Indian Journal of Pathology and Microbiology
Home About us Instructions Submission Subscribe Advertise Contact e-Alerts Ahead Of Print Login 
Users Online: 4632
Print this page  Email this page Bookmark this page Small font sizeDefault font sizeIncrease font size

  Table of Contents    
Year : 2015  |  Volume : 58  |  Issue : 2  |  Page : 146-153
Interpretation of ileal biopsies

Department of Pathology, All India Institute of Medical Sciences, New Delhi, India

Click here for correspondence address and email

Date of Web Publication17-Apr-2015


The ileum is one of the most common sites of intestine to undergo endoscopic biopsy. However, even with the experienced histopathologists, a definite diagnosis can be achieved only in 18% cases. Lack of knowledge about proper tissue handling, tissue orientation, overlapping histological findings, and lack of a standard algorithm based approach results in this low diagnostic yield. In this review article, we have tried to discuss these aspects and give a clear picture how to approach the ileal lesions. It would help the surgical pathologists in effectively interpreting the lesions and to identify the common pitfalls.

Keywords: Acute ileitis, chronic ileitis, crypt architecture, ileal biopsy interpretation, ileal Crohn′s disease, ileal tuberculosis

How to cite this article:
Das P, Gahlot GP, Mehta R, Gupta SD. Interpretation of ileal biopsies. Indian J Pathol Microbiol 2015;58:146-53

How to cite this URL:
Das P, Gahlot GP, Mehta R, Gupta SD. Interpretation of ileal biopsies. Indian J Pathol Microbiol [serial online] 2015 [cited 2023 Feb 5];58:146-53. Available from:

   Introduction Top

Ileum, approximately 3-4 meters (m) in length, has derived its name from the Greek word eilein, meaning "to twist up tightly," as this long tubular structure has to be accommodated in the abdominal cavity within the limited available space. [1] Both its length and the ileo-cecal valve, which separates it from the cecum, makes it prone to stasis and increase chances of infection though there is an active physical and an immunological barrier in place. The physical barrier is formed by the lining epithelial absorptive cells, goblet cells, and mucus secreted by the latter. Epithelial paneth cells and enteroendocrine cells provide immunity by secreting various chemicals, including defensins, while the mucosal and submucosal gut-associated lymphoid tissue or Peyer's patches are the main site of local immunological activation and is the epicenter of local physiological, controlled mucosal inflammation. [2] However, despite being protected extensively, ileal infections are common and hence it is one of the common sites of the gastrointestinal tract (GIT), subjected to endoscopic biopsies. Hence, before interpretation, it is imperative to be aware of the technical factors, which may modify the interpretation. In this review, we have tried to discuss these concerns and tried to give a lucid diagnostic approach.

   Ileal Anatomy Top

The ileal pH ranges between 7 and 8, making it suitable for absorption of Vitamin B12 and bile salts. The mucosal lining is specially designed with plicae circularis, intestinal villi, and microvilli, which help in the absorption, which are more prominent in the proximal, than in the distal ileum. [3] The thumb-like villi resemble the Christmas tree and are lined by simple columnar cells while the crypts of Lieberkuhn are seen at the base of the mucosa. Cell regeneration takes place in the crypt base, and the new cells migrate to the mucosal surface by 4-5 days, to maintain a crypt to the villous ratio of around 1:4. [4],[5] Along with the vessels in lamina propria, thin muscle fibers extend up to the villus tip, the contraction of which results in villous movement. Ileal mucosa hosts a lot of cells with known diverse functions, as: The stem cells, undifferentiated cells, goblet cells, paneth cells, absorptive cells, enteroendocrine cells and M cells. The microvilli on the enterocytes increase the luminal surface area to approximately 14-40 folds. It is covered by a glycocalyx coat, which hosts various protective proteases, lysozymes, lactase, etc., secreted by the underlying paneth cells. The acidic mucin-rich goblet cells are present at uniform distances in between the absorptive cells and are highlighted by the alcian blue staining at pH 2.5. These goblet cells also have a turnaround time similar to the enterocytes; hence loss of goblet cells in ileal biopsy, suggests acute epithelial injury. The paneth cells are flask-shaped, situated in between the crypt basal cells and are identified by the presence of eosinophilic granules containing zinc, growth factors, antimicrobial proteins like cryptdins and are destined to protect the enterocytes and stem cells. The enteroendocrine cells are also present in the crypt base and can be identified in a hematoxylin and eosin stained slide by the presence of a clear halo around them. Among these, the 5 hydroxytryptamine containing cells predominate, however, substance P, serotonin, vasoactive intestinal polypeptide, and somatostatin D secreting cells are also noted. The hormones released by them, help in the regulation of ileal secretion, absorption, motility, and mucosal cell proliferation. [6] The mucosal or submucosal nodular, encapsulated aggregates of about 2-5 cm in length, comprising up to 300 lymphoid follicles, are called the Peyer's patches. [7] The mucosal lining epithelium just above the Peyer's patches is called mucosal dome, which comprises the microfold cells (M), characterized by lack of mucin-secreting ability and presence of microfolds, instead of the microvilli. Luminal antigens after being picked up by the M cells, are included into the cytoplasmic pinocytotic vacuoles and are then transported to the submucosal antigen presenting cells. Hence, these cells are critical in producing intestinal immune reactive effector cells and memory cells. [8],[9] These effector cells then migrate and infiltrate the surface mucosal epithelium (intraepithelial lymphocytes [IELs]). In physiological conditions, up to 4 lymphocytes per 100 IELs are noted in the ileum. [10] Like other parts of small intestinal (SI), the mucularis propria consists of an inner circular and outer longitudinal muscle layers with a myenteric plexus in between. The serosa is the outermost layer, comprising loose fibrous-collagenous tissue [Figure 1]a-e.
Figure 1: H and E photomicrograph of oriented ileal mucosa ((a) ×40) with paneth cells ((b) ×100) peyer's patches and M cells (arrows) ((c) ×40 and (d) ×100). Chromogranin stain shows enteroendocrine cells ((e) ×100). Features of acute ileitis: inflammed edematous villi ((f) ×40) crypt abscesses, muco-depletion (arrow) ((g) ×100) ulceration ((h) ×40) flattened epithelium ((i) ×100) and maintained test tube rack appearance of crypts ((j) ×40). Features of chronic ileitis: distorted crypt architecture with branching ((k) ×40; (l) ×100) loss of mucosal crypts ((m) ×40) pyloric metaplasia ((n) ×40) and hypercrinia (arrows) ((o) ×40)

