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Clinical usefulness of rectal biopsy in Crohn's disease
GASTROENTEROLOGY
Clinical Usefulness Crohn’s Disease ROLLA
B. HILL, THOMAS
77:938-944,1979
of Rectal Biopsy in H. KENT,
and RICHARD
N. HANSEN
Department of Pathology, SUNY-Upstate Medical Center, Syracuse, New York; Department of Pathology, _. University of Iowa, Iowa City, Iowa; and the Division of Gastroenterology, University of Colorado Medical Center, Denver, Colorado
Initial rectal biopsies from 349 patients judged on clinical, radiologic, or pathologic grounds to have Crohn’s disease were studied, and findings were compared with a variety of clinical varibles. Biopsies from only 54 patients (15% of total) contained histologic changes characteristic of Crohn’s disease, and all but one of these were previously known to have colonic involvement. Yield of diagnostic findings was directly associated with the presence of sigmoidoscopic or radiologic abnormality in the distal colon or rectum. Minor, nondiagnostic abnormalities were more common. It is concluded that routine single rectal biopsy in unselected cases of Crohn’s disease has limited diagnostic value under usual conditions of practice, and that histologic abnormalities are most likely to be found in patients with known colonic, and especially sigmoid and rectal involvement.
In the orginal description by Crohn et al.,’ Crohn’s disease was described as involving the terminal ileum. However, it was quickly noted that other parts of the bowel might be involved and within 2 yr it was pointed out that the colon was also susceptible.* For many years the major interest to pathologists of colonic Crohn’s disease was in defining those differential characteristics that would allow them to distinguish Crohn’s disease of the colon from ulcerative colitis. Recently, however, morphologic alterations of the colon have been increasingly scrutinized because of the possibility of further elucidating the nature of the disease. In spite of a number of studies of the rectal mucosa in Crohn’s disease,“-7 some crucial questions have not been answered. Two specific questions have appeared important _Address requests for reprints to: National Cooperative Crohn’s Disease Study, Box B-158, 4200 E. 9th Avenue, Denver, Colorado 80262. 0 1979 by the American Gastroenterological Association OOlS-5085/79/10938-07502.00
to us, namely: “Is rectal biopsy a worthwhile procedure in patients with suspected Crohn’s disease and if so in what way?” and “What sorts of diagnostic classifications can be made of histologic appearance?” Previous analyses of histologic findings in Crohn’s disease have been based on small series. The National Cooperative Crohn’s Disease Study (NCCDS) has made possible a new approach to these questions. The NCCDS has accumulated experience of over 500 patients with Crohn’s disease, and rectal biopsies or resected specimens from the first 349 patients who completed the study were available for such studies. The present report provides data that bear on the first question and indicates that, in general, rectal biopsy is of relatively little value for diagnosis in patients who are not already known to have rectal Crohn’s disease. However, histologic classifications can be made, and our detailed pathologic basis for a diagnostic classification will be published separately. The National Cooperative Crohn’s Disease Study has included only patients in whom a diagnosis of Crohn’s disease has been made according to the criteria given below. Thus, although we have carefully studied tissues from 349 patients, we have not compared them with an equal number of biopsies from unselected patients without Crohn’s disease. This clearly does not allow us to make conclusions that depend on comparison with normals: however, other conclusions that do not depend on such comparisons are valid and are the subject of this paper.
Materials Selection The 349 patients
and Methods of Patients
patients from
included
whom
in this
adequate
study
initial
were
biopsies
the first were
re-
ceived by the Coordinating Center of the National Cooperative Crohn’s Disease Study. The diagnosis of Crohn’s disease
was
established
by one of the following
criteria:
(a)
RECTAL
the characteristic radiographic appearance of the intestine as judged both by study center radiologists and the NCCDS radiology review panel; (b) a resected specimen of intestine showing transmural inflammation or granulomas or both; or (c) typical gross findings at surgery plus a mesenteric lymph node showing a granuloma. Most patients were diagnosed hy radiographic and clinical means, without tissue confirmation. A sigmoidoscopy with rectal biopsy was required of all patients at the time of randomization into the study, and those biopsies form the basis of this report. Some patients had other biopsies, hut these latcar biopsies were not used.
