polyps

378 Arch Pathol Lab Med—Vol 134, March 2010 Pseudoneoplasms of the Gastrointestinal Tract—De Petris & Leung

Pseudoneoplasms of the Gastrointestinal TractGiovanni De Petris, MD; Stanley T. Leung, MD

● Context.—The pathologist plays the leading role in dis-tinguishing pseudoneoplasms from truly neoplastic lesionsin the gastrointestinal tract.

Objective.—This review was conducted to heighten aware-ness of pseudoneoplasms, to help differentiate among the var-ious types of pseudoneoplasms, and to help distinguish pseu-doneoplasms from malignancies.

Data Sources.—This review is based on the medical lit-erature on pseudoneoplasms in MEDLINE and the authors’own experiences. Reference lists of retrieved articles werealso reviewed to identify additional articles.

Conclusions.—A classification of pseudoneoplasms, ac-cording to the mechanism of injury to the gastrointestinaltract, morphologic patterns, and heterotopia, may be use-ful in providing a diagnostic framework in which ancillarytechniques often have a diagnostic role. Several pseudo-neoplasms may be closely associated with true neoplasms(eg, malakoplakia, prolapsetype lesions) because of thenonspecific nature of the response of the intestine toinjury.

(Arch Pathol Lab Med. 2010;134:378–392)

Pseudoneoplasms of the gastrointestinal tract are unusu-ally alarming lesions that result from morphological-

ly worrisome outcomes of the gut’s response mechanismsto injury or from the heterotopic nature of the tissue. Theymay manifest as abnormal intestinal soft tissue reactivechanges (eg, inflammatory fibroid polyp [IFP]), exuberantprolapse-induced changes (eg, colitis cystica profunda),unusual-appearing cellular changes (eg, malakoplakia, bi-zarre stromal cells [BSC], or benign signet ring cells), andmorphologic findings made unusual by their location (het-erotopias). The goal of this necessarily short review is toaid the practicing pathologist by heightening awareness ofthese conditions and by helping differentiate among themand distinguish them from malignancies. The histopath-ologic features of pseudoneoplasms by abnormal patternsof response and heterotopias are discussed, with partic-ular emphasis on inflammatory fibroid polyp, malakopla-kia, atypical cellular infiltrates, and prolapse-related pa-thology. Because the gut reacts to insults with a limitedrepertoire of tissue changes, it is not surprising that manypseudoneoplasms can appear in association with, or be-cause of, a malignancy.

Pseudoneoplasms of the gastrointestinal tract can beclassified by their most likely location (Table 1) or by use-ful histopathologic or etiologic features (Table 2). Whereasnumerous conditions in the gut may be considered pseu-doneoplastic because of endoscopic or radiologic manifes-tations, this review focuses mainly on entities selected for

Accepted for publication November 5, 2008.From the Division of Anatomic Pathology, Mayo Clinic, Scottsdale,

Arizona (Dr De Petris), and the Division of Anatomic Pathology, MayoClinic, Rochester, Minnesota (Dr Leung).

The authors have no relevant financial interest in the products orcompanies described in this article.

Reprints: Giovanni De Petris, MD, Division of Anatomic Pathology,Mayo Clinic, 13400 East Shea Blvd, Scottsdale, AZ 85259 (e-mail:[email protected]).

their histologic mimicry (and the resulting possibility ofdiagnostic pitfalls) and for their clinical relevance.

PSEUDOSARCOMAS OF THEGASTROINTESTINAL TRACT

Inflammatory Fibroid Polyp

Inflammatory fibroid polyp is a rare mesenchymalpseudoneoplasm of the digestive system with unclear his-togenesis. First found in the stomach by Jiri Vanek in1949,1 it was initially called submucosal granuloma with eo-sinophilic infiltration. It has subsequently been identified inthe duodenum, small intestine, esophagus, colon, rectum,and gallbladder. The most common site is the stomach,especially the antrum, where it often appears as a polyp(�4.5% of all gastric polyps are IFPs)2; the next-most-com-mon site is the small intestine. Inflammatory fibroid pol-yps of the esophagus (where they are more likely to occurin the distal third) and of the colon (where they are morelikely in the cecum) are uncommon, whereas IFPs are ex-ceptionally rare in the gallbladder. The familial occurrenceof IFP, unique to date, has been described in a Devon fam-ily (Devon polyposis syndrome).3 Inflammatory fibroidpolyps occur in adults, with a peak incidence occurringbetween ages 60 and 70 years. The size may reach 5 cm.4

Clinical presentation depends on the size and locationof the lesion. Gastric IFPs cause epigastric pain and bleed-ing, whereas colicky pain, occult bleeding, and intussus-ception are associated with intestinal IFPs. Duodenal IFPscan cause obstruction of the common bile duct, and me-lena and dysphagia have been reported in esophagealIFPs.

Microscopically, an IFP appears as a submucosal prolif-eration of mononucleate and monomorphic, bland, spin-dle, and stellate cells in fibromyxoid stroma with an in-flammatory infiltrate often dominated by eosinophils (Fig-ure 1).5,6 Nuclear pleomorphism is considered quite un-usual.6 In a substantial minority of cases, multinucleatedgiant cells are also observed (Figure 2, A). Lymphoid fol-

Arch Pathol Lab Med—Vol 134, March 2010 Pseudoneoplasms of the Gastrointestinal Tract—De Petris & Leung 379

Table 1. Pseudoneoplasms in Various Portions of theGastrointestinal Tract

Site Pseudoneoplasm

Entire alimentary tract Inflammatory fibroid polypXanthomaLipoma-like lesionsEctopias and heterotopiasPseudotumors due to infectionsBenign signet ring cells infiltrate

Esophagus Fibrovascular polypMelanosis of the esophagusPseudodiverticulosis

Stomach Gastritis cystica profundaInverted hyperplastic polypRussell bodies gastritis

Intestines Mucosal prolapse-related lesionsMalakoplakiaTumefactive endometriosisProlapsing mucosal folds of divertic-

ular diseaseHypertrophic and papillaElastofibromatous lesions

Data from Fitzgibbons.93

Figure 1. Inflammatory fibroid polyp. Typical components are nu-merous eosinophils in the background of a proliferation of bland spin-dle cells with prominent vasculature and loose stroma (hematoxylin-eosin, original magnification �200).

Table 2. Useful Histopathologic or Etiologic Featuresof Intestinal Pseudoneoplasms

Pseudoneoplasm Feature

Pseudosarcomas Granulation tissuelikeBizarre stromal cellsVascular proliferationsElastofibromatous abnormalitiesLipomatous changes

Cellular infiltrate ofbenign cells

Eosinophilic cellsFoamy cellsSignet ring cellsLymphoid nodules and hyperplasiaMelanocytesBizarre stromal cells

Prolapse and entrap-ment

Mucosal prolapse syndromesEntrapment of glands

Gastritis cystica profundaEnteritis cystica profundaColitis cystica profunda

Entrapment of airPneumatosis intestinalisPseudolipomatosis

Heterotopias Normal tissue in unusual sitesDiseases of the ‘‘normal’’ tissue ap-

pearing in unusual sites

licles, plasma cells, mast cells, and a regular network ofvariably sized blood vessels are present. Spindle-shapedcells are occasionally concentrically arranged (onion skin-ning) around vessels and mucosal glands; this is betterdemonstrated in the stomach than in other sites. Inflam-matory fibroid polyps originate in the submucosa and canextend throughout the entire thickness of the wall of theintestine. Because of its submucosal origin, an IFP presentsas a sessile or polypoid lesion without a stalk. In the smallintestine, it may assume a dumbbell shape, perhaps be-cause of intussusception (Figure 2, B). The overlying mu-cosa is often ulcerated. Grossly, IFPs may cause splitting,fraying, and atrophy of the muscularis propria.7 Distincthistologic patterns have been described for gastric IFPs (ie,classical, fibrovascular, nodular, sclerotic, and edema-tous).8 There is some evidence that the histologic pattern

of gastric and small bowel IFPs may be determined by theage of the lesion. Smaller lesions have a better-developed,concentric distribution of spindle-shaped cells (Figure 2,C and D), and as the lesion grows, the dominant histologictype progresses through the different phases to becomesclerotic in larger IFP.8 Different histologic patterns maycoexist in the same lesion, and the edematous pattern hasbeen suggested as an artifact of intestinal obstruction.8

The CD34 immunostain is the most useful immunostainto confirm the diagnosis of IFP. The stromal cells of IFPstain positive for CD34, especially around vessels (Figure2, C). Occasionally, CD34 stain is negative, especially incases with no onion skinning in the small bowel, whichmay represent older evolutionary stages of the lesion.4 Theexpression of fascin, CD35, cyclin D1, vimentin, and cal-ponin is also found. A few IFP express smooth muscleactin; CD117 is negative (although mast cells in the lesionwill be positive), and no abnormalities of exons 9 and 11of the c-kit gene have been found.4 The S100 protein is notpresent. Pantanowitz et al9 demonstrated uniform stainingfor CD35 and overexpression of cyclin D1. They concludedthat the proliferating stromal cells are of dendritic cell or-igin with myofibroblastic differentiation and a possible de-fect in cell cycle regulation. Electron microscopy revealsno specific findings.10

The reactive rather than the neoplastic nature of thislesion is suggested by its low mitotic activity, low recur-rence rate, absence of necrosis, and metastases. Inflam-matory fibroid polyp may be a form of reparative tissueresponse to injury. The detection of IFP in association withCrohn disease,11 diaphragm disease,12 previous surgery,13

and areas adjacent to carcinoma14 supports this hypothe-sis. Genotype profiling of 12 predominantly gastric IFPsshowed no loss of heterozygosity at any of 14 commonlyanalyzed tumor suppressor gene loci,15 strengthening theview that these lesions are not neoplastic. Symptom treat-ment and resolution of diagnostic uncertainty may requiresurgical resection of the IFP. Endoscopic polypectomy isthe ideal technique for polypoidal and accessible lesionsin the stomach and colon. However, because IFPs arisefrom the submucosa and may be sessile, there is risk ofperforation or incomplete resection after endoscopic treat-


