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Obliterative muscularization of the small bowel submucosa in crohn disease: a possible mechanism of small bowel obstruction.

Stricture formation in Crohn disease has been traditionally ascribed to fibrosis of the submucosa submucosa /sub·mu·co·sa/ (sub?mu-ko´sah) areolar tissue situated beneath a mucous membrane.

A layer of loose connective tissue beneath a mucous membrane.
 after ulceration. (1-3) In general, fibrosis of the muscularis propria was not a feature, but changes of the muscularis mucosa were noted. (1-4) Fibromuscular proliferation has been mentioned. (3,4) Shepherd and Jass (5) showed that the so-called neuromuscular and vascular hamartoma, characterized by extensive muscular proliferation and associated with small bowel strictures, is actually "burnt out" Crohn disease.

In reviewing resection specimens of Crohn disease from the ileum ileum: see intestine.

Final and longest segment of the small intestine. It is the site of absorption of vitamin B12 (see vitamin B complex) and reabsorption of about 90% of conjugated bile salts.
, we have noted an extensive proliferation of smooth muscle obliterating the submucosa. This observation was distinct from the usual thickening and splaying of the muscularis mucosa described in healed ulcerations/ The aim of our study was to examine whether this pathologic change, obliterative muscularization of the submucosa (OMUS), could be associated with the formation of small bowel strictures.


We reviewed 50 ileal ileal /il·e·al/ (il´e-ahl) pertaining to the ileum.

Of or relating to the ileum.

ileal, ileac

pertaining to the ileum.
 partial resections from adult patients with indisputable diagnosis of Crohn disease examined during 1995-2000. All the patients had advanced Crohn disease, with clinical manifestations present for several years. Features of small bowel obstruction had been recorded in the records of most of the patients. Seven patients had a history of recurrent episodes of intestinal obstruction. The patients had no history of previous surgery or anastomosis anastomosis /anas·to·mo·sis/ (ah-nas?tah-mo´sis) pl. anastomo´ses   [Gr.]
1. communication between vessels by collateral channels.

. All the resection specimens had been examined in the Department of Pathology of Indiana University Hospital Indiana University Hospital is a teaching hospital in Indianapolis, Indiana affiliated with the Indiana University School of Medicine and Clarian Health Partners. As part of Clarian, the hospital works closely with nearby Methodist Hospital and James Whitcomb Riley Hospital for Children. , Indianapolis, following routine procedures. The histopathologic slides were reviewed initially without knowledge of the gross findings by 4 pathologists. Since thickening of the muscularis mucosa and muscularis propria as well as fibromuscular proliferation in the submucosa are not uncommon, OMUS was defined as a thick and continuous muscle layer from the mucosal base to the muscularis propria that was at least 1 cm in length and that lacked distinct bands of scarring. Subsequently, the macroscopic descriptions were reviewed, and the presence and location of OMUS were correlated with the presence and location of strictures. Statistical analysis was performed using the Fisher exact test.

Representative sections from each case showing muscularization of the submucosa were stained with the Gomori 1-step trichrome method without pretreatment pretreatment,
n the protocols required before beginning therapy, usually of a diagnostic nature; before treatment.

pretreatment estimate,
n See predetermination.
 of sections with hot Bouin solution.

In addition, representative sections from each case showing muscularization of the submucosa were analyzed immunohisto-chemically for smooth muscle-specific actin (monoclonal antibody 1A4, Dako Corporation, Carpinteria, Calif) and desmin (monoclonal antibody D33, Dako). A conventional avidin-biotin complex method was used with microwave antigen retrieval. Appropriate positive and negative control slides were stained in parallel.


Patients in this study included 30 females and 20 males (age 17-74 years; average, 37.7 years; median, 36.5 years). Obliterative muscularization of the submucosa was noted in 14 of the 50 ileal resections reviewed. It was characterized by submucosal submucosal /sub·mu·co·sal/ (-mu-ko´sal)
1. pertaining to the submucosa.

2. beneath a mucous membrane.
 muscle fibers organized in compact interlacing See interlace.

1. (hardware) interlacing - A video display system which builds an image on the VDU in two phases, known as "fields", consisting of even and odd horizontal lines.
 bundles, strongly reminiscent of a muscular layer of bowel wall, especially of a very thick muscularis mucosa (Figures 1-4). Indeed, in many cases distinction between muscularis mucosa and OMUS was not feasible. The muscularis propria could be distinguished from OMUS (Figures 1 and 2). As expected, OMUS showed strong immunostaining with antibodies to smooth muscle actin and desmin (Figure 5). A small amount of inflamed connective tissue was also seen in the region of OMUS. Adjacent sections taken from the area of the strictures showed submucosal fibrosis. Additional features of Crohn disease, such as fissuring ulcers, granulomas, lymphoid aggregates, and pseudopyloric metaplasia metaplasia /meta·pla·sia/ (met?ah-pla´zhah) the change in the type of adult cells in a tissue to a form abnormal for that tissue. , were also noted in most of the cases. The mucosa overlying overlying

suffocation of piglets by the sow. The piglets may be weak from illness or malnutrition, the sow may be clumsy or ill, the pen may be inadequate in size or poorly designed so that piglets cannot escape.
 regions of OMUS was inflamed, focally ulcerated Ulcerated
Damaged so that the surface tissue is lost and/or necrotic (dead).

