 or at postmortem examination. Increasing clinical recognition of such infections has made antemortem diagnosis via endoscopy more frequent. In a recent prospective study o f a general hospital population/5 Candida infection was diagnosed in 27 of 370 consecutive esophageal endoscopies (7.3 per cent); only about one third of the affected patients had any predisposing conditions, and the common feature of the remaining patients appeared to be advanced age. Fungal esophagitis is most commonly due to Candida species; rarely, other organisms such as Histoplasma and Aspergillus may be implicated? 6-~a The lesions of Candida are usually confined to the lower third of the esophagus but may be multifocal and diffuse. The gross appearance at endoscopy varies: hyperemia and white plaques or membranes on the mucosa may be evident; the plaques may be present within ulcerations, or the mucosa may be diffusely friable and contain focal white lesions/~ The mucosal biopsy reveals an acute a l)d chronic inflammatory reaction in the epitheliur0 and lamina propria, with occasional ulcerations and.. granulation tissue. T h e typical fungal spores and nonseptate pseudohyphae are best seen with special stains such as the periodic a c i d - S c h i f f (PAS) reaction after diastase pretreatment, or the m e t h e n a m i n e silver stain. T h e organisms may also be detected by examination of direct cytologic smears taken from the plaques by means of an endoscopic brush. In some instances the fungal infection is secondary to prior esophagitis due to reflux or to tissue necrosis from radiation or drug therapy. 19 For proper management o f these cases, it is necessary to determine whether there is actual tissue invasion by the fungi, for which a biopsy is required. Herpes simplex infection of the esophagus occurs in the same clinical settings as does Candida sepsis, with the additional feature that esophageal trauma in the form o f nasogastric i n t u b a t i o n has b e e n d o c u m e n t e d in a p p r o x i m a t e l y 50 per cent o f cases. 13"2~ The esophagus is involved in about 90 per cent of cases of visceral herpes and is the most commonly involved portion of the gastrointestinal tract. Premortem diagnosis can be important in ruling out Candida infection (thereby preventing amphotericinB therapy of "resistant moniliasis"), neoplasm, and radiation effects; if effective antiviral chemotherapy is developed, premortem diagnosis will become even more critical. Recently it has been noted that herpes simplex esophagitis may occur as well in otherwise normal persons. ~2 Typical herpetic gross lesions, which may develop anywhere in the esophagus, are nonspecific, small, discrete "punched-out" ulcers with white exudate in their bases and erythema at the margins. ~3"~~ To be usefld, biopsy specimens must include the ulcer margin, because the epithelium here shows charac-

MUCOSAL BIOPSY OF UPI'ER ALhMENTARY TRACT~GoLD,XtANAND ANTONIOL! teristic changes (fig. 2); biopsy specimens from the ulcer base reveal only nonspecific necrosis, inflammation, and granulation tissue. Squamous epithelial cells at tim margin may contain large intranuclear acidophilic inclusions surrounded by a clear zone and an outer dark margin o f chromatin at the nuclear membrane (Cowdry type-A cells). More frequent are multinucleated syncytial-type squamous cells with nuclei o f the h o m o g e n e o u s "ground-glass" type. Cytologic smears can be p a r t i c u l a r l y u s e f u l in evaluating these features, because cell preservation is optimal and a large surface area can be sampled, an important consideration if only minute lesions are present. Tim squamous epithelial changes, ahhough typical, are not completely specific, since similar lesions can occur in varicella-zoster infection. In addition, cultures should be obtained and special stains utilized to rule out concomitant bacterial or fungal infections, since herpes may be associated with other pathogens. Cytomegalovirus is tim other major virus implicated in inflammatory ulcerative lesions o f tim gut in immunosuppressed, elderly, or otherwise debilitated patients. T h e stomach and intestines are most commonly involved, but esophageal lesions may occur.Z_a'=4 ~The gross lesions are nonspecific ulcerations similar to those of herpes. The characteristic intranuclear and rare intracytoplasmic inclusions are found in glandular but not squam6us epithelial cells and in fibroblasts and endothelial cells o f the granulation tissue at ulcer bases. Therefore, unlike specimens of esoplmgeal lierpes, biopsy and cytology specimens from the center of cytomegalovirus ulcers are more helpftfl than specimens from the ulcer margins.

Corrosive Esophagitis Esophagitis due to tim ingestion of corrosive agents such as lye is characterized by diffuse ulceration and extensive hemorrhage. It typically results from accidental ingestion or from a suicide attempt, and tim clinical presentation and gross endoscopic findings are sufficient to confirm the diagnosis. If the patient survives, the lesions heal with cicatrix formation resulting in obstruction and dysphagia. The chronic phase is reported to be associated with an increased incidence of squamous cell carcinoma in the lower esophagus, 2~ but the frequency of this complication appears to be low. Nevertheless, it has been recommended that patients with strictures be monitored by endoscopy and biopsy to detect malignant transformation.

Reflux (Peptic) Esophagitis The most common use o f esophageal mucosai biopsies is the evaluation o f esophagitis resulting from excessive or pathologic reflux of gastric contents. In most cases this is due to an incompetence of the lower esophageal sphincter, which is of unknown etiology, alone or in combination with some disorder of esophageal motility.=6.=7 Adult patients typically have heartburn, but the symptoms in chiklren may be less obvious, i n c l u d i n g p u l m o n a r y as well as esophageal symptoms3 s Numerous modalities have

been employed to document the abnormal reflux, including barium swallow, milk technetium scan, and manometric measurement o f the lower esophageal sphincter pressure39,3~ T h e most sensitive test appears to be continuous intraesophageal monitoring of the pH, which is typically done for more than 12 honrs and may include a period when the patient is asleep.2S,31,32 ACUTE EVr~:CTS. The gross appearance at endoscopy is highly variable, and many cases reveal, only minimal vascular alterations, such as erythema, or no definite abnormalities. 33,34 Exceptionally, there may be frank ulceration, in which case biopsy is merely confirmatory or is obtained to exclude an ulcerated tumor or an infections process. In milder cases with limited gross alterations, tile biopsy examination is of particular benefit. Tile definite abnormal features that can be appreciated singly or in various combinations in biopsy specimens include a hyperplasia of the basal cells or zone o f the epithelium; an elongation of the length of the lamina propria papillae; the dilatation and rupture of the venules within the papillae; and the presence of eosinoplfils or neutrophils within the epithelial layer (figs. 3 to 5). A basal zone hyperplasia o f greater than 25 per cent and an increase in papillary length in excess of 50 per cent of the total epithelial thickness (figs. 3 and 4) appear to correlate well with functional evidence or reflux. 34-38 However,2these features may be normally present in the distal 3 to 5 cm o f the 40-cm adult esophagus, where i~ is believed that some degree of physiologic retiree may occur? 2 Accordingly, these changes are significant only in biopsy specimens taken above this region, and it is therefore essential that the location o f biopsies by properly identified. The visualization of the basal zone in a biopsy can be accentuated by tim PAS reaction, which stains the glycogen within the squamous cells in the intermediate zone; when the basal zone expands, concomitant reduction in the intermediate zone occurs. These features of basal cell hyperplasia and increased papillary length require optimal orientation for exact estimates or measurements, meaning that the larger aspiration-type biopsies are usually needed. Venular dilatation with focal rupture witlfin the elongated papillae, especially near tim surface (fig. 4), has also been cited as all earl)' sign o f r e f l u x esophagitis, va'4~The endoscopic procedure itself can cause vascular dilatation, presumably as a result of local trauma, but this is usually confined to a more basal location in the papillae. It is not clear at present whether tim vascular dilatation provides any greater specificity for esophagitis than does the associated lengthening of the papillae. As with the other features mentioned, aspiration-type biopsies are required to ensure adequate orientation. Intraepithelial eosinophils (fig. 5) and, to a lesser extent, neutrophils have recently been observed in esophageal biopsy specimens from clfildren with refluxesophagitis.32 About 95 per cent of patients with biopsy specimens showing eosinophils witlfin the epithelium, even when few in number, had acid reflux as evidenced by an abnormal pH probe test. This particular feature appeared to be more sensitive than

425

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Figure 1 (top left). Normal squamous epithelium in the esophagus9 Tile basal layer is only a few cells thick, and the papillae of the lamina propria extend through no more than 50 per cent of tile epithelial thickness. Figure 2 (top right). Esophageal mucosa at the margin of an herpetic ulcer. The squamous epithelium shows disordered maturation. Intranuclear inclusions, ground-glass nuclei, aud muhinucleated cells are present; Figure 3 (middle left). Biopsy specimen showing features 6f esophagitis. Basal cells occupy over one half of the epithelial height, and the papillae extend through 70 per cent of the epithelial thickness. Tile epithelium is infiltrated by granulocytic inllammatory cells, many of which are eoslnophils. Figure 4 (middle center).

426

Esophageal mucosal biopsy with vascular congestion at the tip of an elongated papilla.

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MUCOSAL BIOPSY OF UPPER ALIMENTARY TRACT--GoLD.XlAN ant) AXTOXtOLI Figure 5 (middle right). Higher-power view of eosinophils infiltrating the esophageal epithelium. Figure 6 (bottom left). Biopsyspecimen from Barrett's esophagus developing in a patient with reflux esophagitis.The normal squamous epithelium has been replaced by a variety of glandular elements, with a partially villous surface (at left). Figure 7 (bottom center). High-powerview to demonstrate mixture of surface-foveolar and goblet mucous cells in Barrett esophagus. Figure 8 (bottom right). Glandular elements at base of Barrett's esophagus. Cardiac mucous cells are present at the left of the photograph; the glands at the right contain parietal cells. -4

the other morphologic features, possibly developed at an earlier time, and could be readily appreciated in the smaller endoscopic biopsy specimens without identifiable orientation. We have also n o t e d this finding in adult patients, but precise correlation with fnnctional studies and quantification have not been recorded in this group. It should be noted that certain fixatives such as Bouin solution a n d eosin stains packaged in picric acid may interfere with proper staining o f the eosinophilic granules and prevent recognition o f the inflammatory ceils, especially when they are present in small numbers. Alternative fixatives a n d Giemsa stain m a y be r e q u i r e d in such iustances. T h e p r e s e n c e a n d n u m b e r of other inflammatory cells such as lymphocytes within the epithelium or o f any inflammatory cells in the lamina propria do not correlate with acid reflux. It appears that these cells are n o r m a l l y p r e s e n t a n d t h a t t h e i r n u m b e r may be increased as a result o f the diagnostic procedures. In addition to identifying esophagitis in a case o f reflux, multiple biopsy specimens are often obtained initially to determine the linear extent and severity of the disease. Biopsy specimens taken more proximal!y (e.g., beyond 25 per cent o f the esophageal length above the lower sphincter) that show intraepithelial eosinophils tend to be associated with greater functional deficit and presumably offer objective evidence of more severe disease. 32 Repeat biopsies are indicated to monitor the course following therapy and to detect late or chronic effects o f reflux esophagitis. CHRONIC EFFECTS. T h e late or chronic effects of repeated or sustained reflux esophagitis include the development o f fibrotic stricture, glandular metaplasia (Barrett's esophagus), and carcinoma. Biopsy specimens a n d cytologic preparations are essential to distinguish an inflammatory stricture from a neoplasm m any patient with a persistent esophageal narrowing. Considerable reactive epithelial hyperplasia can combine with degenerative cytologic changes in patients with persistent esophagitis, and these findings must be viewed conservatively to avoid a false-positive diagnosis o f carcinoma. Barrett's esophagus represents the development of a glandular metaplasia o f the esophageal mucosa (figs. 6 to 8). This was originally t h o u g h t to be congenital, but it is now accepted as a sequel to longstanding esophagitis? ~-43 Although the exact prevalence is not known, one review o f 6000 esophagoscopies 44 revealed 140 cases o f Barrett's esophagus, representing about l l per cent o f all patients with reflux. In addition, Barrett's esophagus has been noted at anastomotic regions following esophagogas-