Figure 2. Inflammatory fibroid polyp. Features include A, multinucleated giant cells; B, dumbbell shape; and C and D, circumferential arrangementof constitutive cells around vessels (hematoxylin-eosin, original magnification �200 [A and D], with reactivity for CD34 immunostain, originalmagnification �200 [C]). Figure B courtesy of Thomas C. Smyrk, MD, Mayo Clinic, Rochester, Minnesota.

ment. It is unclear whether the occasional reported recur-rence of IFP after attempted removal is due to incompleteexcision.16

The differential diagnosis includes the various mesen-chymal tumors of the gastrointestinal tract (Table 3) andinflammatory conditions (eg, granulation tissue or eosin-ophilic inflammatory processes). The abundant inflam-matory component of the IFP is distinctive and easily dif-ferentiates it from leiomyoma and desmoid. Eosinophilicgastroenteritis does not form masses and consists of eo-sinophilic infiltrates in the various layers of the gut, main-ly in young patients with a history of asthma and periph-eral eosinophilia. Inflammatory myofibroblastic tumor(IMT) is a myofibroblastic neoplasm that, like IFP, showsan admixture of inflammatory infiltrate with spindle-shaped cells set in myxoid or collagenized stroma (Figure3) with occasional large cells resembling histiocytes organglions. The distinction between IFP and IMT is rele-vant because IMT is a neoplasm of intermediate biologicpotential with occasionally aggressive behavior and asmuch as a 25% rate of recurrence.17–20 Inflammatory my-ofibroblastic tumor occurs mainly in the soft tissue of theabdomen, retroperitoneum, and lung; it rarely arises inthe gastrointestinal tract.17,18 Coffin et al17 identified 3 main

histologic patterns in IMT: (1) myxoid, resembling gran-ulation tissue, and often rich in inflammatory cells; (2)compact spindle cells, resembling fibromatosis or fibroushistiocytoma; and (3) a dense collagen in a platelike pat-tern.17 These patterns can be found within the same tumor.Eosinophils can be prominent in IMT, especially in themyxoid subtype resembling fasciitis, but plasma cells arethe most common inflammatory cells overall.

Makhlouf and Sobin18 have shown that IMT and IFPhave different clinical, histopathologic, and immunohis-tochemical features. Inflammatory myofibroblastic tumoris less common and typically forms larger tumors thanIFP. Persons affected by IMT are younger than those withIFP. Inflammatory myofibroblastic tumor is associatedwith systemic symptoms (eg, fever, abdominal pain, andweight loss) more commonly than IFP, which more oftenpresents with bowel obstruction. Plasma cells predomi-nate most commonly in IMT, whereas eosinophils are nu-merous in IFP. Perivascular onion skinning in IMT is muchless pronounced in the stomach. Immunophenotypically,IMT reacts more commonly than IFP for smooth musclemarkers (86% versus 13%)18 but fails to express CD34. Im-munohistochemical expression of anaplastic lymphoma ki-nase occurs in IMT19,20 and is detected in 50% to 60% of


Table 3. Mesenchymal Lesions of the Gastrointestinal Tract

Lesion Location Site IHC Diagnostic Features

IFP Submucosal Antrum, SB, co-lon, E

CD34�, CD35�, CD117�,S100�, SMA� in �50%of cases

Dumbbell shape; eosinophilic infiltrate; peri-vascular onion skinning; loose stroma; regu-lar vascular pattern; heterogeneous cellpopulation

GIST Mural (Muscu-laris pro-pria)

Stomach, SB, co-lon, E

CD117�, CD34�, CK7� Nonprotruding; cellular, spindly, and epitheli-oid cells; perinuclear vacuolization; nuclearpalisading; homogeneous cell population

IMT Mesenteric,rarely mural

Colon, SB, stom-ach, E

CD34�, ALK� (50% of cas-es), SMA�

Young patients; large tumor; diffuse inflamma-tion with plasma cells often dominant; mul-tiple patterns; scattered ganglion-like cells

Schwannoma Mesenteric,rarely mural(M propria)

Stomach, colo-rectum, E, SB

S100� (strong and diffuse),SMA�, CD117�, CD34�,GFAP�

Peripheral lymphoid cuffing

Fibroblastic polyp Mucosal Left colon S100�, CD117� (faint orrare), CD34�

Separates crypts that may be serrated; mayspare upper mucosa; it may, in fact, be peri-neurioma

Mesenteric fibro-matosis

Mesenteric,retroperito-neal

SB, colon, stom-ach secondaryinvolvement

�-catenin�, CD34�,SMA�/�, desmin�/�,CD117 (usually �)

Infiltrative borders; low cellularity; collagendeposition; no cystic degeneration or necro-sis; small muscular arteries and dilated thinveins with sparse perivascular lymphocytes

Perineurioma Mucosal, sub-mucosal

Left colon, jeju-num

EMA�, claudin-1� (50% ofcases), GLUT1�, S100�,CD117�

Entraps hyperplastic glands; bland spindlecells with pale eosinophilic cytoplasm; nolymphoid cuffing

Synovial sarcoma Mucosal, sub-mucosal

Esophagus, stom-ach

CD117�, AE1/AE3�,CD34�, S100�, CK7�

Rare tumor; high cellularity; tapestry patternwith ropey collagen; SYT-SSX gene fusiontranscript present

F and I dendriticcell sarcoma

Mesenteric or,rarely, mu-ral

Stomach, duode-num, SB, co-lon

F: CD21�, CD35�; I: S100� Rare; evenly distributed inflammatory infiltrateadmixed with spindle cells

Leiomyosarcoma Mural Rare; found fromesophagus torectum

SMA�, desmin� (70%–100%), CD117�, CD34�,�-catenin�, S100�

Cellular atypia; mitotic activity high (�50/50HPF) in most cases

Abbreviations: �, negative; �, positive; �/�, positive �50% of the time; �/�, negative �50% of the time; ALK, anaplastic lymphoma kinase; E,esophagus; F, follicular; GFAP, glial fibrillary acidic protein; GIST, gastrointestinal stromal tumor; HPF, high-power field; I, interdigitating; IHC,immunohistochemistry; IFP, inflammatory fibroid polyp; IMT, inflammatory myofibroblastic tumor; SB, small bowel; SMA, smooth muscle actin.

Figure 3. Inflammatory myofibroblastic tumor. Typical features areplump, ovoid myofibroblastic cells with pale eosinophilic cytoplasm ina collagenous background with numerous lymphocytes and plasmacells and few eosinophils (hematoxylin-eosin, original magnification�200).

cases. No study of anaplastic lymphoma kinase expressionin IFP has been published to date, to our knowledge.

Fibroblastic polyp is a recently described bland prolif-eration of mitotically inactive, vimentin-positive fibroblas-tic cells in the lamina propria of the left colon21 (Figure 4,A). The colonic crypts are widely separated by the prolif-eration and may be serrated. Fibroblastic polyp presentsas a small polyp with no specific disease or associatedsymptoms. In the original report by Eslami-Varzaneh etal21 of 14 cases, the cells showed rare, focal CD34 and actinimmunoreactivity but were negative for S100, epithelialmembrane antigen, c-kit, CD31, and desmin. The spindlecells may spare the upper aspect of the lamina propriaand may show a focal pericryptal and perivascular con-centric arrangement similar to that of IFP or perineurio-ma; however, they do not seem to extend into the sub-mucosa.22

Perineuriomas in the intestine, most often in the left co-lon, have recently been described.23 They are composed ofbland spindle cells with ovoid to tapered nuclei (Figure 4,B) and weakly eosinophilic cytoplasm that may involvethe mucosa and the submucosa. They characteristicallysurround hyperplastic colonic glands and express epithe-lial membrane antigen and claudin-1 but are negative forS100, neurofilament, and CD34. Relying on histologicfindings alone makes it difficult to distinguish between aperineurioma and a fibroblastic polyp. Groisman and Po-lak-Charcon24 recently suggested that fibroblastic polypand perineurioma of the colon represent the same entitybecause of additional ultrastructural evidence (the pres-

ence of external lamina and long, slender cytoplasmic pro-cesses with pinocytotic vesicles) and immunohistochemi-cal evidence (epithelial membrane antigen immunoposi-tivity when high antibody concentration and modified an-tigen retrieval are applied, and GLUT-1 and collagen IVimmunopositivity are found in fibroblastic polyp).


Figure 4. A, Fibroblastic polyp; bland spindle cell proliferation, limited to mucosa, sparing the upper lamina propria. Note the serration of crypts.B, Perineurioma of sigmoid colon; whorls centered on crypts (hematoxylin-eosin, original magnifications �200).

Bizarre Stromal CellsThe presence of BSC has been noted in many different

organ systems (eg, upper respiratory tract, urinary blad-der, endometrium and lower gynecologic tract, prostate,and gut) in association with granulation tissue and in be-nign inflammatory polypoid lesions and ulcerated muco-sa. Large cells that may be spindled, stellate, or epithelioidmake up BSC; they have an alarming vesicular nucleo-megaly, nuclear pleomorphism, and occasional multinu-cleation (Figure 5). The amount of cytoplasm, which isusually eosinophilic, varies. Bizarre stromal cells can bewidely scattered or clustered along the base of an ulcer.They may resemble cells infected with cytomegalovirus organglion cells and, thus, may be so strikingly atypical thatthe differential diagnosis includes malignant cells of high-grade carcinoma, sarcoma, and melanoma. In the gut, BSChas been found in ischemic colitis,25 in esophageal polyps,in the distal esophagus in patients with reflux esophagitis,in gastric ulcers, in pseudopolyps of inflammatory boweldisease, in granulation tissue near surgical anastomoses,and in anal fibroepithelial polyps.26 Mitoses are rarelyfound in BSCs but are not atypical. Immunohistochemicaltests reveal reactivity for vimentin and occasionally forsmooth muscle actin, consistent with a fibroblastic or my-ofibroblastic cell origin.