Collection
and
Evaluation
of Material
Rectal biopsies were obtained by gastroenterologists at each study center and processed and interpreted routinely by the pathology department at that particular study center. The gastroenterologist hiopsied a characteristic lesion if one was present; if the mucosa appeared normal or was diffusely abnormal, the biopsy was taken from the edge of a rectal valve. One or more slides from each biopsy were referred to the pathology review panel consisting of two of us (R. B. Hill and T. H. Kent). Slides were identified only by date. NCCDS number, and a pathology num her. The histologic slides wtare reviewed independently by the two panel members. Findings recorded on a data sheet included presence or absence of decreased mucus production, crypt abscess, suhmucosal fibrosis, inflammation of the lamina propria, submucosal inflammation, and granulomas, including microgranulomas.” The study was not designed to evaluate the presence or significance of “dysplastic:” c:hangcs. An overall impression was recorded as abnormal and typical for Crohn’s disease, abnormal and consistent with Crohn’s disease, abnormal hut probably not Crohn’s disease, and normal. Comments were added as appropriate. In addition, the specimens were assigned a grade according to the outline in Table 1, with grade III indicating those that were highly characteristic of Crohn’s diseasr:. After the initial independent review of coded the authors jointly reached agreement in all specimens, r:odr:d specimens in which there was any difference of opinion. Typical examples of grades I, II, and III are seen in Figures l-4. ‘I’d)evaluate the reliability of the grading system, a final set of slidr:s was evaluated independently by each pathologist. This set consisted of 75 slides, 50 of which were new to the pathologist, thus providing a prospective evaluation of Ihe grading system. The remaining 25 slides were selcctt~rl from previous sets. using a table of random numhers. These slides were included to test intraobserver variations. ‘I’his test resulted in no differences greater than one grade. and only three of the 50 new cases in which the two pathologists had initial disagreement on whether the histologic findings represented severe grade II changes or actually indicated mild grade III. Seven of the 50 new cases provided some disagreement between grade I and II. Those r:ases reflect an anticipated grey zone between “normal” and “minimal inflammation.” Similarly, in three of the 2.~ rcxreoned rxses. there was a change in grading
Table
1. Histologic
BIOPSY
IN CROHN’S
DISEASE
939
Grading
1. Normal variations in ractal mucosa A. Up to 40% of the mucosa consists of lamina propria, with lymphocytes and plasma cells. Further expansion of thr! lamina propria is allowable, if it consists only of histirlcytes or edema. B. Lymphoid follicles are allowed. C. Histiocytes are allowed in any quantity. D. Wide variation in the amount and character of the mucus in thr: epithelial cells and within crypts. E. Although not strictly normal, tissue with atrophy and Iihrosis was included in group I. II. Mild chronic mucosal inflammation A. 4660% of the lamina propria is occupied hy lymphocytes and plasma cr:lls. B. The chronic inflammatory infiltrate is diffuse, not focal. C. Ncutrophils arc allowed hut should not prcdominatr!. D. O-l crypt abscess. E. No ulcer. F. No apprcciablc submucosal infiltratrt. (:. Other findings of group 1. 111. Moderatr: to scvcrr: discasr: A. More scverr: mucosal inflammation. B. Suhmucosal inflammation. C. LJlcer. D. Granuloma (including mir:rogrsnulomas).
between 1 and II by the same observer. The results of this test were thus felt to confirm the reliability of the grading system.
Clinical
Correlations
The clinical data listed in Table 2 had been recorded by study center physicians at the time of biopsy of each patient. Correlations were sought between histologic grade and each of the characteristics in Table 2, using the entire patient group and also subdividing according to the area of bowel involved.
Results Correlation of Disease
of Histologic
Crude
with Location
Table 3 shows the biopsy grade compared with the location of disease as determined radiographically. Of the 349 patients with clinical and radiographic diagnosis of Crohn’s disease, only 54 (15%) were found to have rectal biopsy changes characteristic of Crohn’s disease, and all but one of these were in patients already known to have coionic involvement. In the single exception a microgranuloma was found in the rectal biopsy of a patient thought to have disease confined to the small bowel. When the colon was known to be diseased, only ~2% had characteristically abnormal (grade III) biopsies. The rectal biopsies of two-thirds of the patients with known colonic involvement were within
940
Figure
HILL
GASTROENTEROLOGY
ET AL.