Click here to view

   Technical Aspects of an Ileal Biopsy Top

Before the interpretation of the ileal biopsies, it is imperative to know the type of biopsy taken and in this regard knowledge of the biopsy forceps used is mandatory. The outcome can be affected by various factors, as: Adequacy of bowel preparation, use of accurate sized endoscope, correct and accurate sampling of the lesion, proper orientation and fixation of the biopsy fragments, etc. Commonly acquired ileal samples are: Endoscopic pinch biopsy, suction cup biopsy, endoscopic mucosal resection, brush cytology, and fine-needle aspiration cytology. [11] Endoscopic pinch biopsy is the most commonly done endoscopic biopsy procedure; however, only the superficial part of the mucosa is obtained. The size of these fragments depends on the diameter of the pinch biopsy cups, which measure from 1.8 mm (small cup) to 2.4 mm (medium) and up to 3.4 mm (large cup). [12] Depending on the lesions suspected clinically and endoscopically, appropriate forceps may be used. Histopathologists should also communicate with the gastroenterologists and should advice use of large cup biopsy forceps if the lesion suspected is not present in the superficial pinch biopsies. Suction capsule biopsies are much larger, deeper and can be oriented easily. Mucosal resections are generally reserved for larger mucosal lesions. According to European Crohn's and colitis organization guidelines biopsies should be taken from a minimum of 5 sites of ileocolic regions, with 2 biopsy fragments from each site. [13] Pathologists should train the technicians to submit multiple step sections of the biopsy fragments in one or two slides, to be able to examine the tissue at different depths. Proper fixation is also critical, and 4% buffered formalin should be used for at least 6 h, but not >48 h. Bouin's fluid, Holende's solution, and B5 may also be used, especially where nuclear morphology needs to be preserved better. [14] During interpretation, importance of orientation cannot be overlooked for SI. Like duodenum, vertically oriented 3-4 consecutive crypts on the muscularis mucosae, suggest proper orientation. Presence of round cross-sectional crypts in a biopsy indicates lack of orientation. In this regard always the biopsy fragments should be sent to the pathology laboratory after white filter paper mounting, keeping the mucosal surface up. Filter paper mounting is done by placing the biopsy fragment on a small square of filter paper and 20-30 s waiting will adhere the tissue on the filter paper due to plasma coagulation. Separate filter paper squares should be used for each mucosal bit and after fixing them, all should be transferred to a container containing buffered formalin. If the biopsies have been taken from different parts of the intestine, they should be put in different fixative vials, which need to be labeled properly. Use of 0.1% eosin stain before the fragments are plucked up from the filter papers and embedded, would help to identify the darkly stained mucosal surface during grossing.

   Inflammatory Conditions of Ileum Top

As described, superficial mucosal biopsies are often inadequate to exactly characterize the ileal inflammatory lesions, especially so in chronic active ileitis, where one need to evaluate the depth of ulcers, density and pattern of lymphoid infiltrate in the intestinal wall, presence of deeper granulomas, etc. Furthermore, these lesions can be focal, hence during interpretation, a holistic view should be adopted, as the 2 mm 2 size biopsy fragments are actually a small representation of a few millionth of the gastrointestinal mucosal surface area. In a clinically symptomatic patient, normal ileal biopsy fragments does not rule out the presence of disease and the same should always be communicated to the treating physicians, and the need for deeper biopsy should be documented. It should also be kept in mind that in ileum always a physiologically controlled inflammation persists, hence a few lymphoid and plasma cells may be seen scattered over the lamina propria; however, alteration in the density of these cells, their distribution and composition, e.g., if polymorphs are seen in addition or more plasma cells are noted etc., are indicators of inflammation.