Pseudoneoplastic Vascular Proliferations of theGastrointestinal Tract

The proliferation of benign capillaries in the gut cangive origin to visible lesions and can be sufficiently floridto mimic neoplasms. Benign vascular proliferations havebeen found in association with gastrointestinal tumors(benign and malignant) and intussusception with ulcera-tion. They are often accompanied by microscopic changescaused by prolapse27–29 (Table 4). Intermittent ischemicdamage to the mucosal and submucosal layers that occursduring intussusception or prolapse may give rise to exu-berant vascular proliferation in the granulation tissue thatcan be misinterpreted as neoplastic, especially on biopsyspecimens.28 Paraneoplastic florid angiogenesis of the mu-cosa surrounding an ileal carcinoid may cause multiplesmall polyps. These changes have been ascribed to angio-genic factors secreted by the tumor.30 The distinction from

angiosarcoma is based on the clinical history (angiosar-coma is a rare primary neoplasm of the intestine), on thelobular arrangement of the capillary proliferation found inbenign conditions (reminiscent of pyogenic granuloma),and on cytologic features. The endothelial cells lack sig-nificant hyperchromasia and nuclear pleomorphism,whereas mitotic figures are encountered infrequently andare not atypical in benign vascular proliferations. Muscu-lar fibroplasia of the mucosa (an indication of prolapse),in association with vascular proliferation, should alert thepathologist to the possibility that the vascular lesion maybe a benign reactive condition.

Elastosis and Elastofibromatous Abnormalities of theGastrointestinal Tract

Elastosis (diffuse or focal increase in elastic fibers in thesubmucosal and muscularis mucosae layers of the gut)and elastofibromatous change (if there is an accompany-ing increase in fibrous tissue) are harmless abnormalitiesthat can occasionally develop in the alimentary tract andmay form polypoid lesions. Hobbs et al31 found that mostcases (10 of 13; 77%) of elastosis or elastofibroma occurredin the colon. In 8 of 13 patients (62%), they manifested asyellow or lipoma-like polyps, sometimes with large sub-mucosal vessels (3 of 13; 23%). These changes do not sim-ulate a neoplasm but are indistinguishable from amyloid-osis on routine hematoxylin-eosin staining. They appearas granular or fibrillar, amphophilic, pale eosinophilic togray material occasionally centered on blood vessels. Anegative Congo red stain and a strongly positive elastinstain are diagnostic. The etiology is unclear, but elastosisor elastofibroma may be related to previous injury.

CELLULAR INFILTRATE OF BENIGN CELLSBenign Eosinophilic Cell or Pink Cell Infiltrates

Malakoplakia. Malakoplakia is the best example of apseudoneoplasm characterized by an eosinophilic cell in-filtrate. Diseases consisting of an infiltrate of eosinophiliccells in the alimentary tract are listed in Table 5.

Malakoplakia is a rare condition (fewer than 500 casesin the United States as of 2007),32 but this well-character-ized inflammatory disease has been well described sinceit was first mentioned in 1902 by Michaelis and Gut-


Figure 5. Bizarre stromal cells. Large cells with nucleomegaly, prom-inent nucleoli, and eosinophilic cytoplasm form a small cluster in aninflamed gastric polyp (hematoxylin-eosin, original magnification�400).

Figure 6. Malakoplakia of colonic mucosa. Typical infiltrate of eosin-ophilic histiocytes (von Hansemann cells) containing identifiable Mi-chaelis-Gutmann bodies (inset, hematoxylin-eosin, original magnifi-cation �400) with typically round shape and darker core (hematoxylin-eosin, original magnification �100).

mann.33 Malakoplakia affects people along the entire agespectrum (6 weeks to 88 years), but pediatric cases arerare.32 It occurs most frequently in the genitourinary tract(about 60% of cases) but is also found in many other or-gans (eg, gastrointestinal tract, lungs, liver, pancreas,lymph nodes, adrenal gland, skin, salivary glands, andbrain), with the gastrointestinal tract being the second-most-common site.32 In the intestine, it occurs most fre-quently in the descending colon, sigmoid, and rectum; itis found less commonly in the terminal ileum, stomach,appendix, and cecum.

Malakoplakia is composed of sheets of oval histiocyteswith abundant granular eosinophilic cytoplasm (von Han-semann histiocytes) that contain basophilic, periodic acid–

Schiff (PAS)–positive, diastase-resistant inclusions, andcalcified Michaelis-Gutmann bodies (Figure 6). These of-ten have a targetoid appearance with a darker central coreand can also be extracellular. Michaelis-Gutmann bodiesstain blue with hematoxylin-eosin and are positive for cal-cium and iron with the von Kossa stain and the Perls stain,respectively. The histiocytes stain positively for the CD68antibody and for �1-antichymotrypsin. Gram stain mayidentify gram-negative bacteria. Electron microscopy hasshown curved membrane-bound phagolysosomes con-taining whorled and parallel lamellar phospholipids inthe histiocytes.34

The pathogenesis of malakoplakia is not completely un-derstood, but evidence34–36 supports the hypothesis thatimmunosuppression associated with defective phagoly-sosomal digestion of bacteria is necessary. The defectivebacterial digestion seems related to decreased intracellularcyclic guanosine monophosphate (cGMP). DecreasedcGMPs alter microtubule function and lower the releaseof �-glucuronidase, with resulting impairment in phago-lysosomal digestion. Michaelis-Gutmann bodies appearsin phagolysosomes by sequential, concentric calcificationsaround bacterial debris, caused by deposition of calciumand iron on the bacterial glycolipids. An altered or defi-cient immunoresponse is a contributing factor in the de-velopment of malakoplakia. Gram-negative bacteria, suchas Escherichia coli and Klebsiella pneumoniae, are the mostcommon bacteria involved in the genesis of malakoplakia.Interestingly, different bacteria are implicated in differentclinical conditions (eg, Rhodococcus equi and Pasteurellamultocida are associated with malakoplakia in acquiredimmunodeficiency syndrome).37,38

The gross appearance varies from unifocal, multiple,and even widespread nodular lesions to a large, soft, yel-low (at least initially) mass, usually covered by intact mu-cosa that may be centrally depressed.39,40 Symptoms atpresentation may be absent or may include abdominalpain, hemorrhage, diarrhea, obstruction, and, in extensivedisease, fistulae. Malakoplakia can be found in associationwith several diseases in the alimentary tract (Table 6). Inparticular, as many as 30% of cases of malakoplakia arereported to be associated with colonic adenocarcinoma.41

Malakoplakia can be the origin of clinical conditionsthat mimic an aggressive neoplasm (eg, involvement of anorgan and its regional lymph nodes, extension into an ad-jacent organ, appearance after treatment of adenocarci-noma, and involvement of multiple organs mimicking me-tastases). Erroneous clinical upstaging of carcinoma be-cause of coexisting malakoplakia involving lymph nodesor other organs is a possible clinical pitfall. As with otherpseudoneoplasms of the gastrointestinal tract, it is impor-tant to be aware that the diagnosis of malakoplakia mayindicate an associated malignancy.

Other Eosinophilic Pink Cell Infiltrates. Crystal-stor-ing histiocytosis and Russell bodies gastritis are amongthe most unusual conditions composed of eosinophiliccells in the gastrointestinal tract. Crystal-storing histiocy-tosis is characterized by an infiltrate of eosinophilic his-tiocytes containing crystalline material.42–46 It mainly in-volves bone marrow and lymph nodes but has been de-scribed in lung, thyroid, kidney, and soft tissue. In thegastrointestinal tract, crystal-storing histiocytosis has beendiagnosed in the stomach44 and colon,46 where it can formpolypoid lesions. Crystal-storing histiocytosis of the gas-trointestinal tract is usually associated with an underlying


Table 4. Pseudoneoplastic Vascular Proliferation of the Gut

Entity Site Association

Endoscopicand GrossFindings Diagnostic Features

Benign vascular proliferationof the colon in intussuscep-tion and mucosal pro-lapse27,28

Colon (cecumfavored)

Mucosal prolapse, intussuscep-tion, A-V malformation, lipo-ma leading to intussuscep-tion

Colonic mass Lobular proliferation of small vas-cular channels from submucosathrough thickness of entire in-testinal wall; features of muco-sal prolapse

Angiogenic polypoid prolifer-ation of the small bowel29

Small bowel,adjacent toneoplasm

Small-intestine neoplasm (carci-noid, primary and metastaticadenocarcinoma, GIST, lym-phoma) and prolapse

Sessile polypsadjacent totumor

Club-shaped villi with prominentintramucosal capillaries; fea-tures of mucosal prolapse

Abbreviations: A-V, arteriovenous; GIST, gastrointestinal stromal tumor.