I. Grade I or normal cosa is 37% lamina
rectal mucosa with maximum allowable propria, 63% epithelium. X 125.
normal range histologically. Even when the rectum itself was known to be involved, biopsy showed characteristic abnormalities in only 60%, and 35% were felt to be normal. Only 9% of patients with disease thought to be confined to the small bowel had any abnormality at all in the rectal biopsy.
Figure
2. Grade
II or mild nonspecific
inflammation
of rectal
amount
of chronic
inflammatory
Vol. 77, No. 4, Part 2
cells in lamina
Correlation of Histologic Grade Sigmoidoscopic Appearance
propria.
The mu-
with
The appearance of the rectosigmoid colon was classified by the gastroenterologist as normal, abnormal but atypical, or typical Crohn’s disease.
mucosa
with 52% lamina
propria.
48% epithelium.
X 125.
RECTAL
Figure
3. Grade
III or scvcrc
mucosal
inflammation
Table 4 shows the comparison of the sigmoidoscopic appearance with the rectal biopsy grade for all patients studied. Of the 349 patients, 223 (64%) had a normal sigmoidoscopy; of these 193 had a normal biopsy. Ten patients with a normal sigmoidoscopy had a grade III biopsy. An atypical abnormal rectosigmoid colon was seen in 69 patients (20%), 41 of
Figure
4. Grade III change with granulomas intlammation IS 1~s than in Figure
with 77% lamina
propria,
BIOPSY
IN CROHN’S
~3%~cpithrlium.
DISEASE
941
x 75
whom had a normal biopsy. In the group in which the sigmoidoscopy was reported by the gastroenterologist as typical of Crohn’s disease, 45% had a characteristic biopsy, and 45% were normal. Correlations between sigmoidoscopic appearance and rectal biopsy grade were then sought within subgroups according to the area of bowel involved.
and nonspecific: chronic inflammation 3. the proscmcc: of granulomas classifies
of mucosa the lesion
and suhmucosa. Although as grade 111. x 60.
the degree:
of
942
HILL
GASTROENTEROLOGY
ET AL.
Table 2. Clinical Characteristics Tested for Clinicopathological Correlations
These data for patients with involvement of colononly, small-bowel-only, and both organs are shown in Tables 5-7, respectively. Thirty-four of the 37 patients with colon-only disease had sigmoidoscopic findings reported. Fifteen of these had a normal sigmoidoscopy, and the rectal biopsy was also normal was seen in 1 case of these 15. in 13. A granuloma Six patients had the rectosigmoid colon judged abnormal-atypical on sigmoidoscopy; a grade III biopsy was obtained from 4 of these, of which 2 showed granulomas. Thirteen of the 37 patients with colon-only disease had the typical sigmoidoscopic appearance of Crohn’s disease. Of these, 6 had a normal biopsy and 2 showed granulomas. None of the patients with only the small bowel involved had a sigmoidoscopy judged to be typical of Crohn’s disease (Table 6). There were 110 patients in this subgroup and 96 (87%) had a normal sigmoidoscopy. Eighty-eight of these 96 had a normal biopsy also. In only one case was a granuloma found and this was in the presence of otherwise normal mucosa. Table 7 shows the subgroup with both organs involved. The incidence of rectal biopsy abnormality in this subgroup is intermediate between the subgroups of colon-only and small-bowel-only patients. Other
Crohn’s Disease Activity Index Appearance at sigmoidoscopy Proscncc: of anal fissurc/fistula Prc:sc:nce of diarrhea Prcstmce of lowor gastrointestinal Location of discasc Months since onsct Prior therapy
No correlation was found between the rectal biopsy grade and the following characteristics: Crohn’s Disease Activity Index value”; duration of disease; presence of anal fissure or fistula; diarrhea; rectal bleeding; or medication being taken at the time of biopsy. This was true for the entire group as well as those with small-bowel-only, colon-only, or both colon and small bowel involved.