trectomy. 4~ Tile gross endoscopic appearance may be subtle, and the lesion may be confused with ulceration" or excess luminal mucus. Determination o f the location of the lower esophageal sphincter is usually necessary to ensure that biopsy specimens are obtained from tile esophagus and not from gastric tissue within a hiatus hernia. In most instances, however, the gastric tissue within a hernia is composed o f fully organized gastric fundic mucosa, which can be readily distin.guished from the more heterogeneous glandular mixture m a Barrett's esophagus. Difficulties may arise, however, when concomitant gastritis leads to a more inflamed and regenerative gastric mucosa. Microscopic examination o f Barrett's esophagus reveals patchy or diffuse areas o f glandular tissue (fig. 6) occupying not only tile free surface but often the full thickness o f the epithelium, and the surface frequently has a villiform configurationfi-50 One or more o f a variety of cell types may be present: gastric s u r f a c e - f o v e o l a r , cardiac, and intestinal goblet-type mucous cells; parietal and chief dells; and Paneth and endocrine cells. Intestinal absoi:p.tive cells, however, are rarely present. Paull and tfis associates 48 introduced the term "specialized columnar epithelium" for areas that have a villiform surface and are formed by an admixture o f gastric and intestinal-type mucous cells. T h e histologic a p p e a r a n c e o f the Barrett's change varies greatly a m o n g patients and even a m o n g multiple specimens o f a single case. T h e specialized columnar epithelium, which appears to be most characteristic and to occur most frequently, is located typicall), at the proximal edge o f Barrett's lesion (fig. 7). T h e identification o f this epithelium can be enhanced by the use o f the alcian blue dye at pH 2.5, which stains the intestinal goblet m u c o u s cells very strongly, whereas normal gastric s u r f a c e - f o v e o l a r m u c o u s cells show no reaction. T h e mucous cells o f the Barrett's epithelium, i n c l u d i n g both the goblet- and gastric-type surface cells, will show a focal positive reaction, which can help distinguish this epithelium f r o m an i n a d v e r t e n t l y o b t a i n e d s p e c i m e n o f the stomach proper. Cardiac-type mucous glands prevail a t the base o f the mucosa and in distal portions (fig. 8). T h e parietal and chief cells are least commonly noted; when present, they occur in small clusters and are c o n c e n t r a t e d at the distal a n d basal regions. Paneth cells may be overlooked in tissue fixed in Bouin solution, because the fixative dissolves their granules, leaving empty spaces. Ftmctional studies have revealed that the Barrett's mucosa can produce pepsinogens, hydrochloric acid, and gastrin. 5~'5-~ Patients with Barrett's esophagus, as a marker of long-standing esophagitis, are at increased risk for

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HUMAN I'ATHOI.OGY--VOLUME 13, NUMBER 5 May 1982 the development of esophageal adenocarcinoma?a-s5 With successful surgical thex'apyz6 o f reflux esophagitis, reversion o f the glandular metaplasia to the normal squamous epithelium has been noted in some cases, particularly after relatively long. follow-up periods, and it has been suggested that this reduces the risk of tumor. In contrast, patients with persistent Barrett's epithelium require periodic examination for epithelial dysplasia (fig. 12) and early carcinoma (see Adenocarcinoma).

Other Forms of Esophagitis Radiation damage of the esophagus 57-5'~ is a common complication of therapy directed at tumors of the lung, mediastinum, and esophagus, and its location relates to the site of treatment. Early lesions consist of marked edema and acute ulceration, which may be followed by persistent es0phagitis and stricture formation. Mucosal biopsies are typically performed to exclude opportunisti6 infections and recurrent tumor. Biopsies may reveal areas of acanthosis or necrosis, and the characteristic "atypical" fibroblasts and endothelial cells of radiation damage may be seen in the underlying granulation tissue. Knowledge of a patient's prior exposure to i-adiation is crucial in evaluating the often bizarre epithelial and stromal changes. Most cases of drug-induced esophagitis result from the physical entrapment of undigested pills, leading to discrete ulcerations. ~~ In addition, rare cases of drug esophagitis are due to an immune reaction, 6-"-~~ and biopsy specimens show focal nonspecific degenerative and inflammatory changes. T h e finding o f mucosal eosinophils has led to the claim of esophageal involvemeut in some patients with eosinophilic gastroenteritis, 65 which is thought to be of an allergic nature (see Special Forms of Gastritis). However, we now appreciate the fact that intraepithelial eosinophils are seen in the much more common lesion of reflux esophagitis. It is possihle, therefore, that some of these previously reported cases of allergic esophagitis may have been due instead to concomitant acid reflux, pointing up the necessity of relating all such biopsies to the particular clinical and functional findings. Although systemic sclerosis commonly involves the esophagus, the early lesions are located in the muscularis propria and are not detectable in xnucosal biopsy specimens. However, progressive muscle loss may eventually lead to a motility disorder and reduced lower sphincter pressure, resulting in prominent and persistent reflux esophagitis. G6'G7The strictures that develop in such patients are a relatively late f n d i n g and are a consequence of the esophagitis rather than of the primary lesion. Mucosal biopsies are of assistance in detecting and monitoring the reflux esophagitis in these patients. A similar pathogenesis has been noted in children fi)llowing successful repair o f esophageal atresia. 6s Several of these children develop late postoperative strictures, which appear to result from an associated

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esophageal motor disorder and poor acid clearance rather than from the prior surgery. As with systemic sclerosis, biopsy specimens may show the acute or chronic effects of peptic esophagitis including Barrett's esophagus. Additional neuromuscular disorders that may significantly affect esophageal motility include primary achalasia, Chagas disease, and familial and sporadic visceral myopathy and neuropathy, z6"69-7' In most cases, the principal early problem is obstnlction. Later in the course of the disease, as a result of progressive muscle loss and delayed clearance or following pneumatic dilatation of the esophagus, peptic esophagitis may occur. Esophageal involvement is much less common in other collagen-vascular diseases, and mucosal biopsies, including the larger aspiration-type, appear to be too superficial to detect the vasculitis in these conditions. The esophagus may also be affected in patients with chronic graft-versus-host disease. 7z There appears to be a particular predilection for involvement of the proxinml third of the esophagus, with the development of focal or diffuse necrotizing lesions. Mucosal biopsies reveal nonspecific necrosis and inflammation, and the diagnosis is made on the basis of the restricted location of the lesions and the exclusion o f infectious agents. Some patients also show lesions in the distal esophagus, but .in this region the lesions cannot be readily separate~l from those of reflux disease. Other rare causes i6f. esophagitis that may be detected by mucosal biopsies include pemphigus 7a and Crohn's disease. 74 ESOPtlAGEAL TUMORS

The detection and histologic typing of esophageal tumors are greatly facilitated by obtaining both multiple biopsies and cytologic preparations under direct endoscopic visualization. 7~ The cytologic component is particularly useful in areas of stricture, since the brush can often be passed through the lesion, whereas biopsies o f the edge may miss the tumor.

Squamous Papilloma Squamous papillomas of the esophagus are uncommon lesions that appear as small wart-like projections on the mucosal surface. They are most likely of an inflammatory nature and analogous to skin tags or fibroepithelial papillomas. 76,rr They occur chiefly in elderly men, are located principally in the distal esophagus, are often multiple, and are thought to result from prolonged reflux or nasogastric intubation. Histologic examination reveals a papillary lesion with an uninflamed fibrovascular core covered by an acanthotic epithelium of mature squamous cells (fig. 9). Viral inclusions have not been identified in either epithelial or mesenchymal cells. The differential diagnosis includes proliferating granulation tissue, which can be excluded by the lack of inflammation and the orderly arrangement of the tissues, and ver-

MUCOSAL BIOPSY OF UPPER ALIMENTARY TRACT---GoLD.Xmx AXO Ax'roxmH rucous squamous cell carcinoma. T h e latter entity is also papillary and well differentiated, but careful examination reveals epithelial cell dysplasia and superficial invasion. Excisional biopsies are therefore preferred for full evaluation ofsquamous papillomas. If they are not possible via the endoscope, multiple biopsies o f larger lesions are indicated. Poorly oriented, thickly cut, or poorly stained tissue fragments may make the differentiation o f papilloma from carcinoma difficult. Knowledge of tile radiographic and gross endoscopic features is helpful, since the presence of multiple small polyps strongly indicates a benign entity. The natural history is unknown, but the available data do not suggest progression to malignancy. However, given tile uncertainties regarding these lesions, excision if feasible is recommended. Squamous Cell Carcinoma Squalnous cell carcinoma is r e p o r t e d as accounting for over 90 per cent of esophageal malignancies, with tile large majority in the distal two thirds of the esophagusJ 8"v~ We have the impression, however, that the relative incidence of adenocarcinomas, particularly in the distal esophagus, may be increasing in recent years. Sqttamous cancers in the distal esophagus show a marked predilection for middleaged and elderly men (ratio o f men to women, 4 - 5 : I) and occur with increased frequency in patients with achalasia, chronic esophagitis and stricture secondary to caustic.ingestion, and in abusers of alcohol and tobacco. Carcinomas o f the u p p e r third o f the esophagus make up approximately 10 per cent of the squamous tumors and show marked epidemiologic differences from tile more distal lesions, s~ They develop almost exclusively in the region o f the cricopharyngeus muscle, chiefly in younger women (ratio of men to women, I:10; median age range, 45 to 50 years). In addition, they are associated prominently with tile Plummer-Vinson (or Paterson-Kelly) syndrome, characterized by upper esophageal webs, cheilosis and oral mucosal changes, and refractory iron-deficiency anemia. The major clinical manifestation of esophageal squamous carcinoma, regardless o f its location, is dysphagia. The classic radiographic and endoscopic appearance is that of an eccentrically located ulcerated mass with a projecting or overhanging margin located in a rigid aperistahic segment. Less often, the cancer may. be polypoid or predominately mural; in the latter case the d i f f e r e n t i a t i o n from chronic esophagitis with stricture can be difficuh. Muhiple biopsy specimens from ulcer base and nmrgin and from areas o f surface irregularity increase diagnostic accuracy. The typical biopsy specimen contains invasire nests of malignant squamous cells with various degrees o f differentiation (fig. 10). The major diagnostic prOblem arises in distinguishing malignancy from tile florid proliferation of regenerating immature squamous cells that occurs in esophagitis. The problem is compounded b y the presence o f inflam-