Acute inflammatory conditions

Most commonly encountered inflammatory lesion of ileum is acute nonspecific terminal ileitis. [15] However, this diagnosis is like a dump basket and one should refrain from using this terminology. The "nonspecificity" may be due to technical factors as described before. A majority of acute ileitis are associated with the use of nonsteroidal anti-inflammatory drugs (NSAID). In autopsy studies, ileal mucosal breaks and ulcers have been identified in 8.4-55% subjects taking NSAIDs while in nonusers the same was noted in 0.6-7% subjects. [15] In a study conducted by video capsule endoscopy, similar lesions have been identified in up to 71% NSAID users, including both cyclo-oxygenase (COX-1) and COX-2 inhibitors. [16],[17] In superficial mucosal biopsies though the diagnosis is often difficult, presence of mucosal aphthous ulcers with scattered eosinophils and alternate bands of fibrosis in the lamina propria extending up to the mucosal surface may be found in some cases. The typical pattern of fibrosis in chronic NSAID users separate the intestinal into multiple compartments by thin fibrous membranes with a narrow central hole, named as diaphragm disease. [2] However, the latter is seen only in 2-3% patients consuming NSAID for a long period of time and is extremely difficult to appreciate in mucosal pinch biopsies. When noted in suction biopsies, these fibrous bands would be less vascularized, than the ischemic mucosal fibrosis. The other causes of acute ileitis are predominantly bacterial and rarely be due to viral, fungal infections or parasitic infestations. Amongst the bacteria causing acute ileitis,  Salmonella More Details, Shigella, enterotoxigenic  Escherichia More Details coli,  Yersinia More Details enterocolitica, and Yersinia para-tuberculosis (TB) are main pathogens. [15] Yersinia to our experience is relatively less common in the Indian subcontinent and in most of these infections, ileal biopsy findings are not distinctive. In Yersinia, the ileum shows dense lymphocytic infiltrate in the mucosa with large reactive lymphoid follicles and follicle-centric nonnecrotizing epithelioid cell granulomas in a few cases. However, at many times, these changes are seen only in submucosa while the mucosal villi become broad and edematous with increased mixed inflammatory cell infiltrate, including polymorphs and eosinophils. Features of activity, that is, cryptitis, crypt abscess, superficial ulcerations and loss of goblet cells can be seen in the biopsy fragments. Normally, each crypt should not show >1 polymorphonuclear cell infiltrate and infiltrates more than this, indicates the activity. [2] The most striking histological finding which will differentiate acute from chronic ileitis is the maintained "test tube rack pattern" of the crypts [Figure 1]f-j. [2] The viral ileitis is most commonly seen in the western world and immune compromised subjects. Cytomegalovirus (CMV) infection is however not uncommon in our settings. [18] Among the fungal ileitis, Candida and mucormycosis are commonly encountered, mostly in the immune deficient subjects. The former has been identified extremely rarely in large series. [19] Presence of necrosis in an ileal mucosal biopsy should always raise the suspicion of invasive fungal infection, as mucormycosis, along with suspicion of vasculitis and malignancies. Mucormycosis commonly is a vasoinvasive fungus and causes ischemic mucosal necrosis. Among the parasitic infestations, Giardia induced acute ileitis is common in Western countries though we rarely encounter it in the ileum. Amoebic ileitis is also very rare than the common inhabitants as rectosigmoid, hepatic flexure or cecum. Careful examination of the exudate over ulcers and use of periodic acid Schiff or Masson's trichrome (MT) stains may help to identify the amebic trophozoites. [15] MT especially may highlight the ingested red blood cells within the trophozoites in ulcero-invasive amebiasis [Figure 2]a and b. Use of MT stain may also help to highlight the intranuclear inclusion in CMV infection if one does have immunohistochemical (IHC) stain to confirm it.
Figure 2: H and E features of ileal Crohn's disease: Crypt distortion with dense lymphocytic infiltrate ((a and b) ×40), rail track like deep ulcers ((c) ×40) and pericrypt microgranuloma (arrows) ((d) ×100). Features of ileal tuberculosis: Ulcers with undermined edges ((e) ×40) large confluent necrotizing granulomas (arrows) ((f) ×40), mesenteric necrotizing granulomatous lymphadenitis ((g) ×40). Ileal biopsy in Yersiniosis showing dense lymphoid infiltrate with reactive follicles ((h) ×40), amoebic trophozoites ((i) ×200) and ileal ulcer infested with mucormycosis (arrows) ((j) ×100)