Discussion We have reviewed the histologic findings on rectal biopsies of 349 patients with previously
Table
3. Location
of Disease
by X-ray
Compared
bleeding
established Crohn’s disease, and correlated the findings with certain clinical characteristics of these patients. We cannot answer the question whether rectal biopsy is useful in diagnosis, because we started with diagnosed cases. However, we would speculate that in undiagnosed cases, a single rectal biopsy would be likely to provide a low yield of diagnostic information, since biopsies in known cases do not usually provide diagnostic information. The results of this study indicate that under ordinary conditions of medical practice, a single rectal biopsy provides diagnostic information only when the colon is involved enough to produce either typical or atypical barium enema appearance, or the sigmoidoscopy reveals typical Crohn’s disease or at least abnormal mucosa. Even when typical ulcerated lesions of the rectosigmoid were present, biopsy was not distinctly abnormal in 44% of such instances. This finding may have resulted from failure to biopsy the most abnormal-appearing area of a lesion, from location of the lesion above the peritoneal reflection where biopsy was judged hazardous, or from a true discrepancy between degree of sigmoidoscopic and histologic abnormality. When disease is radiographically confined to the small intestine or the sigmoidoscopy is normal, diagnostic information is obtained rarely by a single rectal biopsy. It is possible that this low yield could be increased by intensive cooperation between endoscopist and pathologist, multiple biopsies, deeper biopsies, and
Correlations
coded
Vol. 77,No. 4, Part 2
with Rectal
Biopsy
Grade
III
I
II
Colon, with rectum Colon, rectum sparod Small bowel only Both organs
7 13 100 140
1 1 9 24
Total
260 (75)”
35
Location
of diwasc:
I’The numbers
in parentheses
equal percent
of total number
of patients.
(10)
Total (I. II. III)
Without granulomas
With granulomas
6 2 0 23
6 1 1 15
20 17 110 202
31 (8)
23 (7)
349
( 100)
October
Table
RECTAL
1979
4. Appearance of Sigmoidoscopy Compared Rectal Biopsy Grade for All 349 Patients
with
Table
in the
Study
BIOPSY
IN CROHN’S
943
6. Appearance of Sigmoidoscopy Compared Rectal Biopsy Grade in 110 Patients with “Small-Bowel-Only” Involved
with
Grade
Grade Appearancr: at sigmoidoscopy
DISEASE
I
II
III
193
20
10
223 (64)”
41 26
II 5
17 26
69 (20) 57(16)
Total
Appearance of sigmoidoscopy
I
II
III
Total
88 I2 0
7 2 ll
1 I) 0
Y6 (87)“ 14(13)
~____ Normal Abnormal, but not typical of Crohn’s disease Typical Crohn’s disease
Normal Abnormal, atypical Typical Crohn’s disease ” The numbers
” The numbers
in parentheses
equal percent
in parentheses
equal percent
of total group.
of total.
serial sections. This study examined the results and implications of .a single biopsy, the most commonly performed and least hazardous tissue sampling procedure. Although the nondiagnostic findings that we termed nonspecific, are not found in normal control it is not clear how these nonspecific patients,“’ changes are helpful in a diagnostic way. It has not been shown, for instance, that these nonspecific changes would help differentiate Crohn’s disease from certain cases of shigellosis, ulcerative colitis, or other inflammatory conditions of the colon.” We would conclude that routine single rectal biopsy is of limited usefulness in Crohn’s disease, generally providing a small amount of positive information in a small proportion of cases. This conclusion is somewhat at variance with the conclusions of several other observers7~“‘~‘2.‘3 who have supported rectal biopsy as a regular procedure for diagnosis or prognosis. Although there is some variation among reports in the percentages of cases reported as revealing diagnostic or nonspecific changes, the differences in conclusion may not reflect major differences in data. Our study indicates that in only 5% of patients with disease confined to the small bowel will routine rectal biopsy of the edge of a rectal valve yield diagnostically useful information (Table 6). This low yield does not seem to justify routine use of a potentially hazardous procedure in this group of patients. (Hemorrhage requiring tranfusion or hospitalization occurred after a
minimum of 0.7% of rectal biopsies done in the NCCDS.) Rectal biopsy may be more useful in defining the nature and extent of observable rectal disease, as when colonic surgery is contemplated. Even here the yield of diagnostic information seems low (Table 7). It must be emphasized that our biopsies were obtained by a large number of physicians under widely varying clinical circumstances and processed in many labs using different l.echniques; this does not reflect the experience of a single center specializing in the study of this disease.‘” Sigmoidostopic observations and biopsies in this study were performed by more than 50 different physicians and the resultant descriptions and biopsy techniques were inevitably diverse. This may account for some of the lack of correlation of clinical with cndoscopic and histologic findings. However, since a common biopsy protocol was followed, it is unlikely that this variability invalidates the major findings of the study. We do not suggest that rectal biopsy under carefully controlled conditions with advanced or experimental techniques be abandoned; this kind of study may lead to further understanding of the nature of the disease, and indeed to specific diagnostic or therapeutic modalities as yet undiscovered. Meanwhile, we find extremely limited diagnostic use of random single biopsy of the apparently uninvolved colon. We do agree with others who report that yield of diagnostic data is much more likely when the colon is known to be involved,“,” or when
Table
Tab/e
5. Appearance of Sigmoidoscopy Compared with Rectal Biopsy Grade in 34 Patients with “ColonOnly” Involved
7. Appearance of Sigmoidoscopy Compared with Rectal Biopsy Crude in 200 Patients with “Small Bowel and Colon” InvoIvotl
Gradt: Appearanw of sigmoidoscopy Normal Abnormal, atypical Typical Crohn’s disease ” The numbers
in parentheses
(;radl!