Table 5. Pathologic Processes Characterized byInfiltrates of Eosinophilic Cells or Foamy Cells in the

Alimentary Tract

Infiltrate Pathologic Process

Eosinophilic cells MalakoplakiaCrystal-storing histiocytosis

Plasma cell dyscrasiasLymphoproliferative disordersClofazimine-induced histiocytosisEosinophilic colitis

Russell bodies gastritisGranular cell tumorDecidual reactionHistiocytic infiltrate of infections

Foam cells XanthomaMuciphagesWhipple diseaseInfections

HistoplasmosisRhodococcus equiMycobacterium avium–intracellulare

complexMelanosis coliHereditary metabolic storage disorders

Table 6. Gastrointestinal Conditions Associated Withthe Pseudoneoplasms Malakoplakia or Benign

Epithelial Signet Ring Cells

Pseudoneoplasm Gastrointestinal Condition

Malakoplakia Adenocarcinoma and adenoma of colonInflammatory bowel diseaseInfections

Klebsiella sppMycobacterium avium–intracellulare

complexEscherichia coli

Immunodeficiency diseasesWhipple disease�-Chain disease and lymphoproliferative

diseasesEpithelial signet

ring cellsPseudomembranous colitisUlcerated tubular adenomaPeutz-Jeghers polypIschemiaAcute erosive gastropathyMucosa-associated lymphoid tissueCystic fibrosisUlcerative colitis

lymphoplasmacytic neoplasm producing monoclonal lightchains or, less commonly, with rheumatoid arthritis, Hel-icobacter pylori infection, use of clofazimine (a leprosydrug), and, exceptionally, with eosinophilic colitis. In thecase of eosinophilic colitis, the crystalline material wasfound to be Charcot-Leyden crystals.46

In 1998, Tazawa and Tsutsumi47 described a peculiar,localized accumulation of plasma cells with cytoplasmicRussell bodies (Mott cells) in the lamina propria of thegastric mucosa, which can cause raised polypoid lesions;they named it Russell bodies gastritis.47,48 Plasma cells ofRussell bodies gastritis are monomorphous but polyclonal.The high density and localized nature of the infiltrate alsodistinguish Russell bodies gastritis from chronic gastritis.Absence of clonality, lymphoepithelial lesions, mitoses,and atypia help distinguish Russell bodies gastritis frommyeloma and mucosa-associated lymphoid tissue lympho-ma.

An additional uncommon pseudoneoplastic lesion ofeosinophilic cells that can be encountered in the gut is dueto infiltration by decidual cells. Decidual cells containabundant ‘‘glassy’’ eosinophilic cytoplasm, with centrallyplaced nuclei lacking atypia (Figure 7, A). Extrauterine,diffuse proliferation of decidual cells rarely forms a massor involves the entire thickness of the intestine (Figure 7,

B). Reported cases of decidual reaction of the intestinehave shown involvement of the appendix, the terminal il-eum, the cecum, and the sigmoid colon, resulting in ob-struction or severe bleeding.49,50 The differential diagnosisin these patients includes metastatic carcinoma (reactiveto cytokeratin antibodies), peritoneal malignant deciduoidmesothelioma (immunoreactive to cytokeratin 5/6 andcalretinin without expression of progesterone receptor),and placental site trophoblastic tumor (immunoreactive toboth cytokeratin and human placental lactogen).

Eosinophilic cellular infiltrate in the gut must also bedistinguished from granular cell tumor (GCT), which canarise anywhere in the gastrointestinal tract, with theesophagus and colon being the most common sites.51 En-doscopic examination of GCT shows whitish nodules orsessile lesions that can be confused with hemorrhoidswhen they occur in the anal canal. These lesions usuallyhave indistinct margins and small dimensions, althoughin rare cases they can reach 5 cm. Granular cell tumorsare composed of nests and sheets of large polygonal toelongated cells with granular eosinophilic cytoplasm anddistinct cell borders; the nuclei are small and round. Gran-ular cell tumor cells originate in Schwann cells, react withantibodies to S100 protein, and stain positive with PASwith diastase. Pseudoepitheliomatous hyperplasia of theesophagus in the area affected by GCT, with GCT cells


Figure 7. Decidual cells. A, Decidual cells with abundant eosino-philic cytoplasm, central nucleus, and no atypia. B, Florid decidualreaction involving small intestine resected during cesarean section (he-matoxylin-eosin, original magnification �400 [A] and �200 [B]; Cour-tesy of Fausto J. Rodriguez, MD, Mayo Clinic, Rochester, Minnesota.Used with permission.)

Figure 8. Pseudoepitheliomatous hyperplasia. A, Squamous cell pro-liferation with keratin pearls deep in lamina propria. B, Granular celltumor adjacent to surface epithelium with abundant eosinophilic cy-toplasm and small, centralized nuclei (hematoxylin-eosin, originalmagnification �200 [A] and �400 [B]).

close to the epithelium, is a notorious pseudoneoplasticlesion that can mimic squamous cell carcinoma (Figure 8;see also ‘‘Selected Pseudoneoplastic Lesions of the Skin’’by Wick and Patterson in this special section). Careful ex-amination of the mucosa and submucosa for GCT is im-portant in patients for whom the diagnosis of squamouscell carcinoma is being considered on the basis of a biopsyof the esophagus.

Benign Signet Ring Cells Infiltrate

Signet ring cells are characterized by a cytoplasmic vac-uole or inclusion that pushes a crescent-shaped nucleus tothe cytoplasmic periphery. They are the hallmark of signetring cell adenocarcinoma. Epithelial signet ring cells, how-ever, may appear in reactive processes52,53 or in associationwith nonepithelial neoplasms, such as mucosa-associatedlymphoid tissue lymphoma54; as a result, they can presenta diagnostic challenge. Table 6 includes a list of diseasesof the gastrointestinal tract associated with nonneoplasticepithelial signet ring cells.

Nonneoplastic epithelial signet ring cells appear to beassociated with ulcerations or ischemia (caused, eg, by tor-

sion in a Peutz-Jeghers polyp) and are limited to the mu-cosa. An awareness of the association among nonneoplas-tic epithelial signet ring cells and degenerated or necroticmucosa, and the lack of infiltrative growth should preventan automatic diagnosis of malignancy when there arebland-appearing signet ring cells (ie, cells lacking nuclearatypia, hyperchromasia, prominent nucleoli, and mitosis)in the gastrointestinal tract.

Nonetheless, the benign nature of nonneoplastic epithe-lial signet ring cells remains difficult to ascertain, espe-cially in biopsy specimens, because signet ring cells car-cinoma can be cytologically bland. Nonneoplastic epithe-lial signet ring cells will express cytokeratins consistentwith their gastrointestinal segments of origin. In a reporton pseudomembranous colitis associated with signet ringcells, Wang and colleagues52 recommended the use of im-munostains for p53, Ki-67, and E-cadherin in difficult cas-es. Nonneoplastic epithelial signet ring cells showedstrong reactivity for E-cadherin but failed to react withantibodies for p53 and Ki-67. Nonneoplastic epithelial sig-net ring cells are not always epithelial in nature: Muci-phages (ie, macrophages with mucin in their cytoplasmthat can appear packaged in vacuoles),55 Schwannoma


cells, and adipocytes (eg, S100-positive signet ring cells inthe subserosa)56 may present as nonneoplastic signet ringcells. Neoplastic signet ring cells have also been reportedin numerous extraintestinal neoplasms (eg, in melanoma,lymphoma, or ovarian tumors). Awareness of the presenceof mimickers of malignant signet ring cells and attentionto cytomorphologic details are necessary for proper inter-pretation.

Foam Cell Infiltrates

Foam cell infiltrates are often found in the gastrointes-tinal tract, especially in the mucosa of the stomach andthe rectum. Conditions characterized by foam cell infil-trates are listed in Table 5. Xanthoma cells and mucipha-ges are the most common cell constituents of foam cellinfiltrates.

Xanthomas are innocuous lesions composed of foamymacrophages characterized by abundant vacuolated cy-toplasm because of the accumulation of lipids and choles-terol and centrally placed nuclei (Figure 9). Xanthomacells reside mainly in the mucosa but occasionally extendinto the submucosa. They are found most frequently inthe stomach as small (usually �3 mm), yellowish or whiteflat lesions, frequently in clusters scattered along the lessercurvature and in the pyloric region. Xanthomas in the co-lon and rectum may appear polypoid.57 Xanthomas havebeen associated with chronic inflammatory states but alsowith malignancies.58,59

Xanthoma cells may be difficult to distinguish from sig-net ring cells of adenocarcinoma without the aid of specialstains (xanthoma cells are immunoreactive for CD68 andare negative for cytokeratin and S100 protein; they stainnegatively for mucicarmin and PAS).60 Xanthoma cells alsohave to be distinguished from the other entities listed inTable 5 and from granular cell tumors.

Muciphages are mucin-rich macrophages originatingfrom the ingestion of mucin released by mucosal damage;they are digested PAS-positive and Alcian blue–positive,whereas xanthoma cells are negative for these mucinstains.55 Bejarano et al61 found muciphages in 38% of rectalbiopsy specimens, mainly from the upper mucosa. Muci-phages may occasionally appear as nodules or polyps.62

They may resemble signet ring cells of adenocarcinoma,and they may be found in lymph nodes.55 As expected,however, they show no labeling for cytokeratin immuno-stains, whereas histiocytic markers are positive.

The foam cells in Whipple disease are replenished withPAS-positive, diastase-resistant bacterial inclusions, andthey are accompanied by dilated lacteals. Immunohisto-chemical tests and polymerase chain reaction tests for 16Sribosomal RNA genes of Tropheryma whipplei are sensitivemethods for the diagnosis of Whipple disease. The gram-positive coccobacillus R equi rarely infects the gastrointes-tinal tract; it has been found in cases of systemic infection,especially in immunocompromised patients. It packs eo-sinophilic macrophages into the mucosa and submucosaand often causes a granulomatous inflammatory response.It is PAS-positive and only weakly and focally positive foracid-fast stain.63

PROLAPSE, ENTRAPPED GLANDS, AND EMPTY SPACES

Prolapse

Du Boulay and colleagues64 proposed the term mucosalprolapse syndrome to indicate a unifying pathogenetic

mechanism for solitary rectal ulcer syndrome and relateddisorders. Prolapse can occur anywhere in the gastroin-testinal tract but is most common in the rectum. In therectum, straining, together with inappropriate puborec-talis muscle contractions and the transition from looselyadherent rectal mucosa to more adherent anal mucosa,produces internal prolapse of the anterior rectal wall. Thesymptoms of solitary rectal ulcer syndrome include rectalbleeding, mucus discharge, sense of prolapse, pain, andstraining. Mucosal prolapse occurs also on the mucosaledges of diverticular openings, at ostomy sites, in hem-orrhoids, adjacent to mass lesions and sigmoid polyps,and in cap polyposis; it is rarely induced by an underlyingcarcinoma.65 Polyps are a manifestation of the variousforms of prolapse; they can be single or multiple, friable,with or without ulceration, and of a red-brown color im-parted by hemosiderin deposition. In older lesions, fibro-sis of the prolapse-induced polyp may be more evident.The so-called inflammatory cloacogenic polyp probablyrepresents a distal manifestation of solitary rectal ulcersyndrome. Diverticula-associated polyps are prolapsingmucosal folds that typically cause bleeding. They are usu-ally worrisome because of their size (2–3 cm). They appearto be formed when prolapse pulls diverticula out of theintestinal wall into the lumen.