Mentioned in: Adenoid Hyperplasia
, and frequently showed prominent pseudopyloric metaplasia. In approximately 30% of the cases, histologic sections, obtained from regions close to OMUS, showed fissuring ulcers frequently associated with thickening and fusion of the muscularis mucosa and muscularis propria. Increased fistula fistula (fĭs`chlə), abnormal, usually ulcerous channellike formation between two internal organs or between an internal organ and the skin.  formation was not seen in the vicinity of OMUS.


Obliterative muscularization of the submucosa was noted in 14 ileal resections, and in 11 of 14 it was detected in the sections obtained from the area of stricture. In the remaining 3 cases, the bowel wall was thick and rigid without grossly identifiable stricture. Correlation between the presence of OMUS and strictures is summarized in Figure 6. Small bowel strictures were by far more common in those specimens showing OMUS (11/14 vs 3/36). The difference was statistically significant (P < .001).



Obliterative muscularization of the submucosa resembles the neuromuscular and vascular hamartoma, considered by Shepherd and Jass (5) as part of the histologic spectrum of Crohn disease. Indeed, these authors mentioned that "we have recently reviewed 50 sequential cases of small intestinal Crohn's disease and histological features identical to those of neuromuscular and vascular hamartoma ... are not uncommon findings." (5) They indicated that "muscularization of the submucosa" can be seen also in ischemic Ischemic
An inadequate supply of blood to a part of the body, caused by partial or total blockage of an artery.

Mentioned in: Antiangiogenic Therapy, Subarachnoid Hemorrhage, Ventricular Fibrillation

 and radiation enteritis enteritis (ĕn'tərī`tĭs), inflammation of the gastrointestinal tract. Acute enteritis is not usually serious except in infants and older people, in whom the accompanying diarrhea can cause dehydration through the loss of fluids. . (5)

The mechanism of OMUS formation is not clear. Direct muscularization of fibrotic submucosa has been considered previously. (5) Alternatively, our findings suggest that OMUS could be the result of proliferation and fusion of reparative re·par·a·tive   also re·par·a·to·ry
1. Tending to repair.

2. Relating to or of the nature of reparations.
 muscularis mucosae and muscularis propria in the vicinity of serpiginous serpiginous /ser·pig·i·nous/ (ser-pij´i-nus) creeping; having a wavy or much indented border.

 or fissuring ulcers, an interpretation implying that OMUS could simply be an epiphenomenon epiphenomenon /epi·phe·nom·e·non/ (ep?i-fe-nom´e-non) an accessory, exceptional, or accidental occurrence in the course of any disease.


Intestinal obstruction is an important feature in the natural history of Crohn disease. (6) Several pathogenetic mechanisms have been proposed. (6) Stricture with fibrostenotic narrowing is considered the main mechanism in advanced Crohn disease, and it is expressed clinically as chronic obstruction.(6) Intermittent obstruction can be seen in early stages of the disease, presumably pre·sum·a·ble  
That can be presumed or taken for granted; reasonable as a supposition: presumable causes of the disaster.
 as the result of edema edema (ĭdē`mə), abnormal accumulation of fluid in the body tissues or in the body cavities causing swelling or distention of the affected parts.  and spasm. (6) Recurrent episodes of acute intestinal obstruction can be superimposed su·per·im·pose  
tr.v. su·per·im·posed, su·per·im·pos·ing, su·per·im·pos·es
1. To lay or place (something) on or over something else.

 on a picture of chronic obstruction. (6) These episodes have been attributed to impaction of food or flare-ups of inflammation and spasm. (6)

All the explanations of the intermittent obstruction invoke a transient mechanism of stenosis, edema, or spasm. Obliterative muscularization of the submucosa could be a suitable pathologic substrate of a spasm-mediated transient stenosis. Indeed, OMUS was found in all 7 patients with intermittent intestinal obstruction in our series.