I
II
III
Total
1:i
0
I I
2 4
15 (44)”
I 6 equal percent
6 of total.
6(l8) I3 (38)
Appcaranc~: of sigmoidoscopy Normal Abnormal, atypical Typical Crohn’s disease ” The numbers
in parentheses
1
II
III
Y3 29 19
13 -l h
F II IX
equal percent
of total group
Total 112 (56)” 47 (23) 43 (21)
944
HILL
ET AL.
the mucosa appears abnormal sigmoidoscopically,“~lo and that histological abnormalities in the colon COPrelate poorly with the severity of the disease.“.”
GASTROENTEROLOGY
8.
9.
Reference 1. Crohn 2. 3. 4. 5. 6.
7.
BB, Ginzburg L, Oppenheimer GD: Regional ileitis. A pathologic and clinical entity. JAMA 99:1323-1329, 1932 Colp R: A case of non-specific granuloma of the terminal ileum and cecum. Surg Clin North Am 14:443-449,1934 Cornes JS, Stecher M: Primary Crohn’s disease of the colon and rectum. Gut 2:189-201,196l Hawk WA, Turnbull RB Jr, Farmer RG: Regional enteritis of the colon. JAMA 201:738-746,1967 Lockhart-Mummery HE, Morson BC: Crohn’s disease of the large intestine. Gut 5:493-509.1964 Morson BC: The technique and interpretation of rectal biopsies in inflammatory bowel disease. In: Pathology Annual. Edited by SC Sommers. Englewood, Cliffs, N.J., Prentice-Hall, Inc., 1974, p 209-230 Goodman MJ, Skinner JM, Truelove SC: Abnormalities in the
10. 11. 12.
13.
14.
15.
Vol. 77, No. 4, Part 2
apparently normal bowel mucosa in Crohn’s disease. Lancet 1275~278,1976 Rotterdam H, Korelitz BI. Sommers SC: Microgranulomas in grossly normal rectal mucosa in Crohn’s disease. Am J Clin Path01 67:550-554,1977 Best WR, Becktel JM, Singleton JW, Kern F Jr: Development of a Crohn’s Disease Activity Index. Gastroenterology 70:439444,1978 Korelitz BI, Sommcrs SC: Rectal biopsy in patients with Crohn’s disease. JAMA 237:2742-2744,1977 Anderson FH. Bogoch A: Biopsies of large bowel in regional enteritis. Can Med Assoc J 98:150-153,1968 Dyer NH, Stansfeld AG, Dawson AM: The value of rectal biopsy in the diagnosis of Crohn’s disease. Stand J Gastroenterol5:491-496, 1970 Korelitz BI, Sommers SC: Differential diagnosis in ulcerative and granulomatous colitis by sigmoidoscopy, rectal biopsy and cell counts of rectal mucosa. Am J Gastroentcrol 61:460469,1974 Goodman MJ, Kirsner JB, Riddell RR: Usefulness of rectal biopsy in inflammatory bowel disease. Gastroenterology 72:952-956,1977 Gear EV Jr, Dobbins WO III: Rectal biopsy: A review of its diagnostic usefulness. Gastroenterology 55:522-544,1968
Clinical Usefulness Crohn’s Disease ROLLA
B. HILL, THOMAS
77:938-944,1979
of Rectal Biopsy in H. KENT,
and RICHARD
N. HANSEN
Department of Pathology, SUNY-Upstate Medical Center, Syracuse, New York; Department of Pathology, _. University of Iowa, Iowa City, Iowa; and the Division of Gastroenterology, University of Colorado Medical Center, Denver, Colorado
Initial rectal biopsies from 349 patients judged on clinical, radiologic, or pathologic grounds to have Crohn’s disease were studied, and findings were compared with a variety of clinical varibles. Biopsies from only 54 patients (15% of total) contained histologic changes characteristic of Crohn’s disease, and all but one of these were previously known to have colonic involvement. Yield of diagnostic findings was directly associated with the presence of sigmoidoscopic or radiologic abnormality in the distal colon or rectum. Minor, nondiagnostic abnormalities were more common. It is concluded that routine single rectal biopsy in unselected cases of Crohn’s disease has limited diagnostic value under usual conditions of practice, and that histologic abnormalities are most likely to be found in patients with known colonic, and especially sigmoid and rectal involvement.