Click here to view

Chronic ileitis

The sine qua non of chronic ileitis is the distortion of the mucosal crypt architecture or loss of "test tube rack appearance" of the ileal crypts. In addition, the predominance of lympho-mononuclear cells, plasma cells, eosinophils, pyloric metaplasia, goblet cell rich crypts (hypercrinia), mucosal basal plasmacytosis, and broadening of the ileal villous tips (drumstick appearance) would qualify for the changes of chronic inflammation. Among these, however, the topographical changes, in the form of crypt branching, crypt shortening and the crypt loss are most dependable indicators of chronicity. In a 2 mm 2 biopsy fragment, not >2 crypts normally show crypt branching. [2] Any biopsy showing branching more than this would qualify for the architectural distortion. Pyloric metaplasia and hypercrinia, when present, are also specific indicators of mucosal chronicity. Basal plasmacytosis is defined as accumulation of polyclonal plasma cells between the bottom of the shortened crypts and the muscularis mucosae; this when present in mucosal biopsy is also considered as an important indicator of chronic inflammation. [2] Mucosal and submucosal lymphoid aggregates in chronic ileitis, are one of the most frequently encountered findings in ileal biopsies in chronic ileitis. [20] In a 2 mm 2 biopsy fragment, not >2 lymphoid aggregates are seen in the normal ileum. Sheets of lymphoid infiltrate in the mucosa or numerous follicles along the 2 mm length of the muscularis mucosae, are suggestive of a chronic inflammatory bowel disease (IBD) [Figure 1]k-o. [2] During the interpretation of the ileal biopsies, a systematic approach should be followed. First, it should be seen that if the mucosal changes are akin to chronic inflammation or acute inflammation. If both are present together, a broad diagnosis of "chronic ileitis with activity" is made. On such occasions, first the chronic changes, then the acute changes (activity), followed by the grade of activity should be assessed. While doing so, it will enable one to document all the changes in an organized manner and would help in the diagnosis. Any complications of chronic inflammation, as, e.g., dysplasia should be noted. Causes of acute exacerbation, in the form of the presence of viral inclusion, fungal profile should be looked for and documented. Examination of multiple step sections to identify any mucosal granuloma and looking into deeper biopsies to identify submucosal granulomas are important. The size of the granulomas, that is, macrogranuloma (>200 μm) or microgranulomas (<100 μm) is needed to be determined. Most mucosal pericryptal microgranulomas are ill-formed and are seen in Crohn's disease (CD). However, these may be confused with the pericryptal mucin granulomas seen in rupture of inflamed crypts, where the giant cells would have ingested mucin. Confluence of microgranulomas and necrosis favors a diagnosis of TB, however, most of these macrogranulomas are seen in the submucosa, deeper layers, and the mesenteric lymph nodes and are mostly not appreciated in superficial mucosal biopsies. These are appropriate to look for in surgically excised specimens, but it is to be kept in mind that small non necrotizing granulomas in lymph nodes may be seen in up to 25% cases of CD. As already described, the identification of chronic ileitis with activity, should compel one to consider the following possibilities: (1) TB, (2) CD or (3) persistent acute on chronic infection in immune compromised patients, etc. In addition to the findings already described, presence of the "rail track"/deeper burrowing ulcers, dense lymphocytic infiltrate in the mucosa with predominance of lymphoid follicles, peri-cryptal microgranulomas, and basal plasmacytosis are indicative of CD in ileal biopsies. Presence of granulomas in CD in comparison to those who did not have granulomas, showed more aggressive clinical course with perianal complications, needed recurrent hospitalization, more surgical interventions and showed poor overall outcome [Figure 2]a-d. [21] In contrast to CD, presence of superficial or deep ulcers with undermined edges, large confluent epithelioid cell granulomas in the mucosa or submucosa with or without the presence of necrosis, are suggestive of TB [Figure 2]e-g. Knowledge about the radiological presence of lymph nodes and necrosis in the nodes will favor TB in these settings. A detailed clinical history regarding contact with TB, previous history of infection, site of involvement, clinical presentation, and endoscopic features would also help one to reach a diagnosis. However, considerable overlap exists and none of these modalities in isolation are sufficient help in the diagnosis. On the other hand, radiological evidence of bowel wall thickening, serosal fat wrapping and the presence of a fistula may suggest a diagnosis of CD. There are many large studies available, where the histological differentiation of the CD from TB was addressed. [22],[23] But in practice and especially in superficial ileal mucosal biopsies, the diagnosis often remains elusive. The authors had also proposed a scoring system based on clinical, endoscopic and histological features with can help to differentiate intestinal CD and TB with a cutoff value of 5.1, with a sensitivity of 83% and specificity of 79%. The higher score will favor a diagnosis of TB over the CD. However, we emphasize, the ultimate differentiation between ileal TB and CD, depends on therapeutic response. These patients who remain borderline after all investigations, are treated with antitubercular therapy for a minimum period of 6 months and thereafter if all signs persist, they are treated as CD, after re-investigation [Figure 3]. [23],[24] It should be kept in mind though dense lymphoid infiltrate in ileal wall is one of the strongest indicators of CD, similar finding can be seen in infections with Y. enterocolitica, Yersinia para-TB and in intestinal lymphomas also. However, Yersinia infection is uncommon in tropical countries. Superficial ileal mucosal biopsies, however, may not be always adequate to bring out the diagnosis [Figure 2]h. [25] Careful examination can rule out the possibility of a lymphoreticular malignancy, as the atypical cells will show features of epithelial injury. In a 2 mm 2 biopsy fragment presence of >2 lymphoid follicles or sheets of lymphocytes indicate a pathological condition. [19] As already have been highlighted, while documenting the histological findings, the disease activity grade must be mentioned. Based on the activity and chronicity the ileitis can be divided into: Active ileitis-degenerative and regenerative changes in mucosal epithelium-all features of chronicity and activity described above would be present with congestion and dilatation of capillary blood vessels; resolving ileitis-decrease in the number of inflammatory cells, returning of goblet cell distribution toward normal with minor architectural variation of crypts; Quiescent ileitis-persistent architectural abnormalities with very sparse chronic inflammation and absence of activity The histological disease activity (HAI) can be graded as grade 1: Activity involving <50% of the crypts, grade 2: Activity involving >50% of the crypts and grade 3: Presence of ulcers, irrespective of the distribution of cryptitis. This grading system has good intra and inter-observer correlation (k = 0.9). [26] Virtually ulcerative colitis (UC) does not primarily involve the ileum, and the disease activity stops at the ileo-caecal junction. However, the distal 10-15 cm of the ileum can be affected in a contiguous fashion in UC, called the backwash ileitis. It can be identified in around 6% of the ileal biopsies and 20% of the ileectomy specimens. [27] Histologically, though it may be difficult to differentiate it from the CD, in backwash ileitis skip lesions, deeper ulcers, fissures, pyloric metaplasia etc., are not seen. If the changes of chronic active ileitis are seen in all the biopsy fragments, diagnosis of CD should be questioned. This lesion has been identified in UC showing higher histological activity grades. [27]
Figure 3: Schematic algorithm showing the suitable histological approach in the interpretation of ileal biopsies