mation and necrosis and by poorly o r i e n t e d or squeezed, distorted biopsy specimens in which tile question of invasion cannot be properly evahmted. Examination of subserial thinly cut well-stained sections may resolve the issue, but cytologic smears of the lesions may give a more definitive answer, since these smears include well-preserved cells obtained from a much larger surface area than that represented in biopsy specimens. T h e combination o f adequate cytologic preparations and at least two endoscopic" mucosal biopsy specimens will provide the specific diagnosis in practically all cases, s~ Multiple endoscopic biopsies obtained longitudinally along the esophagus will help determine the upper border of the cancer and associated dysplasia and detect extension into the stomach. In addition, inucosal biopsies may be useful in identifying the presence and extent of squamous cell dysplasia in patients at increased risk for squamous carcinoma formation, particularly patients in geographic regions where this is more manifest.7~,8z Adenocarcinoma Adenocarcinomas are reported as accounting for approximately 8 per cent of esophageal malignant tumors, 83 and the clinical findings are similar to those in patients with squamous tumors, s~ The "adenocarcinomas are unevenly distribute.d, making up 1 to 3 per cent of cancers in the upper two thirds of tile esophagus but almost 20 per c~nt o f tumors in the lowest third. Furthermore, th.e rdlative prevalence of these tumors in the distal portion may be increasing. Many adenocarcinomas in tile distal portion appear to be primary gastric carcinomas with secondary esophageal spread, representing 71 per cent in one series. 54 O f tile primary esophageal adenocarcinomas, the large majority arise in the Barrett's esophagus. In the series reported by Haggitt et al., 12 o f 14 (86 per cent) of primary esophageal glandular malignancies arose in Barrett's mucosa. 54 Conversely, of 140 patients with Barrett's esophagus in another series, 12 (8.6 per cent) had adenocarcinomas. 4~ The carcinomas in Barrett's esophagus 53-5z'8~ may be muhiple, and they have the same histologic features as do gastric and intestinal tumors (fig. 11). The majority form glands; they may be papillary or mucinous and they often have signet-ring cells. The carcinomas are frequently accompanied by a multifocal spectrum of premalignant changes including mucosal hyperplasia, variable degrees of epithelial dysplasia (fig. 12), adenomas, and adenocarcinoma in situ. T h e condition is analogous to dysplasia and carcinoma in ulcerative colitis, and tile same problems prevail: there is no precise reproducible definition of dysplasia, inflammation and necrosis make interpretation of epithelial changes difficult, and the biopsy specimens may not have been taken from the mbst atypical areas. 55 At present, the diagnosis o f dysplasia should probably be reserved for biopsy specimens that lack prominent acute inflammation and in which epithelial cell nuclei m a n i f e s t m a r k e d atypical

429

HUMAN I'ATHOLOGY--VOLUME 13, NUMBER 5 May 1982

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qop left). Survey of an esophageal papilloma. T h e connective tissue cores are covered by a muhilayered mature squamous

Figure 10 (top right). Biopsy of invasive squamous cell carcinoma of the esophagus, showing cytologic dysplasia. Squamous "pearl" formation is evident in the center o f the illustration. Figure 11

(bottom left). Invasive esophageal adenocarcinoma. T h e neoplasm contains both glandular and undifferentiated areas.

Figure 12 (bottom right). Dysplasia in Barrett's epitheliunL T h e glandular mucosa has a villiform configuration. T h e epithelial cells contain enlarged atypical nuclei that are not oriented at the base of the cells.

changes such as hyperchromatism, palisading, or abnormal mitoses. Cytologic smears may aid greatly in the evaluation of dysplasia and carcinoma? 4's5 Although it is clear that Barrett's esophagus is a premalignant lesion, there have been no prospective studies to delineate the natural history o f the condition. Our current recommendation is to monitor patients with Barrett's esophagus by yearly endoscopic examinations, obtaining cytologic smears and multiple mucosal biopsy specimens of suspicious and random areas. The finding of carcinoma requires definitive treatment, but there are as yet no firm guidelines for the management o f dysplasia.

Other Esophageal Tumors Other forms of esophageal mucosal tumors are much less common and include a d e n o s q u a m o u s " and a d e n o i d cystic 86 carcinomas, e n d o c r i n e cell tumorsfl 7'8s and melanocytic lesions. 8a Mucosal biopsy, specimens are usually sufficient to detect malignancy in such cases, but the specific differentiation may be missed in the small samples. Mural neoplasms make up 1 to 2 per cent of

430

clinically significant esophageal tumors, and the most frequent lesion is tile leiomyoma.9~ Usually an incidental finding at autopsy or at surgery performed for other indications, leiomyomas may cause dysphagia if they are located in a normally narrow zone, as in the region of tile lower esophageal sphincter. These and other intramural masses form smooth-contoured filling defects that are visualized radiographically. On endoscopic examination, an intact or focally ulcerated but freely movable mucosa is stretched over the lesion. Mucosal biopsy will usually not reveal the lesion unless the sample is taken from an ulcerated area, and even then results may be equivocal. As in the case of intramural lesions elsewhere in tile gut, a negative mucosal biopsy specimen does not exclude the presence o f a deeper lesion, but it may be helpful in eliminating the possibility of intramucosal disease such as epithelial malignancy with extensive mural invasion. Other mural tumors are rare and include a variety o f benign and malignant mesenchymal neoplasms, congenital cysts, hamartomas, and metastatic lesions3 a.a~ Lymphoma can involve tile esophagus and will be discussed in the section on mucosal biopsy of tile stomach.

MUCOSAL BIOPSY OF UPPER ALIMENTARY TRACT GOLDMANAND ANTONIOL!

Tumor-like Lesions Glycogenic acanthosis is commonly noted at endoscopy and consists of multiple small, slightly raised white plaques on the mucosal surface, which are due to discrete areas of thickened epithelium. 92-9~ The plaques are usually less than 1 cm in diameter and are most often noted in the distal esophagus. They may be confused initially with membranes like those seen in fungal infections, but there are usually no other signs of inflammation. Mucosal biopsies reveal simple h y p e r p l a s i a o f the g l y c o g e n - r i c h i n t e r m e d i a t e squamous cells without cytologic atypism. With the smaller and more superficial endoscopic biopsy specimens, it may not be possible to appreciate this hyperplasia or acanthosis, but dysplastic or inflammatory lesions can be safely excluded on the evidence provided by such specimens. The pathogenesis of these lesions is not known, but they appear to have no relation to any known inflammatory disease or tumor. Esophageal webs and rings represeni eccentric or circumferential membranous extensions of the mucosa, and most are congenital. They are usually located in the distal third o f the esophagus and cause no problem unless they reduce the luminal caliber to a diameter 0f-12"tnm or less. 9~ Biopsy specimens shbw merely a normal-appearing mucosa with variable acanthosis. Webs and rings may also occur in the upper esophagus at the level of the cricoplmryngeous muscle and may be associated with the PlummerVinson (Paterson-Kelly) syndrome. In this syndrome the squamous epithelium lining the rings or webs may undergo neoplastic transformationfl~ and mucosal biopsy is important in the detection of dysplasia and carcinoma. MUCOSAL BIOPSY OF T H E STOMACH The gastric mucosa is covered in all regions by a continuous layer o f surface mucous cells that extends into the pits (or foveolae) (figs. 13 and 14). These are tall columnar cells with mucin droplets concentrated in the luminal third of the cellsY6,~T Attached to the base of the pits in the cardia and antral-pyloric region are compound glands rich in another form of mucous cells, in which the droplets fill most of the cytoplasm, resulting in eccentric basal placement and flattening of the nuclei (fig. 13). The specialized glands of the stomach, containing the parietal and chief, or zymogen, cells, are present predominantly in the mucosal glands of tile gastric fundus and corpus (fig. 14). The parietal cells, which are responsible for acid production and contain the Bg2 intrinsic factor in humans, are concentrated in the midportion of the glands; these cells are large, polygonal, faintly eosinoplfilic, and finely granular. T h e chief cells are located mainly in the basal portion o f the glands, are more cuboidal and faintly basophilic, and provide pepsinogens. In the transitional zones between the cardia and fundus and the corpus and a n t r u m , there is some admixture Of the specialized cells with the glandular mucous cells. Furthermore, scattered parietal cells

and possibly some chief cells are present throughout the antral-pyloric region and extend into ttle proximal d u o d e n u m ? 8 Additional epithelial cells present throughout the stomach but not appreciated easily in standard hematoxylin and eosin sections include ttle neck mucous cells and tile gut endocrine cells. T h e neck cells are located at the junction of the foveolae and glands and represent the proliferative zone for all epithelial cells. A large variety of dispersed endocrine and paracrine cells in the glandular regions of, all parts of the stomach produce gastrin (mainly in the antrum), somatostatin, histamine, serotonin, and other hormones and reactive substances. These can be visualized by means o f silver stains, and the specific structural and functional types can be demonstrated by means of ultrastructural examination 99'~~176 and imnmnocytochemical stains. ~~176 Between the epithelial elements and their continuous basement m e m b r a n e is the fibrovascular lamina propria, and at the base of the mucosa is the relatively straight muscularis mucosae consisting o f a double layer of smooth muscle. The lamina propria is composed of a loose connective tissue with many blood vessels and fine strands of smooth muscle, which appear to extend up from the muscnlaris mucosae; lymphatics are normally absent from the mucosa except in the most basal region, but these readily appear in areas o f gastritis. Within the lamina propria are various quantities of all forms of inflammatory cells, which greatly increase with age, especially in the antrum. The stomach is subje~zt"to frequent irritations, and practically all pers6ns over 50 years of age will have some degree o f chronic gastritis in the antrum with subsequent extension into the corpus? ~ In addition to the increased inflammatory cells within the lamina propria, this gastritis is often associated with prominent hyperplastic and metaplastic alterations of the epithelial cells and glands (see Chronic Gastritis). T h e epithelial cells, particularly the mucous forms in normal and disease states, can be accentuated and better differentiated by the use of special stains such as the PAS reaction after diastase pretreatment and the alcian blue stains at pH 2.5 and pH 1.0. g~176 The PAS reaction, which identifies neutral g l y c o p r o t e i n s , p r o v i d e s s t r o n g s t a i n i n g o f the surface-foveolar mucous cells and relatively fainter staining of the cardiac-pyloric glandular mucous cells and goblet mucous cells in areas of intestinal metaplasia. It also provides pale staining of the parietal cells, which can be distinguished from the mucous cells by their cytology. The alcian blue stains at pH 2.5 and pH 1.0 reveal the mildly (predominantly carboxylated) and more markedly (nmildy sulfated) acid mucins respectively. With the stain at pH 2.5, a patchy faint reaction of the deep foveolar cells occurs, which is increased in gastritis, whereas no staining of the other mucous cells in the normal stomach is seen. The. goblet mucous cells in areas of intestinal metaplasia show strong reaction with alcian blue staining at both pH 2.5 and pH 1.0. There is also staining of the stromal mucins, particularly at the lower pH.