In the orginal description by Crohn et al.,’ Crohn’s disease was described as involving the terminal ileum. However, it was quickly noted that other parts of the bowel might be involved and within 2 yr it was pointed out that the colon was also susceptible.* For many years the major interest to pathologists of colonic Crohn’s disease was in defining those differential characteristics that would allow them to distinguish Crohn’s disease of the colon from ulcerative colitis. Recently, however, morphologic alterations of the colon have been increasingly scrutinized because of the possibility of further elucidating the nature of the disease. In spite of a number of studies of the rectal mucosa in Crohn’s disease,“-7 some crucial questions have not been answered. Two specific questions have appeared important _Address requests for reprints to: National Cooperative Crohn’s Disease Study, Box B-158, 4200 E. 9th Avenue, Denver, Colorado 80262. 0 1979 by the American Gastroenterological Association OOlS-5085/79/10938-07502.00
to us, namely: “Is rectal biopsy a worthwhile procedure in patients with suspected Crohn’s disease and if so in what way?” and “What sorts of diagnostic classifications can be made of histologic appearance?” Previous analyses of histologic findings in Crohn’s disease have been based on small series. The National Cooperative Crohn’s Disease Study (NCCDS) has made possible a new approach to these questions. The NCCDS has accumulated experience of over 500 patients with Crohn’s disease, and rectal biopsies or resected specimens from the first 349 patients who completed the study were available for such studies. The present report provides data that bear on the first question and indicates that, in general, rectal biopsy is of relatively little value for diagnosis in patients who are not already known to have rectal Crohn’s disease. However, histologic classifications can be made, and our detailed pathologic basis for a diagnostic classification will be published separately. The National Cooperative Crohn’s Disease Study has included only patients in whom a diagnosis of Crohn’s disease has been made according to the criteria given below. Thus, although we have carefully studied tissues from 349 patients, we have not compared them with an equal number of biopsies from unselected patients without Crohn’s disease. This clearly does not allow us to make conclusions that depend on comparison with normals: however, other conclusions that do not depend on such comparisons are valid and are the subject of this paper.
Materials Selection The 349 patients
and Methods of Patients
patients from
included
whom
in this
adequate
study
initial
were
biopsies
the first were
re-
ceived by the Coordinating Center of the National Cooperative Crohn’s Disease Study. The diagnosis of Crohn’s disease
was
established
by one of the following
criteria:
(a)
RECTAL
the characteristic radiographic appearance of the intestine as judged both by study center radiologists and the NCCDS radiology review panel; (b) a resected specimen of intestine showing transmural inflammation or granulomas or both; or (c) typical gross findings at surgery plus a mesenteric lymph node showing a granuloma. Most patients were diagnosed hy radiographic and clinical means, without tissue confirmation. A sigmoidoscopy with rectal biopsy was required of all patients at the time of randomization into the study, and those biopsies form the basis of this report. Some patients had other biopsies, hut these latcar biopsies were not used.