Click here to view

   Rare Biopsy Findings Top

Eosinophilic ileitis

Eosinophilic infiltration in the mucosa in significant numbers (roughly 20 eosinophils/HPF) with evidences of the crypt destruction or significant eosinophilic infiltrate in the submucosa or muscularis propria may raise suspicion of an eosinophilic ileitis. In ileal biopsies, only the mucosal type of eosinophilic ileitis can be diagnosed. However, it is a diagnosis of exclusion and before signing out, detailed clinical information, stool examination report, serum IgE, peripheral blood eosinophil count, absolute eosinophil count etc., should be checked to rule out any allergic or parasitic conditions. Occasionally in the CD also, eosinophils can infiltrate the ileum in significant numbers. [28]

Ischemic ileitis

As already have been mentioned hemorrhagic necrosis of the upper half of the mucosa with preserved crypts, dilated and congested submucosal blood vessels with diffuse mucosal and submucosal fibrosis indicates an ischemic ileitis. It can be differentiated from the NSAID-induced diaphragm disease in the absence of the mucosal findings described above. In addition, the fibrosis pattern would also be different, as described before while describing the diaphragm disease. However, as emphasized, in ileal biopsies, sticking to the typical mucosal features of ischemic injury would help more to differentiate these two conditions. Diaphragm disease is also a rare mucosal and submucosal complication of prolonged NSAID intake (2%). [29]

Other rare conditions

Ileal biopsies can also give clues to identify the graft versus host disease (GVHD), radiation-induced changes and changes secondary to the ileostomy. Cytological atypia with stromal fibrosis, collagenization, sheets of foamy histiocytes and arterial hyalinization characterize radiation-induced changes. Lymphocytic infiltrate, crypt abscesses, increased numbers of apoptotic bodies in the crypts with the crypt loss indicate GVHD. Ileostomy may induce squamous metaplasia and marked submucosal fibrosis and chronic inflammation. However, in these conditions, knowledge of the clinical background is important in making a diagnosis. [30]