The hallmark of prolapse at any site is the musculari-zation of the lamina propria with strands of smooth mus-cle stretching perpendicular to thickened muscularis mu-cosae (Figure 10). These changes are more fully developedin the deep portion of the mucosa. Fibrosis can be prom-inent and is demonstrated by collagen stains. The pres-ence of elastin (not otherwise found in the rectum) hasalso been noted.66 The epithelium may show ulceration,regenerative and ischemic changes, and pseudomem-branes. The crypts often take on a diamond-shaped orangulated appearance rather than maintaining their nor-mal rounded contours. The repeated injury of prolapseresults in villiform-appearing mucosa with hemosiderindeposition and in distorted or serrated glandular archi-tecture. Glands may become trapped in the submucosa ordeeper layers of the wall and appear cystic (ie, colitis cys-tica profunda; see also ‘‘Entrapped Glands’’).

The villiform appearance and the deep glands with re-active atypical epithelium may suggest villous adenomaand invasive adenocarcinoma: The distinction from dys-plastic epithelium relies on clinical and histologic clues.Recurrent lesions at the anal verge in a patient with strain-ing are typical of mucosal prolapse. Maturation of the ep-ithelium from the deep to the superficial aspect of themucosa, superficial fibrin and granulation tissue, and thepresence of intramucosal smooth muscle and diamond-shaped crypts are indicators of prolapse rather than dys-plastic epithelium.

Bleeding may require removal of polyps, but the polypsof prolapse are benign. Patient outcome depends on theunderlying disorder.

Entrapped Glands: Colitis Cystica Profunda, EnteritisCystica Profunda, and Gastritis Cystica Profunda

Glandular epithelium displaced into the submucosa orthe deeper layers of the intestinal wall defines colitis cys-tica profunda, enteritis cystica profunda, and gastritis cys-tica profunda. These lesions in the various portions of thegastrointestinal tract are fundamentally similar and canbe considered together. The most common type is colitis


Figure 9. Xanthoma. Foamy lipid-laden histiocytes with bland-appearing nuclei in a gastric biopsy specimen (hematoxylin-eosin, original mag-nification �400).

Figure 10. Prolapse-induced changes in colon mucosa. Changes are indicated by perpendicular smooth muscle fibers streaming from the mus-cularis mucosae into the lamina propria with no evidence of arborization. Some crypts appear pointy rather than rounded (hematoxylin-eosin,original magnification �100).

Figure 11. Hamartomatous polyp of the small bowel. This hamartomatous polyp led to intussusception in a patient with Peutz-Jeghers syndrome.Asterisk (*) indicates entrapped cystic gland in the wall of the intestine (enteritis cystica profunda; hematoxylin-eosin, scanning magnification).

Figure 12. Colitis cystica profunda. Rounded mucin pools with peripheral epithelium are displaced in the submucosa in a case of mucosalprolapse of the colon (hematoxylin-eosin, original magnification �100).

cystica profunda, followed by enteritis cystica profundaand then gastritis cystica profunda.67 Because chronic per-sistent injury leads, through ulceration and repair, to en-trapment of glands deep in the intestinal wall, thesechanges can be found in conditions such as prolapse, se-vere infection, ischemia, inflammatory bowel disease, andPeutz-Jeghers syndrome68 (Figure 11), in irradiated tissueand along surgical anastomotic lines. The mechanisms ofmisplacement may include herniation, implantation afterulceration, mucosal microdiverticula, and reepithelializa-tion of fistulae (eg, in Crohn disease). Entrapped glandsin the intestine can reach all the way into the subserosa.

Patients may be asymptomatic or may present withsigns and symptoms of the underlying condition. Intesti-nal lesions can enlarge and can cause obstruction or in-tussusception.69,70

Colitis cystica profunda is generally localized and only

rarely diffuse.71 The localized form is more likely in therectum because of its association with rectal prolapse. Thefindings at gross examination include thickened intestinalwall and cysts in submucosal spaces. Glands entrappedin the walls of the intestine commonly undergo dilatationand cystic change and often have a loss of epithelium be-cause of pressure atrophy. Acellular mucin pools are thenleft behind and may show calcium deposition or even os-sification.

The differential diagnosis is invasive adenocarcinoma.Diagnosis may be complicated by the occasional associa-tion of carcinoma with colitis cystica profunda.72

The cytologic features of the entrapped benign glandsin colitis cystica profunda (Figure 12) are usually blandand, in most cases, easily distinguished from those of car-cinoma. If sections show a connection to the surface epi-thelium or the presence of luminal material in the glan-


Figure 13. Esophageal intramural pseudodiverticulosis. A, Outpouch-ings in esophageal submucosa. B, Ducts of dilated submucosal glandsopening into esophageal lumen (hematoxylin-eosin, original magnifi-cation �20 [A] and �40 [B]; Courtesy of F. J. Bilbao, Basque CountryUniversity, Bilbao, Spain. Used with permission.)

Figure 14. Carcinoma cuniculatum of esophagus. Note disorderlylabyrinthine, deeply penetrating growth in the wall of the esophaguswith cystic and slit-shaped spaces lined by well-differentiated squa-mous cells (hematoxylin-eosin, original magnification �40).

dular lumina, the lesion is more likely to be benign. Deep-er sections can prove invaluable in this respect. The pres-ence of hemosiderin, foreign body giant cells, and laminapropria around the epithelium also indicate a benign pro-cess. The presence of dysplasia in surface epithelium in-dicates neoplasia; however, pseudoinvasion in adenomasis a well-known phenomenon.

Mucin-dissecting stroma may suggest invasive mucin-ous carcinoma. If dissecting mucin is associated with typ-ical angulated malignant glands, the diagnosis of adeno-carcinoma is easily accomplished. The features of benignlesions include lack of cytologic atypia, lack of desmopla-sia, presence of lamina propria, rounded contours of theepithelial border, and a rim of a single layer of cells alongthe edge of the mucin pool (not floating in the mucin).

Endometriosis should also be considered in the differ-ential diagnosis of colitis cystica profunda: On gross ex-amination, it manifests as brown fluid-filled cysts withsurrounding fibrosis. Endometriosis affects the sigmoidcolon, colon, appendix, cecum, ileum, rectum, and smallintestine in decreasing order of frequency.73 It can involveall intestinal layers, especially the muscularis propria.

Endometriosis consists of small, often widely spaced,endometrioid glands accompanied by a variable amountof endometrial stroma. Endometrial stroma, which ex-presses CD10, is denser than the stroma of the laminapropria or submucosa. Endometriosis can induce changesin every layer of the intestine. Mucosal changes are remi-niscent of those induced by Crohn disease, prolapse, and,occasionally, ischemia; polypoid endometriosis74 can mim-ic carcinoma macroscopically. Endometriosis offers addi-tional diagnostic challenges when it is affected by decid-ual change (see also ‘‘Benign Eosinophilic Cell Infiltrate’’)or when it consists only of endometriotic stroma. In thefirst case, endometriosis may mimic epithelial carcinoma,whereas in the second case, it may mimic a soft tissuetumor, such as Kaposi sarcoma (which is, however, CD10negative). Reactive changes of the mucosa to an underly-ing endometriotic lesion are also a source of possible con-cern because they can mimic carcinoma.

In 1901, Lubarsch75 was the first to use the term esoph-agitis cystica to indicate what today is referred to as esoph-ageal intramural pseudodiverticulosis (Figure 13). Prolapse is

not at play in this rare disease, but unusual-appearing in-tramural changes are found in it. Esophageal intramuralpseudodiverticulosis is characterized by multiple flask-shaped outpouchings in the esophageal wall that are onlya few millimeters in size and that communicate with theesophageal lumen by a short neck. These pseudodivertic-ula represent dilated excretory ducts of deep submucosalglands of the esophagus.76 Endoscopic and radiologic im-ages typically show, respectively, the tiny ostia of thepseudodiverticula (in about 20% of cases) and, with con-trast medium, the outpouchings into the wall. Esophagealintramural pseudodiverticulosis causes dysphagia. It isthought to follow esophageal motility disorders or esoph-agitis (including candidiasis or esophagitis due to herpes-virus), causing squamous metaplasia of the ducts of theesophageal glands with plugging.

Esophageal intramural pseudodiverticulosis is unlikelyto be confused with a neoplasm, except perhaps with therecently described carcinoma cuniculatum of the esopha-gus (Figure 14), a variant of well-differentiated esophagealsquamous cell carcinoma.77 Carcinoma cuniculatum is de-fined by the deep, labyrinthine, burrowing growth of cyst-like spaces that are continuous with the tumor surface.Histologic features include hyperkeratosis, papillomatosis,acanthosis, and squamous cell differentiation without koi-locytosis. The interface between tumor and stroma maybe of the pushing type or jagged with an invasive border.Carcinoma cuniculatum forms masses, deeply penetratesthe wall of the esophagus, and is difficult to diagnose inendoscopic biopsy specimens from the esophagus. Carci-noma cuniculatum lacks the typical endoscopic and radio-logic appearance of esophageal intramural pseudodiver-ticulosis.