431

HUMAN I'ATHOLOGY--VOLUME 13, NUMBER 5 May 1982 Endoscopic examination with mucosal biopsy and cytologic preparation of the stomach is employed regularly for the initial identification and monitoring of cases of gastritis, peptic ulcer disease, and tumors. TlIese biopsies are usually of the smaller type taken directly at endoscopy and consist only of the superficial half of the mucosa, except in children and in patients with an atrophic mucosa. Aspiration-type biopsies are used when the full thickness of the mucosa is needed, but this is uncommon. As with biopsy in the esophagus, the mucosal structure may be altered slightly by the preparation and tlie endoscopic procedure. Ttiis may result in a variable degree of edema, vascular dilatation, and focal fresh hemorrhage in the lamina propria as well as some flattening of the surface epithelial cells. These findings can be usually distinguished from significant mucosal injury by the absence of both epithelial cell degeneration and acute inflammatory cells in the epithelial layer. GASTRITIS

There are several classifications of gastritis based on duration (whether acute or chronic), etiology and pathogenesis, distribution of lesions within the stomach, and histologic features. The microscopic alterations have been studied in great detail, but findings have been based-largely on examination of specimens obtained at surgery or autopsy. As a result, many of the early features in acute gastritis have received limited attention, but these can be appreciated in studies o f Inucosal biopsies and experimental models. ~08-n0 Acute Gastritis

Acute gastritis resuhs typically from the ingestion of ethanol, salicylates, or other anti-inflammatory drugs, or by the reflux of bile salts, m-u3 All of these substances are thought to cause injury by damaging the mucosal barrier at the level of the surface epithelial cell membranes, n4'"5 This leads to enhanced back diffusion of hydrogen ions, tissue acidosis and vascular compromise, and mucosal necrosis. In addition, it has recently been suggested that endogenous prostaglandins may serve to protect the mucosa H6.n7 and that various drugs including salicylates may act by inhibiting local prostaglandin synthesis. A diffuse acute gastritis or more localized acute ulcer (so-called stress ulcer) may also occur in patients with severe burns, other trauma, or hypovolemia, and it is probable that reduced inucosal blood floss" is a major precipitating factor in these cases, als't19 Patients with distal gastrectomy and gastrojejtmostomy are also prone to develop gastritis, both acute and chronic, presumably owing to bile refltIX?2~ The patients with acute gastritis o f any cause typically have pain and hematemesis, and the diagnosis is usually evident from the clinical information and gross endoscopic examination. In most instances, endoscopy is performed not only to confirm the presence of an acnte gastritis but also to exclude an-

432

other cause of hemorrhage, such as varices, chronic ulcer, or tumor. The gross lesions as perceived at endoscopy are highly variable but usually show a diffuse or focal hemorrhagic mucosa with occasional snperficial erosions. In most cases, biopsy specimens are not obtained or are taken only from areas in which tumor is suspected. The earliest histologic features of acute gastritis consist only o f vascular dilatation and fresh hemorrhage in the superficial lamina propria without obvions epithelial alterations or increase in acute inflammatory cells (fig. 15A). Unfortunately, these features cannot be safely distinguished from the traumatic effects o f the endoscopy. More certain, diagnostic features inchide necrosis of the epithelial cells lining the surface and foveolae and numerous neutrophils within the pit and glandular lumina (fig. 15B). Biopsy specimens obtained from grossly eroded or ulcerated areas reveal inore prominent hemorrhagic necrosis of part or all of the inucosa. In most cases, especially when acute gastritis is due to the ingestion of ethanol or drugs, there will be a prompt clinical response to medical therapy and rapid and complete restoration of normal mucosal structure in a few days. Mucosal biopsy specimens obtained during this healing phase show prominent regeneration o f the epithelium, characterized by elongation of the pits; the surface-foveolar mucous cells contain larger nuclei), less mucus, and numerous mitoses (fig. 16). T h e r e l m a y be some focal residual clusters of neutrophils Within the pit lumens but no active epithelial degeneration. Rarely, an acute gastritis may lead to loss of the specialized glandular cells and to gastric atrophy? 22 In e v a h i a t i n g a n d r e p o r t i n g the r e s n h s o f mucosal biopsies performed for acute gastritis, the particular clinical indication for the biopsy should be filly considered. On the basis of the combined clinical and histologic findings, reports may indicate 1) the absence or presence o f other specific lesions such as infections or tumors, 2) minimal findings compatible with either the procedure or early gastritis, and 3) definite evidence o f an active gastritis or a healing phase. Chronic Gastritis

Unfortunately, tile term chronic gastritis has been used by clinicians and pathologists for a variety o f independent diseases and morphologic features. At a clinical level, chronic gastritis refers not only to cases involving repeated attacks o f acute gastritis as discussed earlier, but also the evolving disorder of mucosal atrophy associated in its complete form with primary pernicious anemia. ~23-125 It had been proposed that cases o f chronic gastritis be separated into those with involvement limited primarily to~ither the proximal stomach (so-called type A) or the antrum (type B)? 26 However, there appears to be more diffuse involvement o f the entire stomach in most cases with proximal lesions? 25"1z7The cases with persistent antral gastritis more often involve acute episodes of injury requiring antacid therapy, and there may be

MUCOSAL BIOPSY OF UPPER ALIMENTARY TRACT--GoLDMAX ,X.XDA.XTOXU)H greater destruction of indigenous mucosal elements including the gastrin-producing endocrine cells. In contrast, the more diffuse form probably has an immunologic basis, is more insidious and less likely to produce acute episodes; and is associated with more ecific destruction o f the specialized parietal and chief cells, whereas the antral gastrin cells undergo a reactive hyperplasia. ~s-~3~ Employing this distinction between diffuse and antral forms o f gastritis, we can establish a good correlation of the two types o f gastritis with the observed rnorphologic features. In the more limited form, the antral mucosa reveals evidence of acute and chronic gastritis, whereas the corpus-fimdus is relatively spared; in the more diffi~se type, the striking effect is the reduction o f the specialized glandular elements of the corpus-fundus, with evidence of repair in all portions of the stomach. The effect on the endocrine cells--reduction in the antral form and hyperplasia in the diffuse form----can be appreciated only by means of special immunocytochemical stains and usually requires larger specimens for adequate quantification? 3m32 These are not required, however, when serum gastrin levels can be readily obtained. If use o f the term chronic gastritis were limited to the classification of these clinical-functional entities, there would be little confusion. However, there is a tendency among morphologists to diagnose chronic gastritis when changes are present in more restricted areas, such as at the edge of ulcers, or in just a few mucosal biopsy specimens. We strongly urge that themore descriptive phrase "chronic inflammation" be employed in such instances to avoid confusion with significant states of chronic gastritis. Indeed, if the particular clinical indication for the biopsy is considered, it might be most appropriate to specify that there is no tumor (e.g., in a biopsy taken from an ulcer edge) or that there is no evidence of acute or active gastritis. Further efforts to quantify the extent or severity o f gastritis, whether diffuse or focal and whether superficial or deep, are useful only when the features are combined with the functional data and only after evaluation of numerous biopsy specimens. T!le. gross endoscopic appearance o f chronic gastrms xs relatively limited; there may be evidence of an active phase, more promiuent vessels in diffuse atrophy, or some alteration of tile rugae. The rugal folds may become exaggerated when there is prominent regeneration, or simplified when there is marked atrophy. Mucosal biopsies in patients with chronic gastritis are most often performed to confirm the presence of an active phase in the antral form or to detect or exclude dysplasia or carcinoma in grossly suspicious areas or in random specimens from patients at increased risk for tumor development. The features of active disease were described earlier (see Acute Gastritis). In addition, the biopsy specimens obtained from patients with chronic gastritis reveal variable degrees of epithelial regeneration, hyperplasia, and metaplasia as well as increased inflammatory cells in the lamina propria (fig. 17). Possible findings in such cases include any combination of

1) lengthening o f the gastric pits with an increase in the number of regenerative and mature surfacefoveolar mucous cells; 2) increase in the pyloric-type glands in the antrum, and the appearance of these mucous glands in the damaged corpus (pyloric or pseudo-pyloric metaplasia), where they tend to replace the lost parietal and chief cells; and 3) the presence o f intestinal metaplasia, ranging from focal goblet mucous and absorptive cells to complete intestinal villi and P~ineth cells. These epithelial cells can, be accentuated with the alcian blue stains, which highlight the hyperplastic foveolar mucous and intestinal goblet mucous cellsJ ~ In cases with particularly florid hyperplasia, the term hypertrophic gastritis has been occasionally used, but this tends to obscure the fact that there may be significant atrophy o f the specialized gastric epithelial cells. O f particular importance is tile identification of patients with chronic gastritis who are at increased risk of developing carcinoma. This group includes patients with diffuse mucosal atrophy and pernicious anemia, ~33-135patients in whom the residual proximal stomach is prone to develop chronic gastritis following gastrectomy) 36-'39 adult patients with Menetrier's disease, ~4~ and patients with muhiple'and recurring gastric hyperplastic polyps. H2 In all these patients, periodic surveillance is r e q u i r e d tO identify early tumors, and multiple random biopsies are required to detect epithelial dyspl~sia. Caution should be the rule in identifying dysplasia and distinguishing it from the c o m m o n repara[]ve and metaplastic epithelial changes that occur in chronic gastritis (see Adenocarcinoma). As mentioned previously, it is especially important to consider the clinical data in evaluating the biopsy results o f patients with chronic gastritis. The pathologic report of such evahmtion should include, as needed, statements concerning the presence or absence of acute gastritis, the atrophy of specialized c o r p u s cells, r e p a r a t i v e epithelial hyperplasia and metaplasia, and dysplasia or carcinoma.

Special Forms of Gastritis Primary infections o f the stomach are uncommon but may be seen as a complication of gastritis and stress ulcer in severely burned patients and in immunocompromised patients. In addition, it has recently been noted that some patients with peptic ulcer disease develop secondary infections, particularly due to Candida organisms. 143 Ill burn patients, the infecting organisms are usually bacteria, which are best identified by culture. Mucosal biopsy specimens and cytologic preparations are useful for the detection of fungi ~-1s'144a45 and herpes 146 and cytomegalovirus inclusions 23 (see Infectious Esophagitis) or for the identification of gastritis due to less specific viruse~ 14~ Radiation damage 5s's9 is less common in the stomach than in the esophagus, since fewer tumors in the gastric area receive radiation therapy (see Other Forms of Esophagitis). Clinically, granulomatous gastritis may mimic an

433

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Figure 13 (first row, left). Biopsy of gastric antrmn. Tile glands are formed predominantly of mucous cells. Figure 14 (first r o w , r i g h t ) . Normal gastric corpus biopsy, showing surface-foveolar mucous cells at top. Parietal cells are evident in the gastric glands. "-I'here is mild edema (from procedure) but only minimal inflammation in the lamina propria. Figure 15 (second r o w ) . A , areas of acute hemorrhage in the gastric lamina propria. This lesion may result from acute gastritis, but also may develop from tile trauma of endoscopy. Endoscopy is the likely cause in this case because of the absence of an inflammatory cell response and, on tile right, tile artifactitious separation of the surface epithelium from the lamina propria. B , biopsy specimen showing definite evidence of acute gastritis. Gastric pits are dilated and lined by flattened epithelium; the hnnens contain neutrophils. There is also inllammatory infiltrate in the lamina propria.