Ileal tumors

Small intestinal tumors may be classified as epithelial and nonepithelial tumors, including the mesenchymal tumors and malignant lymphomas. Despite the larger surface area and higher rate of cell turnover in the mucosa, the epithelial tumors are rare in SI due to shorter transit time, lower bacterial load, more liquid luminal contents, and presence of more lymphoid tissue in comparison to the colon. [31] Among the epithelial tumors, SI adenoma constitutes <0.05% of all intestinal adenomas, and duodenum near the ampulla of Vater is the most common site of adenomas (50%). It is possibly due to the influence of biliary and pancreatic secretions, whereas ileum being the least preferred site. [31] Presence of chronic inflammation, particularly long standing CD (86 times more), celiac disease, radiotherapy, pouch surgery or ileostomy, polyposis syndromes, Meckel's diverticulum are risk factors for ileal tumors. Most ileal biopsies are, however, superficial and show only surface fragments from the tumors, but do not give information regarding the submucosal infiltration. In such conditions, a repeat deeper biopsy should always be advised. In comparison to the epithelial tumors, ileum (31%) is the preferred site for the GI neuroendocrine tumors (GI-NETs) (2% of all, GIT tumors and 50% of all NETs). [32] The other common sites of GIT-NET are: Rectum (21%), appendix (17%), colon (12%), stomach (6%), and 3% each by the duodenum and jejunum. As these lesions present as mucosal or submucosal nodules, they can be easily sampled by mucosal pinch biopsy. Presence of monomorphous population of polygonal cells with eosinophilic granular cytoplasm and stippled nuclear chromatin, arranged in insular/nest (type A), trabecular/festoons (type B), acinar (type C), and poorly differentiated (type D) patterns are diagnostic of NETs. [31] If suspected, at least two neuroendocrine markers should be tested for confirmation of diagnosis along with assessments of the mitotic index over an 2 mm 2 area or 40 HPF (for standard microscopes) and Ki67 labeling index in at least 2000 tumor cells in the regions of highest proliferation. Based on these, the WHO grading of NETs (2010) should always be mentioned in the report. [33],[34] Occasionally in biopsy specimens, glandular elements can be seen in these tumors, where IHC expression of epithelial markers must be checked to rule out the possibility of a mixed adeno-neuroendocrine carcinoma, as the latter has prognostic implications [Figure 4]a-d. [31]
Figure 4: Photomicrographs showing a mixed adenoneuroendocrine carcinoma, with focal glandular pattern (arrow) ((a and b) H and E, ×40). There is diffuse positivity for cytokeratin and chromogranin (arrow) in >30% of the tumor areas ((c and d) H and E, ×100). An ileal biopsy showing features of lymphomatous polyposis with diffuse effacement of mucosal structure by sheets of intermediate size atypical cells. The tumor cells are immunopositive for CD20 ((F) immunohistochemical [IHC] [CD20] ×40), CD5 ((g) IHC [CD5] ×40) and cyclin D1 ((h) IHC [cyclin D1] ×40), suggesting their mantle cell origin

Click here to view

The GIT is the most common (50%) primary site of extranodal lymphomas, particularly nonHodgkin's lymphomas (NHL). Criteria to classify malignant lymphoma of the small bowel include: Their presumed primary versus systemic nature, their cell lineage (B, T, NK cell) and type of associated and/or predisposing factors. [35],[36] The most common sites involved are stomach followed by the SI, ileocecal region, and the colon. Recognized risk factors include chronic IBDs, like CD, acquired or congenital immune deficiency states, etc. The most prevalent NHL is diffuse large B-cell type (50%), followed by the marginal zone B-cell lymphoma (including immunoproliferative SI disease) and mantle cell lymphomas [Figure 4]e-h. [37],[38],[39] Rarely Burkitt's lymphoma, enteropathy-type T-cell lymphoma (5% associated with celiac disease), follicular lymphoma (4%), and peripheral T-cell lymphomas can also be found; whereas the ileocecal region is the most common site of manifestation of sporadic Burkitt's lymphoma. This sub-typing, however, is often not possible on histology alone in small biopsy specimens and warrants the need to apply a judicious IHC panel. Differentiating the ileal NHL from the ileal CD in mucosal biopsies, may be a daunting task in mucosal biopsies, as the latter may show significant infiltration of lymphoid cells. The presence of a monomorphous population of CD20 or CD3 positive cells in more than half of a low power microscope field in such conditions should raise a possibility of a lymphoma. Presence of crypt destruction and absence of reactive lymphoid follicles would also favor a lymphoma. [37] Hurlstone reported an early-phase mantle cell lymphoma, microscopically mimicking CD in the terminal ileum. [40] Mesenchymal tumors rarely affect SI, are mostly deep-seated and often missed in the superficial mucosal biopsies. The common examples are: The gastrointestinal stromal tumors and sarcomas (14% of malignant SI tumors) including leiomyomas and leiomyosarcomas. [41] Secondary tumors, mostly metastasized from melanoma, lung, breast, colon, and kidney, are most frequently located in SI than any other sites of the GIT. [42] Hematogenous dissemination or direct invasion from the adjacent viscera are the main modes of spread. In biopsy specimens, the mucosa adjacent to the infiltrating tumor should be looked for the presence of dysplasia or the presence of any predisposing conditions as IBD. Clinical knowledge and radiology are also valuable in such conditions and would help to fetch information regarding past illnesses and extent of the current lesion under consideration.

   Conclusion Top

Ileal biopsy should be critically analyzed with a detailed knowledge of the patient's clinical presentation and radiological detail. The role of histopathologists should start from choosing the optimum fixative to the proper orientation of the biopsy fragments and then histological interpretation. A systematic approach can give vital clues regarding the histological diagnosis, which then should be correlated with the clinical and radiological detail. Ileal CD and TB are common, and there is no single histological parameter which can differentiate them, hence, the classical findings should always be searched for. Histologically normal appearing biopsy fragments, in a symptomatic patient with endoscopic findings of erythema, erosion or ulcer, does not rule out the existence of a disease and the limitation of superficial mucosal biopsy should be discussed with clinicians. Requirement of deeper suction biopsies should always be communicated and documented in such conditions. Writing report in a standard format as described would bring uniformity in practice, interpretation, and follow-up of patients across different hospitals.