Empty Spaces: Pneumatosis IntestinalisPneumatosis intestinalis is defined by the collection of

gas in the intestinal wall and the formation of clear cysticspaces lined by histiocytes and giant cells in the submu-cosa (Figure 15), along with pseudolipomatosis (small, air-filled, clear, cystic spaces of the lamina propria, often inthe proximity of lymphoid nodules), disarray of crypts,and eosinophilia.78 Pneumatosis intestinalis is rare, and its


Figure 15. Pneumatosis intestinalis (PI). A, Pale polypoid PI alongsidenormal-appearing (nl) colon in gross specimen. B, Clear, air-filled sub-mucosal spaces lined by multinucleated giant cells and smaller clearspaces in lamina propria (pseudolipomatosis; hematoxylin-eosin, orig-inal magnifications �100 [A and B] and �400 [B, inset]).

Table 7. Heterotopias of the Gastrointestinal Tract

Type Sitea

Gastric Upper esophagus, duodenum, Meckeldiverticulum, rectum

Pancreatic Antrum, ampulla, Meckel diverticulum,remaining segments of intestine

Sebaceous glands Throughout esophagusSalivary glands Rectum, perianalProstate gland Anal canalThyroid and

parathyroidglands

Upper esophagus

a In decreasing order of frequency.

etiology is unknown. Pneumatosis intestinalis is foundmore often in the small bowel than in the colon (especiallythe left). In 80% of patients, pneumatosis intestinalis isassociated with gastrointestinal conditions that cause com-promised mucosal integrity or increased luminal pressure(eg, traumatic, infectious, inflammatory, or drug-inducedconditions) or it is associated with extraintestinal diseases,especially obstructive pulmonary disease. Pneumatosis in-testinalis can be asymptomatic, or it can cause obstruction,intussusception, volvulus, and blood in the stool. Polypsor mucosal folds are soft, bluish, and often sessile and arethe most common gross manifestations of pneumatosis in-testinalis; such features may resemble colonic polyposis.A ‘‘bubble wrap’’ crackling noise produced by handlingthe specimen is typical. Pneumatosis intestinalis can bedifficult to diagnose by biopsy, especially if the cysticspaces are collapsed. Pneumatosis intestinalis is seldomconfused with a neoplasm at microscopic examination,with perhaps the exception of acellular mucin of colloidcarcinoma. In that case, negative stains for mucin wouldfacilitate diagnosis.

HETEROTOPIASHeterotopia indicates findings of the presence of normal

tissue at a site where it usually does not reside and where

it lacks anatomic and vascular connections with the parentorgan. The mechanism of formation of heterotopia is ob-scure; hypotheses include errors in embryologic develop-ment (eg, incomplete regression of vestigial structures, ab-normal differentiation of local tissues, or dislocation of aportion of a definitive organ rudiment during develop-ment). The most commonly reported heterotopias in thegut are gastric and pancreatic heterotopias (Table 7).79,80

Sebaceous heterotopia of the esophagus is less common;rarer still are salivary gland heterotopia of the rectum,prostate gland heterotopia of the anal canal, and thyroidand parathyroid glands heterotopia of the upper esopha-gus.81,82

Gastric Heterotopia

Gastric heterotopia has been found throughout the bow-el, but it is mainly encountered in the upper esophagus(the so-called inlet patch, found in 1%–10% of patients atendoscopy but more frequently at autopsy),79 the duode-num (especially the bulb), Meckel diverticulum, and therectum. Gastric heterotopia may manifest as polyps, nod-ules, or thickening of the mucosa and ulcerations. In ex-ceptional cases, gastric heterotopia appears disseminatedand can be associated with celiac disease.83,84

Inlet Patch

Schmidt85 first described the inlet patch in 1805. Endo-scopically, it appears to be salmon-colored mucosa with asharp edge positioned just at or below the upper esoph-ageal sphincter, and it is usually no more than 3 cm. Thegastric mucosa can be oxyntic or less commonly antral. Itsneoplastic potential is low, but there are several reports ofadenocarcinoma arising in inlet patch.86,87 There are nodata reported in the medical literature, to our knowledge,that would justify regular biopsies or follow-up.

Pancreatic Heterotopia

The frequency of pancreatic heterotopia in autopsy se-ries shows large variability (0.55%–25%), which indicatesthat the lesion often goes undetected and is largely harm-less. Symptomatic pancreatic heterotopia has a peak inci-dence in the fourth to sixth decades of life with a male tofemale ratio of 3:1. Pancreatic heterotopia can cause pain,bleeding, obstruction, and intussusception, and it can becomplicated by the development of virtually any diseaseof the orthotopic pancreas, including neoplasms and pan-creatic intraepithelial neoplasias. Pancreatic heterotopia ismost common in the duodenum, the upper jejunum, andthe stomach (typically the prepyloric region, the greatercurvature, and the posterior wall). It can be found


Figure 16. Duct-only pancreatic heterotopia. Pancreatic ducts in themidst of thick bundles of smooth muscle of the muscularis propria ofthe stomach (hematoxylin-eosin, original magnification �40).

Figure 17. Sebaceous heterotopia in the esophagus. Sebaceousglands are located in the mucosa and appear adherent to the superficialepithelium (hematoxylin-eosin, original magnification �200).

Table 8. Differential Diagnosis of Pancreatic Heterotopia

Diagnostic Dilemma Condition Diagnostic Features

Pancreatic heterotopia versuspancreatic acinar metaplasia

Metaplasia Lack of mass formation; located in mucosa (especially of cardia and distalesophagus); secondary to inflammation; only acini present

Endocrine pancreatic heteroto-pia versus neuroendocrinetumor

Endocrine pancre-atic heterotopia

Lack of mass formation; nests of small endocrine cells scattered in deep layersof intestinal wall; no stromal response

Pancreatic heterotopia versusinvasive adenocarcinoma

Pancreatic hetero-topia

Normal lobular arrangement of pancreatic acini and ducts; no atypical cytolo-gy; no stromal response; admixed smooth muscle bundles

Data from Iacobuzio-Donahue.94

throughout the alimentary tract, including the tongue, andin the spleen, liver, gallbladder, biliary tract, mesentery,lungs, mediastinum, fallopian tube, umbilicus, subman-dibular salivary glands, and lymph nodes. In the gut, pan-creatic heterotopia appears as round or lobulated intra-mural nodules usually measuring less than 3 cm. It is usu-ally found in the submucosa but has also been found inthe muscularis propria or subserosa. The overlying mu-cosa can show umbilication at the site of the draining duct

and yet remain normal.80 In many cases, the deep locationprevents diagnosis by endoscopic biopsy.

Pancreatic heterotopia may contain any type of pancre-atic tissue in various proportions (total heterotopia), itmay be composed only of ducts (Figure 16), or it maycomprise only acinar cells (exocrine heterotopia) or isletcells (endocrine heterotopia). When pancreatic ducts pre-dominate, there is often a proliferation of thick smoothmuscle bundles of the muscularis around the ducts. Thus,additional descriptive terms (eg, myoglandular hamarto-ma, adenomyomatous hamartoma, or adenomyoma) maybe used to indicate this type of pancreatic heterotopia,which is usually found in the periampullary region of theduodenum or in the gastric antrum.

Pancreatic heterotopia can pose various diagnosticproblems. Table 8 lists the most common diagnostic dilem-mas and provides clues to their correct diagnosis. Theseinclude, for example, the correct interpretation of the be-nign heterotopic glands during laparoscopic examinationin a patient with a mass in the pancreas, the distinctionfrom well-differentiated adenocarcinoma, the distinctionfrom a neuroendocrine tumor of an endocrine heterotopiain the stomach,88 the distinction of the cystic change inpancreatic heterotopia from a duplication,89 the presenceof pancreatic adenocarcinoma in an ectopic site,90 the pos-sibility of false-positive cytologic findings at laparoscopy,and the distinction from Paneth cells and from pancreaticacinar metaplasia.

Neuroendocrine markers (eg, synaptophysin or chromo-granin), hormone markers (eg, insulin, glucagon, or so-matostatin in physiologic isletlike distribution), and exo-crine markers (eg, trypsin, lipase, or chymotrypsin) canaid diagnosis. Cytokeratin 7 (ie, the cytofilament of pan-creatic centroacinar and ductal cells) may help highlightexcretory ducts in stains of biopsy specimens from thestomach.91

Sebaceous glands are found occasionally in the epithe-lium and lamina propria of the esophagus where theyform flat, yellowish bumps (Figure 17); they are likely tobe more frequent in this location than suggested by re-ports in the medical literature. In individual cases, theymay be quite numerous. The heterotopic and, therefore,congenital nature of sebaceous glands in the esophagushas been questioned by various observations suggestingthat they are metaplastic. In a large necropsy study thatexamined the esophagi of 1000 pediatric subjects, no casesof sebaceous glands heterotopia were found.79 In another,more recent, study, bulbous nests of proliferating basalcells with sebaceous differentiation were found to expressCK14 (a cytokeratin found in the progeny of dormant stemcells),92 which is suggestive of metaplastic change.


CONCLUSION

In summary, awareness of the various pseudoneoplasmsthat may present in the gastrointestinal tract and aware-ness of their possible pathogenetic mechanisms allow forrecognition of these entities. Immunohistochemistry andmolecular techniques are sometimes helpful. The maingoal of the pathologist is to distinguish pseudoneoplasmsfrom malignancies. This is particularly important whenpseudoneoplasms (eg, malakoplakia or prolapse lesions)are associated with a true neoplasm.

We thank F. Bilbao, Department of Pathology, University of theBasque Country (Bilbao, Spain) and F. J. Rodriguez, MD, of theDepartment of Pathology, Mayo Clinic (Rochester, Minnesota),for their insightful comments on esophageal intramural pseu-dodiverticulosis and deciduosis of the gastrointestinal tract.