434

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MUCOSAL BIOPSY OF UPPER ALhMENTARY TRACT--GoLt~.XtAX axo ANTONIOL! Figure 16 (third row, left). Healing gastritis, with regeneration of gastric pit epithelium. There is a lack of mucin production, but the nuclei, although large, slmw no pleomorphism. Figure 17 (third row, right). Gastricatrophy involving the corpus. The mucosa is thin and the number of glands is decreased. Parietal and chief cells are absent, having been replaced by pyloric-type tissue in the left half of the photomicrograph and b); glands showing intestinal metaplasia in the right half. There is prominent chronic inflammation. Figure 18 (fourth row, left). Survey view of antral biopsy specimen from a patient with eosinopbilic gastroenteritis. There is a diffuse increase in inflammation within the lamina propria and mucin depletion of epithelial cells at the base of the foveolae and in the pyloric glands. Figure 19 (fourth row, center). High-power view of ensinophilic gastroenteritis showing a foveolar abscess filled with eosinophils. Figure 20 (fourth row, right). Gastric fundic-corpus biopsy in a patient with Menetrier disease. There are marked hyperplasia of surface-foveolar mucous cells and lengthening of the gastric pits. infiltrating carcinoma, with thickening o f ttle gastric wall, aperistalsis in the distal stomach, and outlet obstruction. T h e differential diagnosis includes sarcoidosis, tuberculosis a n d some fungal infections, Crohn's disease, and foreign-body reaction? 4s-~5~T h e specific diagnosis d e p e n d s on the evaluation o f o t h e r gastrointestinal and visceral lesions and on the results o f a p p r o p r i a t e special stains and cultures. Rare cases o f isolated idiopathic gastric g r a n u l o m a s have been r e p o r t e d ? 5~.tsz In all cases, the m a j o r role o f the biopsy is in the detection o f the granulomas, which leads to the special differential studies and to the exclusion o f neoplasia. T h e t e r m e o s i n o p h i l i c g a s t r o e n t e r i t i s has b e e n applied to at least t h r e e separate conditions: 1) a mucosal f o r m that probably has an allergic etiology and involves.both the stomach and small intestine, 2) a m u r a l type with m a r k e d infiltration by eosinophils o f the musculature in the lower stomach and pylorus, r e s u l t i n g in g a s t r i c o b s t r u c t i o n , a n d 3) a r a r e eosinophilic serositis) 5a T h e mucosal type, also called allergic g a s t r o e n t e r o p a t h y , ~54 is a relatively u n c o m mon cause o f persistent diarrhea and malabsorption in adults. It appears to be m o r e c o m m o n in children, in w h o m it has less obvious features, such as failureto-thrive o r chronic bleeding with iron-deficiency anemia? s5 T h e lesion tends to be focal within the small intestine and may easily be missed by a single jejunal biopsy. It has been observed, primarily in children but also in a d u h s , that gastric antral involvement is m o r e constant and may be detected by means o f a single biopsy. F u r t h e r m o r e , the presence in such cases o f gastritis with associated enteritis helps distinguish this disorder from viral enteritis and celiac disease, which d o not directly affect the stomach. T h e gastric antral localization o f allergic g a s t r o e n t e r o p a t h y can b e a p p r e c i a t e d also u p o n r a d i o g r a p h i c a n d e n d o s c o p i c e x a m i n a t i o n s . 156 It should be stressed that gastric mucosal biopsy specimens must be obtained from the a n t r u m , since the m o r e proximal stomach is usually not involved. T h e antral mucosal biopsy reveals an acute gastritis with p r o m i n e n t infiltration o f e o s i n o p h i l s (figs. 18 and 19), which varies in severity from scattered inflamed pits to m o r e diffuse mucosal necrosis. Such a l a r g e infiltrate o f eosinopbils is not ordinarily s e e n in acute gastritis d u e to ingestion o f ethanol o r d r u g s o r to bile reflux. Eosinophils have been described in association

with chronic g r a n u l o m a t o u s disease and infiltrative disorders such as amyloidosis attd t u m o r , but these conditions can be easily distinguished. T h u s , it appears that an antral mucosal biopsy specimen showing an acute gastritis associated with m a n y eosinophils is relatively specific for the mucosal f o r m o f eosinophilic (or allergic) gastroenteritis. Ill some patients with specific forms o f allergy, such as milk protein sensitivity, involvement o f tile stomach as well as o f the small intestine may also be evident, ~7 but the gastric lesions tend to be m o r e focal. Menetrier's disease o f the stomach is characterized by a m u l t i f o c a l o r d i f f u s e h y p e r p l a s l a o f t h e surface-foveolar mucous cells, leading to p r o m i n e n t protein loss and hypoalbuminemia. ~58"~59T h e lesion is c o n c e n t r a t e d in t h e p r o x i m a l s t o m a c h , a n d the a n t r u m is usually spared. In adtdts, this may be a sign o f a diffuse chronic gastritis,'and some adult patients a p p e a r to be at increased risk for carcinoma. ~6~ In children, however, the d i s o r d e r is invariably selflimited a n d f r e q u e n t l y follows a r e s p i r a t o r y tract infection. 16~ T h e d i s o r d e r can be suspected if radiographic and endoscopic examinations reveal a restricted localization, and mucosal biopsies are perf o r m e d to confirm the diagnosis and to exchtde the possibility o f an infiltrative t u m o r . Mucosai biopsy specimens obtained f r o m the corpus, in contrast to those obtained f r o m . t h e a n t r u m , reveal a m a r k e d increase in m a t u r e surface-foveolar mucous cells without any associated inflammation (fig. 20). With the smaller and more superficial endoscopic biopsy specimens, there usually wiU be no u n d e r l y i n g glands and one must be wary o f a possible misinterpretation d u e to a tangential cut o f the surface region. In such cases, an aspiration-type biopsy, which would pernfit better orientation and include part o f the u n d e r l y i n g glands, may be n e e d e d ; this would also provide a better sample to exclude gastritis and t u m o r . T h e biopsy features described are not specific, since they may be seen in a localized area o f any case o f gastritis. W h e n these features are evaluated with the clinical and gross features, however, an accurate diagnosis is usually possible, thus avoiding the need for an operative, full-thickness biopsy. T h e gastric r u g a e may also be exaggerated in cases o f Zollinger-Ellison s y n d r o m e or as a resuh o f infiltration with carcinoma o r l y m p h o m a . ZollingerEllison s y n d r o m e can usually be d e f i n e d by functional

435

HUMAN I'ATHOLOGY--VOLUME 13, NUMBER 5 31a)' 1982 studies o f acid and gastrin levels, and mucosal biopsy is rarely performed. With tile larger aspiration biopsy specimens, hyperplasia of the parietal cells can be suspected if these cells are present high in the foveolae, but precise cell counts are ideal for diagnosis. Some of these cases appear related to gastrin-cell hyperplasia of the antrum, and it may prove possible to measure the number of endocrine cells in aspiration biopsy specimens from the a n t r u m ) 32"16z In the case of tumor infiltration, the folds are often very irregular, and multiple biopsies with cytologic preparations should be performed, in particular from any ulcerated area. Hypertrophic but otherwise wellformed rugae may be present in some normal persons, 1G3 and mucosal biopsies performed to exclude tumor may reveal completely normal mucosa without hyperplasia or inflammation. It is probable that the enlarged rugae in these cases are due to an expansion o f the submucosal component. C t l R O N I C PEPTIC ULCER

The most common site for chronic peptic ulcer ( a b o u t 75 per cent o f cases) is the p r o x i m a l duodenum. It is believed tbat hyperacidity at the resting level or, more commonly, in response to feeding is the nmjor pathogenic tactor in both duodenitis and chronic duodenal ulcer. ~6~'165 The diagnosis in most cases is established by-history and radiographic findings, and endoscopic examination is reserved for patients with equivocal findings. Since a d u o d e n a l tumor, particularly an adenocarcinoma of the proximal portion of the duodenum, is rare, biopsies are not usually performed to confirm the nature of an ulcer lesion. When no duodenal ulcer is found, however, mucosal biopsies ma)/ be helpful in d e t e r m i n i n g w h e t h e r t h e r e is e v i d e n c e o f d u o d e n i t i s (see Duodenitis). Tile second major location of chronic peptic ulcer (about 20 per cent of cases) is tile stomach, especially the antrum and pyloric regions. An increase in gastric acid secretion does not occur in most cases, and it has been suggested that chronic gastritis from exogenous agents or bile reflux is the major factor p r o m o t i n g chronic ulcer formation in the stomach. ~66-~6s Indeed, because of damage to the mucosal barrier and enhanced back-diffusion o f hydrogen ions, the gastric acid content is usually depressed. Most cases of chronic peptic ulcer of the stomach, as o f the duodenum, are diagnosed by history and radiographic findings, but in the stonmch, carcinoma must also be considered and excluded. In tile event of an)' suspicious radiographic findings, less-thanrapid healing of tile ulcer following medical therapy, or any recurrence, gross endoscopic vistmlization with appropriate mucosal biopsies and cytologic preparation is mandatory. It should be stressed that even with the best gross evaluations there will b~ errors in the detection of carcinoma in the range of 15 to 25 per cent. ~69

436

In evaluating gastric ulcers, it is best to take multiple biopsy specimens from the ulcer edge and at least one sample from the central necrotic area, thus providing optimal specimens for the detection of tile various forms of carcinoma and other tumors (see Gastric Tumors). The pathologic features of chronic peptic ulcer are well recorded, ~7~ but particular care must be taken in evaluating epithelial and inflammatory changes in the mucosal biopsy specimens. Marked alterations of the epithelia of a degeneralive and regenerative nature may be present (fig. 21), and the nuclei of stromal and endothelial cells in active granulation tissue may be considerably enlarged (fig. 22); this evaluation is even more difficult in small and distorted biopsy specimens. Although it is common practice to refer to such reactive changes as "atypical" or "dysplastic," we strongly urge that these descriptive words, in particular "dysplasia," be strictly reserved for conditions that are clearly neoplastic and have potential for carcinoma formation. A conservative approach should be the rule. Biopsy specimens from the central ulcerated area reveal coagulative necrosis and acute inflammation. Exceptionally, in larger ulcers, they may contain fragments of adjacent organs, such as the spleen, into which the ulcer has penetratedJ TM In a small number of cases the ulcers may be complicated by the presence of opportunistic infectious agents, especially fungi, in the necrotic area~;143 Which may lead to greater destruction with persistence o f ulcer and perforation. Biopsy specimehs obtained from tile ulcer edge should also be "inspected for the presence of increased chronic inflammation in the lamina propria as well as for regenerative and metaplastic epithelia. Increased inflammation is invariably noted at the edge of chronic gastric ulcers but may be absent in cases involving acute and drug-related ulceration. T h u s , about h a l f o f patients with ulcers o f the stomach due to salicylate ingestion lmve a normal mucosa at the ulcer edge, ~73ara which we have observed in association with other anti-inflammatory drugs such as indomethacin as well. I f the mucosa from tile edge is normal or shows only minimal inflammation, this observation should be included in the report to call attention to the possibility of a drug etiology or other cause of acute ulcer. GASTRIC TUMORS