   Acknowledgment Top

We acknowledge the support of the respected HOD, Pathology, Professor S K panda.

   References Top

Robertson JG, editor. Robertson's Words for a Modern Age: A Cross Reference of Latin and Greek. Germany: Senior Scribe Publications; 1991. p. 75.  Back to cited text no. 1
Cuvelier C, Demetter P, Mielants H, Veys EM, De Vos M. Interpretation of ileal biopsies: Morphological features in normal and diseased mucosa. Histopathology 2001;38:1-12.  Back to cited text no. 2
Neutra MR, Padykula HK. The gastrointestinal tract. In: Weiss L, editor. Modern Concepts of Gastrointestinal Histology. 1 st ed. New York: Elsevier; 1984. p. 658-706.  Back to cited text no. 3
Rubin W. The epithelial "membrane" of the small intestine. Am J Clin Nutr 1971;24:45-64.  Back to cited text no. 4
Gramilch T, Petras R. The small intestine. In: Sternberg SS, editor. Histology for Pathologists. 3 rd ed. Philadelphia: Lippincott Williams & Wilkins; 2006. p. 603-26.  Back to cited text no. 5
Wouters MM, Gibbons SJ, Roeder JL, Distad M, Ou Y, Strege PR, et al. Exogenous serotonin regulates proliferation of interstitial cells of Cajal in mouse jejunum through 5-HT2B receptors. Gastroenterology 2007;133:897-906.  Back to cited text no. 6
Cornes JS. Number, size, and distribution of Peyer's patches in the human small intestine. Part I. The development of Peyer's patches. Part II. The effect of age on Peyer's patches. Gut 1965;6:225-33.  Back to cited text no. 7
Wolf JL, Bye WA. The membranous epithelial (M) cell and the mucosal immune system. Annu Rev Med 1984;35:95-112.  Back to cited text no. 8
Mestecky J. The common mucosal immune system and current strategies for induction of immune responses in external secretions. J Clin Immunol 1987;7:265-76.  Back to cited text no. 9
Istvanic S, Yantiss RK, Baker SP, Banner BF. Normal variation in intraepithelial lymphocytes of the terminal ileum. Am J Clin Pathol 2007;127:816-9.  Back to cited text no. 10
Upchurch BR, Vargo JJ. Small bowel enteroscopy. Rev Gastroenterol Disord 2008;8:169-77.  Back to cited text no. 11
Feldman M, Friedman LS, Brandt LJ, editors. Sleisenger and Fordtran's Gastrointestinal and Liver Disease. 9 th ed. Philadelphia: Saunders Elsevier; 2010.  Back to cited text no. 12
Dignass A, Van Assche G, Lindsay JO, Lémann M, Söderholm J, Colombel JF, et al. The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: Current management. J Crohns Colitis 2010;4:28-62.  Back to cited text no. 13
Bancroft JD, Marilyn G. Theory and Practice of Histological Techniques. 6 th ed. China: Churchill Livingstone Elsevier; 2008. p. 85.  Back to cited text no. 14
Dilauro S, Crum-Cianflone NF. Ileitis: When it is not Crohn's disease. Curr Gastroenterol Rep 2010;12:249-58.  Back to cited text no. 15
Lee FD. Drug-related pathological lesions of the intestinal tract. Histopathology 1994;25:303-8.  Back to cited text no. 16
Schneider AR, Benz C, Riemann JF. Adverse effects of nonsteroidal anti-inflammatory drugs on the small and large bowel. Endoscopy 1999;31:761-7.  Back to cited text no. 17
Kaufman HS, Kahn AC, Iacobuzio-Donahue C, Talamini MA, Lillemoe KD, Hamilton SR. Cytomegaloviral enterocolitis: Clinical associations and outcome. Dis Colon Rectum 1999;42:24-30.  Back to cited text no. 18
Cuvelier C, De Vos M. Analysis of 2324 terminal ileal biopsies taken at colonoscopy. Acta Gastroenterol Belg 1995;58:C32. (Abstract).  Back to cited text no. 19
Goldstein NS. Isolated ileal erosions in patients with mildly altered bowel habits. A follow-up study of 28 patients. Am J Clin Pathol 2006;125:838-46.  Back to cited text no. 20
Heresbach D, Alexandre JL, Branger B, Bretagne JF, Cruchant E, Dabadie A, et al. Frequency and significance of granulomas in a cohort of incident cases of Crohn's disease. Gut 2005;54:215-22.  Back to cited text no. 21
Jenkins D, Balsitis M, Gallivan S, Dixon MF, Gilmour HM, Shepherd NA, et al. Guidelines for the initial biopsy diagnosis of suspected chronic idiopathic inflammatory bowel disease. The British Society of Gastroenterology Initiative. J Clin Pathol 1997;50:93-105.  Back to cited text no. 22
Makharia GK, Srivastava S, Das P, Goswami P, Singh U, Tripathi M, et al. Clinical, endoscopic, and histological differentiations between Crohn's disease and intestinal tuberculosis. Am J Gastroenterol 2010; 105:642-51.  Back to cited text no. 23