While the association of OMUS and spasm-induced intestinal obstruction is not more than tentative, the association of OMUS with small bowel strictures is certain. The nature of this association is not clear. Several hypotheses are possible. Obliterative muscularization of the submucosa could undergo a prolonged or intense spasm causing unresolving bowel constriction. If this were true, "eel in rigor mortis" could be more than a mere historical and graphic description of bowel involved by Crohn disease. (7) Alternatively, OMUS, by minimizing the vasoprotective role of normal submucosa, could cause ischemia contributing to bowel scarring. Finally, OMUS could be an epiphenomenon, simply an indicator of advanced Crohn disease with excessive repair. (8,9)

In a recent study, intestinal smooth muscle cells were recovered from intestine with Crohn disease and sustained in culture. (10) These cells showed amplified contractile contractile /con·trac·tile/ (kon-trak´til) able to contract in response to a suitable stimulus.

Capable of contracting or causing contraction, as a tissue.
 activity, and they expressed increased gelsolin gel·sol·in  
A calcium-dependent actin-binding protein that modulates actin filament length and gelation and thus influences the structure of the cytoskeleton and plays a key role in cellular motility and differentiation.
, an actin-binding protein. (10) These findings suggest a role for contractility contractility /con·trac·til·i·ty/ (kon?trak-til´i-te) capacity for becoming shorter in response to a suitable stimulus.


a capacity for becoming short in response to suitable stimulus.
 in stricturing and obstruction, and the possibility that obstruction could reflect more diverse pathologic processes than mere scarring. The need for better understanding of stricture formation in Crohn disease is further indicated by the successful application of more conservative therapeutic approaches, including stricturoplasty, (11) and inhibition of tumor necrosis factor-alpha Tumor necrosis factor (TNF, cachexin or cachectin and formally known as tumor necrosis factor-alpha) is a cytokine involved in systemic inflammation and is a member of a group of cytokines that all stimulate the acute phase reaction.  by using a chimeric chi·mer·ic
1. Relating to a chimera.

2. Composed of parts of different origin.
 monoclonal antibody. (12) Rapidly developing obstructive symptoms have been recently reported in a subgroup of patients receiving this medication. The pathologic changes included increased collagen deposition in muscularis mucosa, submucosa, and muscularis propria, as well as "variable increase of myofibroblasts/ smooth muscle cells" in the submucosa. (12)


(1.) Morson BC, Dawson IMP, Day DW, Jass JR, Price AB, Williams GT. Inflammatory disorders. In: Morson and Dawson's Gastrointestinal Pathology. 3rd ed. Oxford, England: Blackwell Scientific Publications; 1990:240-302.

(2). Ming SC, Goldman H. Ulcerative colitis and Crohn's disease. In: Pathology of the Gastrointestinal Tract. Philadelphia, Pa: WB Saunders Co; 1992:643-681.

(3.) Lewin KJ, Riddel RH, Weinstein WM. Crohn's disease. In: Gastrointestinal Pathology and Its Clinical Implications. New York, NY: Igaku-Shoin Medical Publishers; 1992:858-903.

(4.) Tanaka M, Riddell RH. The pathological diagnosis and differential diagnosis of Crohn's disease. Hepatogastroenterology. 1990;37:18-31.

(5.) Shepherd NA, Jass JR. Neuromuscular and vascular hamartoma of the small intestine: is it Crohn's disease? Gut. 1987;28:1663-1668.

(6.) Feldman M, Scharschmidt BF, Sleisinger MH. Crohn's disease. In: Slesinger and Fordtran's Gastrointestinal and Liver Disease. 6th ed. Philadelphia, Pa: WB Saunders Co; 1998:1708-1734.

(7.) Dalziel TK. Chronic intestinal enteritis. Br Med J. 1913;2:1068-1069.

(8.) Kelly JK, Sutherland LR. The chronological sequence in the pathology of Crohn's disease. J Clin Gastroenterol. 1988;10:28-33.

(9.) Kelly JK, Siu TO. The strictures, sinuses, and fissures of Crohn's disease. J Clin Gastroenterol. 1986;8:594-598.

(10.) Ehrlich HP, Allison GM, Page MJ, Kolton WA, Graham M. Increased gelsolin expression and retarded collagen lattice contraction with smooth muscle cells from Crohn's diseased intestine. J Cell Physiol. 2000;182:303-309.

(11.) Tonelli F, Ficari F. Strictureplasty in Crohn's disease: surgical options. Dis Colon Rectum. 2000;43:920-926.

(12.) Sidham VB, Komorowski R, Asma Z, et al. Histomorphologic changes in patients presenting with obstruction secondary to Infliximab therapy in Crohn's disease [abstract 547]. Mod Pathol. 2001;14:95A.

Accepted for publication June 4, 2001.

From the Department of Pathology, School of Medicine, Indiana University, Indianapolis.

Reprints: George K. Koukoulis, MD, University Hospital, Department of Pathology, Room 3465, 550 N University Blvd, Indianapolis, IN 46202-5280 (e-mail:
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Author:Koukoulis, G.; Ke, Y.; Henley, J.D.; Cummings, O.W.
Publication:Archives of Pathology & Laboratory Medicine
Geographic Code:1USA
Date:Oct 1, 2001
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