With tile stomach, as with tile esophagus, it is i m p o r t a n t that cytologic preparations as well as mucosal biopsy specimens be obtained to improve diagnostic accuracy. It has been noted that the combination of four mucosal biopsies in conjunction with cytologic preparations provides the correct diagnosis in practically all cases of carcinoma) ~

Gastric Polyps Tile great majority o f gastric polyps (well over 90 per cent) appear to be o f an inflammatory or repara-

MUCOSAL BIOI'SY OF UPPER ALIMENTARY TRACT~GoLDMAN AND ANTONIOLI tire nature and have been termed regenerative or hyperplastic polyps. ~5'176 These are composed o f a variable admixture of hyperplastic surface-foveolar epithelium and pyloric glandular tissue with lamina propria containing increased inflammatory cells and smooth muscle in most cases (fig. 23). The surface epithelium may show active regeneration, especially when adjacent to ulcerated areas, but a true dysplasia is not present. Therefore, these polyps should not be confizsed with or termed adenomas. Most hyperplastic polyps are small and sessile, multipl!city is observed in about 20 to 25 per cent o f cases, and the uncommon large lesions may develop a stalk) 77 The polyps rarely produce symptoms and are usually observed incidentally at gross inspection o f the stomach, but an increased incidence has been noted in gastric remnants following distal gastrectomy? ~8 Clinical problems may ensue with the larger polyps, since they may twist on their stalks, leading to superficial ulceration and hemorrhage. They may also.prolapse into the pyloric region, resulting in intermittent obstruction, or cause concern because of their large size? 79 Superficial biopsies o f small polyps reveal a mixture of hyperplastic and inflammatory tissue similar to that in any area of chronic gastritis, and the polypoid nature of the lesion cannot be readily appreciated. However, the most important microscopic observation is the absence of adenomatous or dysplastic epithelium. T h e polypoid configuration of the larger lesions, if they are not fragmented, may be easier to interpret. In.cases involving multiple recurrences, Hoit is important to look for evidence o f more diffuse chronic gastritis. Patients with multiple recurrences are probably at increased risk for carcinoma, but the tumors may occur in the flat mucosa as well as in the polypoid lesions? 7~ T r u e gastric a d e n o m a s (fig. 24), i n c l u d i n g adenomatous polyps and villous adenomas, are relatively rare. C o m p a r e d with hyperplastic polyps, adenomas tend to be larger, usually greater than 2 cm in size, more often occur singly, and have a definite propensity for carcinoma f o r m a t i o n ? s~ Mucosal biopsy of such lesions reveals the definite dysplastic features o f adenomatous epithelium, which is indistinguishable from that seen in much more common adenomas o f the colon. These lesions should be carefully inspected for intramucosal and invasive carcinomas, which are present in approximately 40 per cent of cases. If any polyp reveals on biopsy a dysplastic or adenomatous epithelium, it is essential that the entire lesion be removed, even if this requires a partial gastrectomy. In addition to the isolated cases, there are exceptional instances o f familial adenomatons polyposis coli, in which adenomas are present in the stomach as well. ~8~-~83 Other polyps arising from the gastric mucosa are uncommon and include cases o f generalized juvenile polyposis, ls4"ts5 the Peutz-Jeghers syndrome, is6 and the Cronkite-Canada s y n d r o m e ? s7 T h e polyps in these syndromes are thought to represent hamar-

tomas, and they are composed of hyperplastic and inflammatory tissue with variably cystic glands. They cannot be readily distinguished histologically, especially by means o f limited mucosal biopsies, from the more common hyperplastic-regenerative polyps in the stomach, and their nature is best appreciated by the total distribution of lesions in the gut and other tissues. T h e major role of biopsy in these cases is to exclude an adenoma or carcinoma. Another rare mucosal polyp in the stomach is the inflammatory, fibroid polyp, 79"18swhich contains a characteristic core o f connective tissue rich in fibromuscular tissue and often containing many eosinophils; however, a biopsy specimen is usually obtained only from the surface epithelium. Occasional mucosal biopsy o f a grossly polypoid area, particularly in the fundus-corpus region in older patients, reveals only focal dilatation of the gastric pits and glands. The mucosa o f such lesions is otherwise normal, and the nature of these lesions is unknown. In summary, biopsy o f a gastric mucosal polyp is p e r f o r m e d to determine whether the polyp is an a d e n o m a o r p o l y p o i d a d e n o c a r c i n o m a . I f no dysplastic or a d e n o m a t o u s epithelium is seen on biopsy and if the lesion has been remoVed or adequately sampled, the lesion can be regarded generically and r e p o r t e d as an i n f l a m m a t o r y or nonneoplastic polyp. Further particular designation of the type o f polyp, whether the cdmmon hyperplasticregenerative type or one o f the special hamartomatous types, depends on the to(all.clinical information available. Adenocarcinoma

Although a decline in the incidence o f gastric carcinoma has been noted in many countries, including the United States, there appears to be a levelingo f f o f this trend. It has been noted that relatively more cases are being encountered in younger patients and that the ratio of men to women is approaching 1 : 1.~89-19~This trend applies in particular to lesions of the body and antrum of the stomach and is asociated with a large increase in tumors containing many signet-ring cells and having an infiltrative growth pattern, t92 Also noted recently is an apparent increase in the incidence o f primary carcinoma o f the gastric cardia, which may represent one fourth o f all gastric tumorsVJ"; of interest, these tumors occur most often in older men and have fewer signet-ring cells and less associated gastritis. T h e r e are numerous classifications o f gastric adenocarcinoma, based on the size and gross configuration o f the tumors; on the dominant histologic features, as of intestinal or diffuse typeset; and on the growth pattern, as ofexpansile or infiltrative types. ~9~ Advanced gastric carcinomas are readily appreciated on both radiographic and endoscopic examinations; sucll tumors have been described as polypoid or tim. gating, ulcerative, and infiltrative. O f special impor-

437

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Figure 21 (top/eft). Regenerating epithelium at the margin of a chronic Peptic ulcer. Tbe nuclei are variahle in size and many have large nucleoli, llowever, the background chromatin is evenly distributed. Figure 22 (top center). Granulation tissue and inflammation at the base of a benign chronic peptic ulcer. The prominent endothelial cells of proliferating blood vessels can mimic infiltrating adenocarcinoma. Figure 23 (top right). Biopsy specimen of a gastric hyperplastic polyp. A variety of glandular configurations is evident, hut all glands are lined bY mature or regenerating epithelial cells with small, mostly basal nuclei and copious muein. Figure 24 (middle left). High-power view of epithelium from a gastric adenoma. Nuclei are enlarged, show some chromatin aberration. and are beginning to stratify. Mucin accumulation is somewhat diminished. Figure 95 (middle center).

438

Biopsy specimen of gastric adenocarcinoma (bottom) with dysplastic gland formation.

Legends continue on opposite page.

MUCOSAL BIOPSY OF UPPER ALIMENTARY TRACT--GoLD.xmy AND ANTONIOLI Figure 26 (middle right). Signet-ring cells in gastric adenocarcinoma. The neoplastic nuclei are eccentric owing to the accumulation of cytoplasmicmucus. Figure 27 (bottomleft). Mucosalbiopsy specimen of leiomyosarcoma. Figure 28 (bottomright). Biopsyspecimen of gastric lymphoma. The monomorphic nature of the infiltrate helps to separate it from a reactive inflamnmtory process, but the distinction from undifferentiated carcinoma may be difficult without special studies such as electron microscopy.

tance in the endoscopic examination is the appreciation o f the gross features o f early gastric cancer? 95a96 These have been extensively analyzed in J a p a n , ~9r-~99 but it is now apparent that they occur as well in all geographic regions. 2~176176 A recent study in the United States disclosed that early tumors represented 13 per cent o f all gastric carcinomas and that the relative reported percentage increased when the lesions were actively sought? 89 These early tumors are o f various sizes, but they are usually very small and are associated with subtle gross alterations o f the mu'cosal surface. T h e y have been categorized as polypoid, barely raised, flat, barely depressed, and ulcerated. Regardless of their classification, the gross lesions may not suggest a t u m o r so much as an inflammatory lesion. T o ensure that their true nature is determined, it is essential that biopsy specimens be routinely obtained at the time o f endoscopy. Whatever the size, gross form, and degree of suspicion associated with the lesion, multiple mucosal biopsy specimens from the edges and center, together with cytologic preparations, should be obtained. T h e biopsy specimens f r o m the e d g e are particularly useful in detecting tumors with dysplastic gland formation (fig. 25), which appear to be more directly related to prolonged states o f chronic gastritis. Care must be exercised in distinguishing t u m o r tissue from non-neoplastic epithelial changes o f regeneration and metaplasia. T h e truly dysplastic tissue 2~176 contains cells with a greater increase in nucleocytoplasmic ratio and irregular increases in nuclear chromatin. These are often accompanied by more complex gland formation with a cribiform appearance and by the presence o f a looser and more vascularized stroma as evidence o f t u m o r penetration o f the mucosa (socalled intramucosal carcinoma). Biopsy specimens from fiat or ulcerated areas in particular may occasionally reveal invasion into the submucosa, but it should be stressed that the primary role o f the biopsy is to detect the t u m o r and not the degree o f mural depth. A p r o m i n e n t intestinal metaplasia within.the t u m o r s is o f t e n p r e s e n t , r e s e m b l i n g i n t e s t i n a l adenocarcinomas. Goblet-type mucous cells and occasional Paneth cells may be present, and mucin stains reveal a mixture o f gastric and intestinal-type mucus witlfin the t u m o r cells? ~176 We have noted in recent years that about 39 per cent o f cases o f gastric carcinoma in o u r hospital are composed in large part o f signet-ring cells, tgz T h e r e fore, special attention should be directed to the detection o f such cells in the lamina propria o f the tumors (fig. 26). T h e malignant signet-ring cells may

be few in n u m b e r and confused with mucin-fiiled" macrophages, but they are readily identifiable by t h e i r i r r e g u l a r a n d h y p e r c h r o m a t i c nuclei. Carcinomas with m a n y signet-ring cells are more often associated with an infiltrative growth pattern, and t u m o r cells may be more easily fbund in areas o f ulceration. Since signet-ring t u m o r cells may occasionally be seen in other malignant tumors, including leiomyosarcomas and lymphomas, it is advisable to obtain epithelial mucin stains such as the PAS reaction or mucicarmine to confirm a carcinoma in the absence o f obvious gland formation. In addition to facilitating the specific t u m o r diagnosis and providing evidence of mucosal extent in cases with overt gross lesions, endoscopy with mucosal biopsy can be of considerable aid in monitoring patients who are at increased risk for carcinoma, including patients with diffuse gastric atrophy and pernicious anemia and patients who have had a distal subtotal gastrectomy and gastrojejufi0stomy, usually for peptic ulcer disease? 36-ta9 Some'. degree o f bile reflux and c h r o n i c gastritis in the prokimal gastric stump and a definite increase in adenomas and carcinomas invariably develop in the latter patients after ten to 15 years. It has been estimated that these neoplastic lesions occur in about 3 per cent of patients 15 years after the original gastric surgery, and it is expected that the reported incidence will increase as more extensive follow-up studies are p e r f o r m e d . In such lfigh-risk patients, it would seem p r u d e n t to provide annual endoscopic examination with biopsy starting ten years after surgery in o r d e r to detect gross lesions o f early cancer, and to obtain r a n d o m biopsy specimens in o r d e r to identify areas o f severe dysplasia. Although the findings o f prospective studies regarding therapy of dysplastic lesions in the stomach are not yet available, the presence and persistence of such lesions may well justify removal of the residual stomach.