References1. Vanek J. Gastric submucosal granuloma with eosinophilic infiltration. Am J

Pathol. 1949;25(3):397–411.2. Trillo AA, Rowden G. The histogenesis of inflammatory fibroid polyps of the

gastrointestinal tract. Histopathology. 1991;19(5):431–436.3. Allibone RO, Nanson JK, Anthony PP. Multiple and recurrent inflammatory

fibroid polyps in a Devon family (‘Devon polyposis syndrome’): an update. Gut.1992;33(7):1004–1005.

4. Daum O, Hes O, Vanecek T, et al. Vanek’s tumor (inflammatory fibroidpolyp): report of 18 cases and comparison with three cases of original Vanek’sseries. Ann Diagn Pathol. 2003;7(6):337–347.

5. Kolodziejczyk P, Yao T, Tsuneyoshi M. Inflammatory fibroid polyp of thestomach: a special reference to an immunohistochemical profile of 42 cases. AmJ Surg Pathol. 1993;17(11):1159–1168.

6. Wille P, Borchard F. Fibroid polyps of intestinal tract are inflammatory-re-active proliferations of CD34-positive perivascular cells. Histopathology. 1998;32(6):498–502.

7. Benjamin SP, Hawk WA, Turnbull RB. Fibrous inflammatory polyps of theileum and cecum: review of five cases with emphasis on differentiation frommesenchymal neoplasm. Cancer. 1977;39(3):1300–1305.

8. Kim YI, Kim WH. Inflammatory fibroid polyps of gastrointestinal tract: evo-lution of histologic patterns. Am J Clin Pathol. 1988;89(6):721–727.

9. Pantanowitz L, Antonioli DA, Pinkus GS, Shahsafaei A, Odze RD. Inflam-matory fibroid polyps of the gastrointestinal tract: evidence for a dendritic cellorigin. Am J Surg Pathol. 2004;28(1):107–114.

10. Navas-Palacios JJ, Colina-Ruizdelgado F, Sanchez-Larrea MD, Cortes-Can-sino J. Inflammatory fibroid polyps of the gastrointestinal tract: an immunohis-tochemical and electron microscopic study. Cancer. 1983;51(9):1682–1690.

11. Campbell AP, Mortensen N. Inflammatory fibroid polyps in Crohn’s dis-ease. Histopathology. 1993;22(4):405.

12. Muniz-Grijalvo O, Reina-Campos F, Borderas F. Could a fibroid polyp bea manifestation of enteropathy induced by nonsteroidal anti-inflammatory drugs?Am J Gastroenterol. 1997;92(1):170–171.

13. Tysk C, Schnurer LB, Wickbom G. Obstructing inflammatory fibroid polypin pelvic ileal reservoir after restorative proctocolectomy in ulcerative colitis: re-port of a case. Dis Colon Rectum. 1994;37(10):1034–1037.

14. Mori M, Tamura S, Enjoji M, Sugimachi K. Concomitant presence of in-flammatory fibroid polyp and carcinoma or adenoma in the stomach. Arch PatholLab Med. 1988;112(8):829–832.

15. Ozolek JA, Sasatomi E, Swalsky PA, Rao U, Krasinskas A, Finkelstein SD.Inflammatory fibroid polyps of the gastrointestinal tract: clinical, pathologic, andmolecular characteristics. Appl Immunohistochem Mol Morphol. 2004;12(1):59–66.

16. Zinkiewicz K, Zgodzinski W, Dabrowski A, Szumilo J, Cwik G, WallnerG. Recurrent inflammatory fibroid polyp of cardia: a case report. World J Gas-troenterol. 2004;10(5):767–768.

17. Coffin CM, Watterson J, Priest JR, Dehner LP. Extrapulmonary inflammatorymyofibroblastic tumor (inflammatory pseudotumor): a clinicopathologic and im-munohistochemical study of 84 cases. Am J Surg Pathol. 1995;19(8):859–872.

18. Makhlouf HR, Sobin LH. Inflammatory myofibroblastic tumors (inflam-matory pseudotumors) of the gastrointestinal tract: how closely are they relatedto inflammatory fibroid polyps? Hum Pathol. 2002;33(3):307–315.

19. Cook JR, Dehner LP, Collins MH, et al. Anaplastic lymphoma kinase (ALK)expression in the inflammatory myofibroblastic tumor: a comparative immuno-histochemical study. Am J Surg Pathol. 2001;25(11):1364–1371.

20. Coffin CM, Hornick JL, Fletcher CD. Inflammatory myofibroblastic tumor:comparison of clinicopathologic, histologic, and immunohistochemical featuresincluding ALK expression in atypical and aggressive cases. Am J Surg Pathol.2007;31(4):509–520.

21. Eslami-Varzaneh F, Washington K, Robert ME, Kashgarian M, GoldblumJR, Jain D. Benign fibroblastic polyps of the colon: a histologic, immunohisto-chemical, and ultrastructural study. Am J Surg Pathol. 2004;28(3):374–378.

22. Groisman GM, Polak-Charcon S, Appelman HD. Fibroblastic polyp of the

colon: clinicopathological analysis of 10 cases with emphasis on its commonassociation with serrated crypts. Histopathology. 2006;48(4):431–437.

23. Hornick JL, Fletcher CD. Intestinal perineuriomas: clinicopathologic defi-nition of a new anatomic subset in a series of 10 cases. Am J Surg Pathol. 2005;29(7):859–865.

24. Groisman GM, Polak-Charcon S. Fibroblastic polyp of the colon and co-lonic perineurioma: 2 names for a single entity? Am J Surg Pathol. 2008;32(7):1088–1094.

25. Serra S, Chetty R. Bizarre stromal cells in ischemic bowel disease. AnnDiagn Pathol. 2005;9(4):193–196.

26. Shekitka KM, Helwig EB. Deceptive bizarre stromal cells in polyps andulcers of the gastrointestinal tract. Cancer. 1991;67(8):2111–2117.

27. Bavikatty NR, Goldblum JR, Abdul-Karim FW, Nielsen SL, Greenson JK.Florid vascular proliferation of the colon related to intussusception and mucosalprolapse: potential diagnostic confusion with angiosarcoma. Mod Pathol. 2001;14(11):1114–1118.

28. Ramsden KL, Newman J, Moran A. Florid vascular proliferation in repeatedintussusception mimicking primary angiomatous lesion. J Clin Pathol. 1993;46(1):91–92.

29. Abrahams NA, Vesoulis Z, Petras RE. Angiogenic polypoid proliferationadjacent to ileal carcinoid tumors: a nonspecific finding related to mucosal pro-lapse. Mod Pathol. 2001;14(9):821–827.

30. Cai YC, Barnard G, Hiestand L, Woda B, Colby J, Banner B. Florid angio-genesis in mucosa surrounding an ileal carcinoid tumor expressing transforminggrowth factor-�. Am J Surg Pathol. 1997;21(11):1373–1377.

31. Hobbs CM, Burch DM, Sobin LH. Elastosis and elastofibromatous changein the gastrointestinal tract: a clinicopathologic study of 13 cases and a reviewof the literature. Am J Clin Pathol. 2004;122(2):232–237.

32. Yousef GM, Naghibi B. Malakoplakia outside the urinary tract. Arch PatholLab Med. 2007;131(2):297–300.

33. Michaelis L, Gutmann C. Ueber einschlusse in blasentumoren. Z Klin Med.1902;47:208–215.

34. Rickert CH, August C, Brandt M, Wagner V, Paulus W. Cerebral malako-plakia associated with Escherichia coli infection. Acta Neuropathol. 2000;99(5):595–598.

35. Dobyan DC, Truong LD, Eknoyan G. Renal malacoplakia reappraised. AmJ Kidney Dis. 1993;22(2):243–252.

36. Govender D, Essa AS. Malakoplakia and tuberculosis. Pathology. 1999;31(3):280–283.

37. Bastas A, Markou N, Botsi C, et al. Malakoplakia of the lung caused byPasteurella multocida in a patient with AIDS. Scand J Infect Dis. 2002;34(7):536–538.

38. de Peralta-Venturina MN, Clubb FJ, Kielhofner MA. Pulmonary malaco-plakia associated with Rhodococcus equi infection in a patient with acquiredimmunodeficiency syndrome. Am J Clin Pathol. 1994;102(4):459–463.

39. Gustavo LC, Robert ME, Lamps LW, Lagarde SP, Jain D. Isolated gastricmalakoplakia: a case report and review of the literature. Arch Pathol Lab Med.2004;128(11):e153–e156.

40. Hayden AJ, Hardy DC, Jackson DE Jr. Malacoplakia of the colon. Mil Med.1986;151(11):567–569.

41. McClure J. Malakoplakia of the gastrointestinal tract. Postgrad Med J. 1981;57(664):95–103.

42. Lebeau A, Zeindl-Eberhart E, Muller EC, et al. Generalized crystal-storinghistiocytosis associated with monoclonal gammopathy: molecular analysis of adisorder with rapid clinical course and review of the literature. Blood. 2002;100(5):1817–1827.

43. Jones D, Bhatia VK, Krausz T, Pinkus GS. Crystal-storing histiocytosis: adisorder occurring in plasmacytic tumors expressing immunoglobulin kappa lightchain. Hum Pathol. 1999;30(12):1441–1448.

44. Joo M, Kwak JE, Chang SH, et al. Localized gastric crystal-storing histio-cytosis. Histopathology. 2007;51(1):116–119.

45. Sukpanichnant S, Hargrove NS, Kachintorn U, et al. Clofazimine-inducedcrystal-storing histiocytosis producing chronic abdominal pain in a leprosy pa-tient. Am J Surg Pathol. 2000;24(1):129–135.

46. Lewis JT, Candelora JN, Hogan RB, Briggs FR, Abraham SC. Crystal-storinghistiocytosis due to massive accumulation of Charcot-Leyden crystals: a uniqueassociation producing colonic polyposis in a 78-year-old woman with eosino-philic colitis. Am J Surg Pathol. 2007;31(3):481–485.