Pulimood AB, Ramakrishna BS, Kurian G, Peter S, Patra S, Mathan VI, et al. Endoscopic mucosal biopsies are useful in distinguishing granulomatous colitis due to Crohn's disease from tuberculosis. Gut 1999;45:537-41.  Back to cited text no. 24
Puylaert JB, Van der Zant FM, Mutsaers JA. Infectious ileocecitis caused by Yersinia, Campylobacter, and Salmonella: Clinical, radiological and US findings. Eur Radiol 1997;7:3-9.  Back to cited text no. 25
Fiel MI, Qin L, Suriawinata A, Xu R, Qui L, Bitar M, et al. Histological grading of disease activity in chronic IBD Inter-and intra-observer variation among pathologists with different levels of experience. Mod Pathol 2003;16:118a.  Back to cited text no. 26
Goldstein N, Dulai M. Contemporary morphologic definition of backwash ileitis in ulcerative colitis and features that distinguish it from Crohn disease. Am J Clin Pathol 2006;126:365-76.  Back to cited text no. 27
Bates AW. Diagnosing eosinophilic colitis: Histopathological pattern or nosological entity? Scientifica (Cairo) 2012;2012:682576.  Back to cited text no. 28
Lu CC, Chen HH, Lin SE. Ischemic versus non-ischemic obstructive ileocolitis secondary to colorectal cancer: A review of 393 cases. Jpn J Clin Oncol 2010;40:927-32.  Back to cited text no. 29
Bojic D, Markovic S. Terminal ileitis is not always Crohn's disease. Ann Gastroenterol 2011;24:271-75.  Back to cited text no. 30
Noffsinger A. Epithelial neoplasm of the small intestine. In: Odze RD, Goldblum JR, editors. Surgical Pathology of the GI Tract, Liver, Biliary Tract, and Pancreas. 2 nd ed. Philadelphia: Saunders Elsevier; 2009. p. 581-96.  Back to cited text no. 31
Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, et al. One hundred years after "carcinoid": Epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 2008;26:3063-72.  Back to cited text no. 32
Burke AP, Thomas RM, Elsayed AM, Sobin LH. Carcinoids of the jejunum and ileum: An immunohistochemical and clinicopathologic study of 167 cases. Cancer 1997;79:1086-93.  Back to cited text no. 33
Rindi G. The ENETS guidelines: The new TNM classification system. Tumori 2010;96:806-9.  Back to cited text no. 34
Banks PM. Gastrointestinal lymphoproliferative disorders. Histopathology 2007;50:42-54.  Back to cited text no. 35
Crump M, Gospodarowicz M, Shepherd FA. Lymphoma of the gastrointestinal tract. Semin Oncol 1999;26:324-37.  Back to cited text no. 36
Hornick JL. Tumors of the small and large intestine, including anal canal. In: Fletcher CD, editor. Diagnostic Histopathology of Tumors. 4 th ed. Philadelphia: Saunders Elsevier; 2013. p. 434-76.  Back to cited text no. 37
Isaacson PG. Gastrointestinal lymphomas of T- and B-cell types. Mod Pathol 1999;12:151-8.  Back to cited text no. 38
Maclaurin BP, Cooke WT, Ling NR. Impaired lymphocyte reactivity against tumour cells in patients with Crohn's disease. Gut 1972; 13:614-20.  Back to cited text no. 39
Hurlstone DP. Early phase mantle cell lymphoma: Macroscopic similarities to terminal ileal Crohn's disease. Am J Gastroenterol 2002;97:1577-8.  Back to cited text no. 40
Thomas RM, Sobin LH. Gastrointestinal cancer. Cancer 1995;75:154-70.  Back to cited text no. 41
Laurent JC, Filoche B, Depadt G, Proye C, Combemale B, Lagache G. Study of a series of 32 tumors of the small intestine. Lille Med 1972;17:104-10.  Back to cited text no. 42

Correspondence Address:
Dr. Prasenjit Das
Department of Pathology, All India Institute of Medical Sciences, New Delhi - 110 029
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0377-4929.155302

Rights and Permissions


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

This article has been cited by
R. V. Savchuk, F. I. Kostyev, V. V. Vit
World of Medicine and Biology. 2020; 16(71): 115
[Pubmed] | [DOI]
2 Primary Colonic Eosinophilia and Eosinophilic Colitis in Adults
Kevin O. Turner,Richa A. Sinkre,William L. Neumann,Robert M. Genta
The American Journal of Surgical Pathology. 2017; 41(2): 225
[Pubmed] | [DOI]


    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Email Alert *
    Add to My List *
* Registration required (free)  

   Ileal Anatomy
    Technical Aspect...
    Inflammatory Con...
   Rare Biopsy Findings
    Article Figures

 Article Access Statistics
    PDF Downloaded1242    
    Comments [Add]    
    Cited by others 2    

Recommend this journal