Other Gastric Tumors Endocrine cell or carcinoid tumors o f the stomach are u n c o m m o n , 2~ but an increased incidence of these tumors together with gastrin-cell hyperplasia has been noted in patients with severe chronic gastritis and pernicious anemia. 2x2-~t4 T h e diagnosis can be established by argyrophilic and argentaffin stains, a n d - t h e specifc cell type can be identified by imm u n o p e r o x i d a s e stains. 2~5 However, since most o f these tumors are localized at the base o f the mucosa,

439

HUMAN I'ATHOLOGY--VOLUME 13, NUMBER 5 May 1982 they may be missed in superficial biopsy specimens. More often noted are variable numbers of endocrine cells in tumors that are predominantly adenomas or adenocarcinomas,2~6-2~8 and there has been a recent proliferation of terms such as adenocarcinoid or goblet-cell carcinoid to describe such tumors. These composite tumors are more common in the colon 2~8-22~ and the appendix, ~2~a2-~ and their behavior is probably equivalent to ttmt of the pure adenocarcinomas. 22~ T h e e n d o c r i n e cells are dispersed as single cells or small clusters within the carcinoma glands, and they usually can be appreciated by their basal location and the fine red granules within the cytoplasm. Paneth cells also contain cytoplasmic eosinophilic granules and may be present in carcinomas, 224 but these tend to have larger and more refractile granules and be situated adjacent to the glandular lumen. A large variety o f submucosal and other mural nodules may be seen in the stomach;, the more common are ectopic pancreas, leiomyoma, and lipoma. 22~-227 These can be seen readily on endoscopy, but mucosal biopsy specimens show only the compressed and partially atrophic overlying mucosa. The major role of biopsy in these cases, as in cases of esophageal tumors, is to exclude a primary mucosal lesion. T h e malignant stromal lesions, the most common o f which is the leiomyosarcoma,227"22stend to be larger and often cause ulceration o f the adjacent mucosa; biopsies performed preferentially in the ulcerated area can be diagnostic (fig. 27). Additional mural lesions that may extend into the mucosa include leukemias, mycosis fungoides, Kaposi tumors, and metastatic tumors mainly o f breast origin and melanomas. 79 Malignant lymphoma may be a localized or diffuse lesion limited to the stomach, or it may be part of a more generalized involvement of the gastrointestinal tract or o f systemic disease. 2z~-232 When confined to the stomach, lymphomas often cannot be readily distinguished grossly from tim more common adenocarcinomas. Since a lymphoma tends to be concentrated in the wall of the stomach, the most accurate diagnosis is made possible by taking the mucosal biopsy specimen from an ulcerated area. I f lymphoma is suspected on the basis of clinical findings or prior biopsy results, it is desirable to place some tissue in Bouin solution or a related fixative for improved nuclear morphology, and to obtain additional material for uhrastructural examination. As with evaluation of lymphomas located elsewhere, the histologic study can be facilitated by the use o f thinner sections and special stains such as the Giemsa stain a n d tim PAS reaction. In a d d i t i o n , immunoperoxidase stains for the identification of cellular immunoglobulins can be utilized. 233 Considerable difficulty may be encountered in distinguishing lymphoma from florid inflammation in the small biopsy specimens, and it is best to require that the cells be relatively large and monomorplfic before a diagnosis of lymphoma is made (fig. 28). In other

440

instances, the specimen will disclose a malignant tumor, but with the small biopsy specimen it may not be possible to distinguish a lymphoma from an undifferentiated carcinoma. Immunoperoxidase staining and electron microscopy are very useful in such cases. Tumor-like Lesions

Xanthelasmas of the stomach, which are uncommon, are small, usually multiple yellow nodules in the mucosa. 234'235 Biopsy reveals clusters of macrophages with lipid-rich foamy cytoplasm in the lamina propria, which can be distinguished from muciphages by the absence of mucus on special stains. Xanthelasmas are not related to hyperlipidemic lesions and have no apparent clinical significance. It has been suggested that they represent sequellae of localized areas of mucosal hemorrhage. Malacoplakia of the digestive tract usually affects the colon, but rare cases have been recorded in the esophagus and stomach. 236"237 It is thought to result from defective monocyte function with promotion of infectious agents. 23s The gut disorder may occur in persons of any age, including children; the characteristic early gross lesions are plaques with small central ulcers. More advanced cases show extensive fistulas, perforation, and obstruction. Histologic examination is specific,~39a4~ re~jea!ing masses of macrophages with n u m e r o u s e9larged lysosomes and mineral-encrusted inclusio'fis.. (Michaelis-Guttman bodies). These cellular features are best seen by means of the PAS reaction for lysosomes and stains for iron or calcium to identify the inclusions. Gastritis cystica profunda is a localized or confluent polypoid area of gastritis with surface and glandular epithelial hyperplasia and often prominent cystic glands. T M It is distinguished from a hyperplastic polyp by the presence o f mature glands extending into the gastric wall, usually into just the submucosa. These lesions are less common than equivalent lesions affecting the rectum, 2~2 and their pathogenesis is not known. Superficial mucosal biopsy of such lesions usually fails to identify the characteristic submucosal component and is typically performed instead to exclude a neoplastic growth. Submucosal glands, if seen, nmst be distinguished from a well-differentiated early gastric cancer, which will show definite epithelial dysplasia and tumor stroma. Pseudolymphoma is a florid l y m p h o i d inflammatory lesion that may be confused with lympholna. z43'244 This designation, if used at all, should be limited to the complete lesion. With multiple sections of the mucosal biopsy, tim inflammatory nature can be suspected by noting the presence of plasma cells and the absence o f masses o f large lymphoid elements. In reporting the results of mucosal biopsies in such cases, it is advisable to avoid the use of the term pseudolymphoma and~note instead whether tim features indicate an inflammatory or neoplastic lesion.

MUCOSAL BIOPSY OF UPPER ALIMENTARY TRACT--Got.DXm.~ AND AN'roNIOL! MUCOSAL BIOPSY OF THE pROXIMAL D U O D E N U M

T h e m u s o c a l structure of the proximal duodenum (fig. 29) is generally similar to that of the jejunum, with tall villi and short crypts, except for the additional presence of Brunner glandsY ,z45 T h e villous epithelial cells include the columnar absorptive cells and the less frequent goblet mucous cells, which are rich in acid mucins. Within the crypts are the proliferative cells, the immature forms o f absorptive and mucous ceils, and concentrated at the base are the Paneth cells. With fixatives containing picric acid, such as Bouin solution, the characteristic bright red granules of the Paneth cells remain unstained and appear as irregular vacuoles. As in all parts of the gut, there are numerous interspersed endocrine cells, which tend to be localized in the basement membrane region; these contain fine red granules and are best visualized by means of silver stains and specific imnmnocytochenfical techniques. The lamina propria often contains a large quantity of acute and chronic inflammatory cells, a n d occasional mononuclear cells extend into the epithelial layer of the villi. Also present are focal lymphoid nodules, which are covered_by a flattened specialized epithelium, termed microfold or M-cellsYaG The Brunner glands, with their large mucous cells, are concentrated in the submucosa and are not always seen in sxfiall endoscopic biopsy specimens, but foci of smaller Brunner mucous cells may be present at the base o f the mucosa. In contrast to the mucosa of the more distal d u o d e n u m and the j e j u n u m , the mucosa o f the proxinml d u o d e n u m often shows a mild degree of injury characterized by slight villous shortening and reactive crypt hyperplasia. These features may appear in response to the presence o f undiluted acid in this region. A h h o u g h such features might be categorized as a mild duodenitis, they are commonly present in many patients without specific symptoms, and the clinical significance o f tiffs degree o f damage is uncertainY Endoscopic e x a m i n a t i o n with biopsy o f the proximal d u o d e n u m is most commonly performed for evaluating and monitoring patients with suspected duodenal ulcers (see Chronic Peptic Ulcer) or duodenitis. Less often, it is used to detect both primary tumors and tumors from adjacent tissues and, as an initial screening procedure, to detect possible absorption disorders. D UODENITIS

Iia some patients with clinically suspected peptic ulcer, endoscopic examination reveals no ulcer but does reveal vascular alterations such as erythema and variable friability in the duodenal mucosa. These cases have been interpreted grossly as duodenitis, 247'24s and it is believed that they have the same pathogenesis as peptic ulcer but represent a milder form o f injury. Other cases appear to be due to exo-

genous agents including ethanol and drugs, z4'a,2~~ There have been sonae detailed studies o f the histology of the duodenal biopsy specimens in these cases, 25t-zSz but the correlation with gross findings lias been variable. TM It has been our experience that in cases with milder gross alterations, such as erythema only, the histologic features are often nonspecific. This may be due in part to the presence of a mild degree of duodenitis in normal persons, as noted previously, but it is also probable that the morphologic examination is not able to identify milder vascular changes or distinguish them from the traumatic effects of the procedure. T h e more certain histologic features of acute duodenitis (fig. 30) include greater shortening of the villi and crypt hyperplasia, with their ratio approaching 1:1, and degeneration o f the villous epithelium with appearance o f neutrophils and increased lymphocytes in this layer. Since the proper estimate of villous and crypt heights requires welloriented specimens, which are not often available with endoscopic biopsies, the finding of inflamed and degenerated epithelial cells is the most dependable in the diagnosis o f acute duodenitis. In cases o f extreme hyperacidity such as the Zollinger-Ellison syndrome, necrosis with superficial erosions may occur, but this is rare. In addition, epithelial cell hyperplasia and metaplasia may be present in the form Of increased Brunner gland mucous cells and may be associated with the presence of gastric-type'surface mucous cells (fig. 31).~ 5 6 It has been suggested that these epithelial alterations may signify a chronic duodenitis. Other cau.~es of duodenal necrosis and increased inflammation include radiation, 59'2~r stress ulceration, and infections. Biopsy in such cases is used chiefly to identify opportunistic infectious agents such as fungi or cytomegalovirus23,~44,~45 or to exclude tumor. Crohn's disease may uncommonly affect the proximal duodenum, ~49aS~ and biopsy is helpful if the specimen shows a focal ulcer and granulom a. There are also isolated reports of endoscopic biopsies revealing helminthic infections,z6~ localized vascular lesions, 26z and pigment deposition, z6~ MALABSORPTIVE DISORDERS