47. Tazawa K, Tsutsumi Y. Localized accumulation of Russell body-containingplasma cells in gastric mucosa with Helicobacter pylori infection: ‘Russell bodygastritis.’ Pathol Int. 1998;48(3):242–244.

48. Erbersdobler A, Petri S, Lock G. Russell body gastritis: an unusual, tumor-like lesion of the gastric mucosa. Arch Pathol Lab Med. 2004;128(8):915–917.

49. Bashir RM, Montgomery EA, Gupta PK, et al. Massive gastrointestinal hem-orrhage during pregnancy caused by ectopic decidua of the terminal ileum andcolon. Am J Gastroenterol. 1995;90(8):1325–1327.

50. Rodriguez FJ, Abraham SC, Sendelbach KM, Nascimento AG. Florid de-cidual reaction mimicking gastrointestinal malignancy in a primipara woman.Histopathology. 2006;49(1):82–85.

51. Johnston J, Helwig EB. Granular cell tumors of the gastrointestinal tractand perianal region: a study of 74 cases. Dig Dis Sci. 1981;26(9):807–816.

52. Wang K, Weinrach D, Lal A, et al. Signet-ring cell change versus signet-ring cell carcinoma: a comparative analysis. Am J Surg Pathol. 2003;27(11):1429–1433.

53. Biedrzycki OJ, Arnaout A, Coppen MJ, Shepherd NA. Isolated intramucosal


goblet cells in subacute ischaemic enteritis: mimicry of signet ring cell carcinoma.Histopathology. 2005;46(4):460–462.

54. Zamboni G, Franzin G, Scarpa A, et al. Carcinoma-like signet-ring cellsin gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Am J SurgPathol. 1996;20(5):588–598.

55. De Petris G, Lev R, Siew S. Peritumoral and nodal muciphages. Am J SurgPathol. 1998;22(5):545–549.

56. Houghton O, Herron B. Benign signet ring cells in the subserosa of thesmall intestine: a pseudoneoplastic phenomenon. Ulster Med J. 2006;75(1):93–94.

57. Nakasono M, Hirokawa M, Muguruma N, et al. Colorectal xanthomas withpolypoid lesion: report of 25 cases. APMIS. 2004;112(1):3–10.

58. Isomoto H, Mizuta Y, Inoue K, et al. A close relationship between Heli-cobacter pylori infection and gastric xanthoma. Scand J Gastroenterol. 1999;34(4):346–352.

59. Muraoka A, Suehiro I, Fujii M, et al. Type IIa early gastric cancer withproliferation of xanthoma cells. J Gastroenterol. 1998;33(3):326–329.

60. Kumar PV, Monabati A, Naini MA, Lankarani KB, Fattahi MR, Asadilari M.Gastric xanthoma: a diagnostic problem on brushing cytology smears. Acta Cytol.2006;50(1):74–79.

61. Bejarano PA, Aranda-Michel J, Fenoglio-Preiser C. Histochemical and im-munohistochemical characterization of foamy histiocytes (muciphages and xan-thelasma) of the rectum. Am J Surg Pathol. 2000;24(7):1009–1015.

62. Shepherd NA. What is the significance of muciphages in colorectal bi-opsies? Muciphages and other mucosal accumulations in the colorectal mucosa.Histopathology. 2000;36(6):559–562.

63. Hamrock D, Azmi FH, O’Donnell E, Gunning WT, Philips ER, Zaher A.Infection by Rhodococcus equi in a patient with AIDS: histological appearancemimicking Whipple’s disease and Mycobacterium avium-intracellulare infection.J Clin Pathol. 1999;52(1):68–71.

64. du Boulay CE, Fairbrother J, Isaacson PG. Mucosal prolapse syndrome: aunifying concept for solitary ulcer syndrome and related disorders. J Clin Pathol.1983;36(11):1264–1268.

65. Singh B, Mortensen NJ, Warren BF. Histopathological mimicry in mucosalprolapse. Histopathology. 2007;50(1):97–102.

66. Warren BF, Dankwa EK, Davies JD. ‘Diamond-shaped’ crypts and mucosalelastin: helpful diagnostic features in biopsies of rectal prolapse. Histopathology.1990;17(2):129–134.

67. Aftalion B, Lipper S. Enteritis cystica profunda associated with Crohn’s dis-ease. Arch Pathol Lab Med. 1984;108(7):532–533.

68. Dippolito AD, Aburano A, Bezouska CA, Happ RA. Enteritis cystica pro-funda in Peutz-Jeghers syndrome: report of a case and review of the literature.Dis Colon Rectum. 1987;30(3):192–198.

69. Bentley E, Chandrasoma P, Cohen H, Radin R, Ray M. Colitis cystica pro-funda: presenting with complete intestinal obstruction and recurrence. Gastro-enterology. 1985;89(5):1157–1161.

70. Karnak I, Gogus S, Senocak ME, Akcoren Z, Hicsonmez A. Enteritis cysticaprofunda causing ileoileal intussusception in a child. J Pediatr Surg. 1997;32(9):1356–1359.

71. Magidson JG, Lewin KJ. Diffuse colitis cystica profunda: report of a case.Am J Surg Pathol. 1981;5(4):393–399.

72. Valiulis AP, Gardiner GW, Mahoney LJ. Adenocarcinoma and colitis cys-tica profunda in a radiation-induced colonic stricture. Dis Colon Rectum. 1985;28(2):128–131.

73. Yantiss RK, Clement PB, Young RH. Endometriosis of the intestinal tract: astudy of 44 cases of a disease that may cause diverse challenges in clinical andpathologic evaluation. Am J Surg Pathol. 2001;25(4):445–454.

74. Dadmanesh F, Young RH, Clement PB. Polypoid endometriosis (PE): a clin-icopathological study of 15 cases [abstract]. Mod Pathol. 1999;12:155A.

75. Lubarsch O. Arbeiten aus der Pathologisch-anatomischen Abteilung des Kon-igl. Hygienschen Instituts zu Posen. Wiesbaden, Germany: Bergmann; 1901.

76. Umlas J, Sakhuja R. The pathology of esophageal intramural pseudodi-verticulosis. Am J Clin Pathol. 1976;65(3):314–320.

77. De Petris G, Lewin M, Shoji T. Carcinoma cuniculatum of the esophagus.Ann Diagn Pathol. 2005;9(3):134–138.

78. Koreishi A, Lauwers GY, Misdraji J. Pneumatosis intestinalis: a challengingbiopsy diagnosis. Am J Surg Pathol. 2007;31(10):1469–1475.

79. Rector LE, Connerley ML. Aberrant mucosa in the esophagus in infantsand in children. Arch Pathol. 1941;31(3):285–294.

80. Hsia CY, Wu CW, Lui WY. Heterotopic pancreas: a difficult diagnosis. JClin Gastroenterol. 1999;28(2):144–147.

81. Downs-Kelly E, Hoschar AP, Prayson RA. Salivary gland heterotopia in therectum. Ann Diagn Pathol. 2003;7(2):124–126.

82. Tekin K, Sungurtekin U, Aytekin FO, et al. Ectopic prostatic tissue of theanal canal presenting with rectal bleeding: report of a case. Dis Colon Rectum.2002;45(7):979–980.

83. Tribl B, Aschl G, Mitterbauer G, Novacek G, Vogelsang H, Chott A. Severemalabsorption due to refractory celiac disease complicated by extensive gastricheterotopia of the jejunum. Am J Surg Pathol. 2004;28(2):262–265.

84. Lambert MP, Heller DS, Bethel C. Extensive gastric heterotopia of the smallintestine resulting in massive gastrointestinal bleeding, bowel perforation, anddeath: report of a case and review of the literature. Pediatr Dev Pathol. 2000;3(3):277–280.

85. Schmidt FA. De Mammalian Oesophage Atque Ventriculo [dissertation].Halle: University of Halle, Germany; 1805.

86. Christensen WN, Sternberg SS. Adenocarcinoma of the upper esophagusarising in ectopic gastric mucosa: two case reports and review of the literature.Am J Surg Pathol. 1987;11(5):397–402.

87. Pech O, May A, Gossner L, et al. Early stage adenocarcinoma of the esoph-agus arising in circular heterotopic gastric mucosa treated by endoscopic mucosalresection. Gastrointest Endosc. 2001;54(5):656–658.

88. Hammock L, Jorda M. Gastric endocrine pancreatic heterotopia. ArchPathol Lab Med. 2002;126(4):464–467.

89. Cheung FMF, Leong HT. Heterotopic pancreas masquerading as duplica-tion cyst of the stomach: a case report. Int J Surg Pathol. 1995;3(2):141–144.

90. Makhlouf HR, Almeida JL, Sobin LH. Carcinoma in jejunal pancreatic het-erotopia. Arch Pathol Lab Med. 1999;123(8):707–711.

91. Lindtner RA, Schreiber F, Langner C. Cytokeratin 7 immunostaining facil-itates recognition of pancreatic heterotopia in gastric biopsies. Pathol Int. 2007;57(8):548–550.

92. Nakanishi Y, Ochiai A, Shimoda T, et al. Heterotopic sebaceous glands inthe esophagus: histopathological and immunohistochemical study of a resectedesophagus. Pathol Int. 1999;49(4):364–368.

93. Fitzgibbons PL. Pseudoneoplastic lesions of the alimentary tract. In: WickMR, Humphrey PA, Ritter JH, eds. Pathology of Pseudoneoplastic Lesions. Phil-adelphia, PA: Lippincott-Raven; 1997.

94. Iacobuzio-Donahue CA, ed. Gastrointestinal and Liver Pathology. Phila-delphia, PA: Churchill Livingstone/Elsevier; 2005.

polyps

Documents

enteritis

gastritis

acquired immunodeciency

colitis cystica

esophageal

russell bodies

helicobacter

russell body