Malabsorptive disorders are generally evaluated by means o f one or more aspiration-type biopsy specimens o f tile distal d n o d e n u m and jejunum. 5 However, proximal duodenal biopsies may be useful, especially as a screening procedure. Thus, normal mucosal biopsy findings would tend to exclude celiac disease (gluten-sensitive enteropathy), since this in the active and untreated form is a diffuse disorder involving tile duodenum. 261,2G5Conversely, abnormal findings on proximal duodenal biopsy cannot be used as evidence of celiac disease, because celiac disease cannot be distinguished from the more common peptic duodenitis. It is possible that biopsy could be used also to exclude other diffuse disorders of tile small intestine such as tropical sprueY S~ Exception-

441

'

Figure 29 (top left). Biopsy specimen of essentially normal duodenal mucosa. The villi are somewhat irregular in shape. Brunner glands are evident at the base of the specimen (on the right). Figure 30 (top center). Villus in acute duodenitis. The epithelial ceils show degenerative changes and are infiltrated by inflammatory cells. The lamina propria shows a marked increase in inflammatory cells. Figure 31 (top right). Epithelial gastric metaplasia in a duodenal villus. The villous tip is lined by surface-foveolar mucous cells and the sides by intestinal absorptive and goblet cells. Figure 32 (bottom). A, biopsy specimen of duodenal adenoma. The papillary configuration is characteristic of a villous lesion. B, hlgher-power view of duodenal villous adenoma. The epithelial cells have enlarged hyperchromatlc nuclei stratified in the cytoplasm, and there is a decrease in mucin.

ally, duodenal mucosal biopsy may be used to identify Giardia lamblia in patients with reduced gastric acid production 267and to provide direct specimens o f focal areas o f Whipple disease 2Gs or lymphangiectasia. 269 DUODENAL TUMORS

Longer endoscopes that allow direct visualization o f tile d u o d e n u m t h r o u g h its second portion are available, and cannulation o f the papilla o f Vater can be readily accomplished. It is therefore possible to visualize any mass lesions in this area and to obtain biopsy and cytologic specimens. Villous adenomas .with or without carcinoma occur in the d u o d e n u m , chiefly in the second portion including the papilla areaY ~ These a p p e a r as isolated cases or may be associated with adenomatous polyposis coli (Gardner

442

syndrome), ls',~s3,z73,zr4 It is important to distinguish these primary neoplasms from invasive tumors o f adjacent tissues such as pancreatic or biliary carcinomas, since the f o r m e r may be more suitable for extirpative surgery. In this regard, the biopsy may reveal a benign neoplastic c o m p o n e n t (fig. 32), which would serve to identify the mass as a primary lesion, whereas the finding o f carcinoma alone would not be conclusive. Cannulation o f the papilla of Vater has been used extensively to obtain radiographs of tile biliary and pancreatic ducts, and recent studies have showed that the ductal drainages can be used to prepare cytologic smears for t u m o r detectionY 5 Mural tumors in the d u o d e n u m include princi" pally the nodules o f B r u n n e r gland hyperplasia, ectopic pancreas, and mesenchymal lesions. 22~ As in other areas o f ttte gu t, these cannot usually be identi-

MUCOSAL BIOPSY OF UPPER ALIMENTARY TRACT--GoLnXmx AND A,~TO.~IOt.I fled by endoscopic biopsy, which provides samples only o f the overlying, o f t e n a t t e n u a t e d , mucosa. Biopsy is mainly e m p l o y e d to exclude a p r i m a r y m u cosal lesion. L y m p h o m a s o f the small intestine, inchtding b o t h p r i m a r y a n d systemic cases, m a y be manifested as multiple n o d u l e s a n d m a y involve the d u o d e n u m , z29"23~ Direct endoscopic or, m o r e often, rnnltiple aspiration biopsies f r e q u e n t l y can p r o v i d e diagnostic tissue (see Gastric L y m p h o m a ) . CONCLUSION T h e past decade has occassioned the developrnent a n d extensive use o f flexible e n d o s c o p e s for visualization o f large areas o f the a l i m e n t a r y tract. At times it a p p e a r s that we are being besieged by the n u m e r o u s small g r a s p biopsies that are p e r f o r m e d to d e t e r m i n e the diagnosis a n d course o f a large variety o f i n f l a m m a t o r y a n d neoplastic disorders. In this review, we have c o n c e n t r a t e d o n the u s e s ' a n d i n t e r p r e tation o f e n d o s c o p y a n d biopsy o f the u p p e r alimentary t r a c t i n c l u d i n g t h e e s o p h a g u s , s t o m a c h , a n d proximal duodenum. O p t i m a l evaluation requires that the p e r t i n e n t clinical i n f o r m a t i o n a n d particular reason for a biopsy be available and evaluated with the histologic findings. In m a n y instances the biopsy features p r o v i d e a p a t t e r n o f injury, w h i c h - m u s t be c o m b i n e d with the h m c t i o n a l data b e f o r e an intelligent i n t e r p r e t a t i o n can be m a d e . Reports should be responsive to the particular i n f o r m a t i o n sought, including the p r i m a r y diagnosis o r its exclusion, the e x t e n t o r d e g r e e o f disease, the effects o f t h e r a p y , and the a p p e a r a n c e o f complications. At a technical level, it is usually helpful to obtain multiple sections o f each biopsy, a n d special stains are indicated in selected cases. We have also a t t e m p t e d to s h o w t h e l i m i t a t i o n s o f e n d o s c o p i c biopsies with respect to their size, superficial n a t u r e , and i m p e r f e c t o r i e n t a t i o n in the evaluation o f s o m e disorders. P e r h a p s the most challenging a n d p r o d u c t i v e aspect o f mucosal biopsy study has b e e n the histologic indentification o f the earlier stages o f various disorders. We now appreciate the effects of peptic esophagitis that p r e c e d e ulcer and stricture f o r m a t i o n a n d can readily m o n i t o r its course; we are a t t e m p t i n g to detect t u m o r s still c o n f i n e d to the m u c o s a as well as to identify high-risk patients with dysplastic lesions in b o t h the e s o p h a g u s a n d stomach; a n d we have greatly i m p r o v e d o u r diagnostic accuracy in t u m o r s by m o r e directed biopsies c o m b i n e d with cytologic studies. We have a c q u i r e d a n d are a p p l y i n g new i n f o r m a t i o n such as tlmt p e r t a i n i n g to the distribution a n d special app e a r a n c e o f s o m e f o r m s o f esophagitis, the use o f gastric antral biopsy in allergic conditions, the n e e d to obtain biopsies o f ulcerated areas f o r m u r a l t u m o r s , the a p p r e c i a t i o n o f signet-ring cell f o r m s in gastric carcinomas, a n d the ability to r e a c h t u m o r s in the d u o d e n u m . Aside f r o m the obvious satisfaction o f e x p a n d i n g o u r k n o w l e d g e o f gastrointestinal lesions, it is clear that this e x t e n d e d use a n d study o f mucosal

biopsies has c o n t r i b u t e d significantly to the clinical m a n a g e m e n t o f m a n y patients. ACKNOWLEDGMENT We wish to e x p r e s s o u r a p p r e c i a t i o n to Ms. Paula L. C o h e n for h e r e x p e r t secretarial assistance a n d to David G. F r e i m a n , MD, f o r his e n c o u r a g e m e n t a n d advice in the p r e p a r a t i o n o f this m a n u s c r i p t . REFERENCES 1. Morrissey JF: Gastrointestinal endoscopy. Gastroenterology 62:1241, 1972. 2. Colcher H: Diagnostic fiberoptic gastroscopy. JAMA 288:891, 1977. 3. Winawar SJ, Sherlock P, Hajdu SI: The role of upper gastrointestinal endoscopy in patients with cancer. Cancer 37:440, 1976. 4. Trier JS: Diagnostic value of peroral biopsy of the proximal small intestine. N Engl J Med 285:1470, 1971. 5. Perera DR, Weinstein WM, Rnbin CE: Small intestinal biopsy. Hum Pathol 6:157, 1975. 6. Whitehead R: Mucosal Biopsy of tile Gastrointestinal Tract, 2nd Ed. Philadelphia, WB Saunders Co, 1979. 7. Lee FD, Toner PG: Biopsy Pathology of the Small Intestine. Philadelphia, JB Lippincott Co, 1980. 8. Kobayashi S, ProllaJC, KirsnerJB: Brushing cytology of the esophagus and stomach under direct vision by fiberscopes. Acte Cytol 14:223, 1970. 9. Hanson JT, Tborenson C, Morrissey JF: Brush cytology in the diagnosis of upper gastroi1"~testinal malignancy. Gastrointest Endosc 26:33, 1980. 10. Qizilbash AH, Casteli M, Kowalsk] MA, et ah Endoscopic brush cytology and biopsy iff the diagnosis of cancer of the upper gastrointestional tract. Acta Cytol 24:313, 1980. 1I. Geboes K, Desmet V: Histology of the esophagus. Front Gastrointest Res 3:1, 1978. 12. Weinstein WM, Bogoch ER, Bowes KL: The normal buman esopbageal mucosa: a histological reappraisal. Gastroenterology 68:40, 1975. 13. Lightdale CJ, Wolf DJ, Marcucci RA et al: Herpetic esophagitis in patients with cancer: antemortem diagnosis by brush cytology. Cancer 39:223, 1977. 14. Rumfeld W, Jenkins D, Scott BB: Unsuspected gastroesophageal candidiasis: an endoscopic study. Gut 21 :A895, 1980. 15. Kodsi BE, Wickremesinghe PC, Kozinin l:J, et al: Candida esoplmgitis: a prospective study of 27 cases. Gastroenterology 71:715, 1976. 16. SmithJMB: Mycosesof the alimentary tract: Progress report. Gut 10:1035, 1969. 17. Miller DP, Everett ED: Gastrointestinal histoplasmosis.J Clin Gastroenternl 1:233, 1979. 18. Knohe M, Bernhardt H: Endoscopic aspects of mycosisin the upper digestive tract. Endoscopy 12:295, 1980. 19. Lefkowitz M, Elsar JL, Levine RJ: Candida infections complicating peptic esophageal ulcer. Arch Intern Med 113:672, 1964. 20. Nash G, Ross J: Herpetic esophagitis: a common cause of esophageal ulceration. Hum Pathol 5:339, 1974. 21. Buss DH, Scharyl M: lterpes virus infection of the esophagus and other visceral organs in adults. Am J Med 66:457, 1979. 22. Depew WT, Prentice RS, Beck IT, et ah Herpes simplex ulcerative esoplmgitis in a t~ealthy subject. Am J Gast~oenterol 68:381, 1977. 23. Freeman HJ, Shnitzka TK, Piercey JRA, et al: Cytomegalovirus infection of the gastrointestinal tract in a patient with late onset immunodeficiency syndrome. Gastroenterology 73:1397, 1977.

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