Collection
and
Evaluation
of Material
Rectal biopsies were obtained by gastroenterologists at each study center and processed and interpreted routinely by the pathology department at that particular study center. The gastroenterologist hiopsied a characteristic lesion if one was present; if the mucosa appeared normal or was diffusely abnormal, the biopsy was taken from the edge of a rectal valve. One or more slides from each biopsy were referred to the pathology review panel consisting of two of us (R. B. Hill and T. H. Kent). Slides were identified only by date. NCCDS number, and a pathology num her. The histologic slides wtare reviewed independently by the two panel members. Findings recorded on a data sheet included presence or absence of decreased mucus production, crypt abscess, suhmucosal fibrosis, inflammation of the lamina propria, submucosal inflammation, and granulomas, including microgranulomas.” The study was not designed to evaluate the presence or significance of “dysplastic:” c:hangcs. An overall impression was recorded as abnormal and typical for Crohn’s disease, abnormal and consistent with Crohn’s disease, abnormal hut probably not Crohn’s disease, and normal. Comments were added as appropriate. In addition, the specimens were assigned a grade according to the outline in Table 1, with grade III indicating those that were highly characteristic of Crohn’s diseasr:. After the initial independent review of coded the authors jointly reached agreement in all specimens, r:odr:d specimens in which there was any difference of opinion. Typical examples of grades I, II, and III are seen in Figures l-4. ‘I’d)evaluate the reliability of the grading system, a final set of slidr:s was evaluated independently by each pathologist. This set consisted of 75 slides, 50 of which were new to the pathologist, thus providing a prospective evaluation of Ihe grading system. The remaining 25 slides were selcctt~rl from previous sets. using a table of random numhers. These slides were included to test intraobserver variations. ‘I’his test resulted in no differences greater than one grade. and only three of the 50 new cases in which the two pathologists had initial disagreement on whether the histologic findings represented severe grade II changes or actually indicated mild grade III. Seven of the 50 new cases provided some disagreement between grade I and II. Those r:ases reflect an anticipated grey zone between “normal” and “minimal inflammation.” Similarly, in three of the 2.~ rcxreoned rxses. there was a change in grading
Table
1. Histologic
BIOPSY
IN CROHN’S
DISEASE
939
Grading
1. Normal variations in ractal mucosa A. Up to 40% of the mucosa consists of lamina propria, with lymphocytes and plasma cells. Further expansion of thr! lamina propria is allowable, if it consists only of histirlcytes or edema. B. Lymphoid follicles are allowed. C. Histiocytes are allowed in any quantity. D. Wide variation in the amount and character of the mucus in thr: epithelial cells and within crypts. E. Although not strictly normal, tissue with atrophy and Iihrosis was included in group I. II. Mild chronic mucosal inflammation A. 4660% of the lamina propria is occupied hy lymphocytes and plasma cr:lls. B. The chronic inflammatory infiltrate is diffuse, not focal. C. Ncutrophils arc allowed hut should not prcdominatr!. D. O-l crypt abscess. E. No ulcer. F. No apprcciablc submucosal infiltratrt. (:. Other findings of group 1. 111. Moderatr: to scvcrr: discasr: A. More scverr: mucosal inflammation. B. Suhmucosal inflammation. C. LJlcer. D. Granuloma (including mir:rogrsnulomas).
between 1 and II by the same observer. The results of this test were thus felt to confirm the reliability of the grading system.
Clinical
Correlations
The clinical data listed in Table 2 had been recorded by study center physicians at the time of biopsy of each patient. Correlations were sought between histologic grade and each of the characteristics in Table 2, using the entire patient group and also subdividing according to the area of bowel involved.
Results Correlation of Disease
of Histologic
Crude
with Location
Table 3 shows the biopsy grade compared with the location of disease as determined radiographically. Of the 349 patients with clinical and radiographic diagnosis of Crohn’s disease, only 54 (15%) were found to have rectal biopsy changes characteristic of Crohn’s disease, and all but one of these were in patients already known to have coionic involvement. In the single exception a microgranuloma was found in the rectal biopsy of a patient thought to have disease confined to the small bowel. When the colon was known to be diseased, only ~2% had characteristically abnormal (grade III) biopsies. The rectal biopsies of two-thirds of the patients with known colonic involvement were within
940
Figure
HILL
GASTROENTEROLOGY
ET AL.
I. Grade I or normal cosa is 37% lamina
rectal mucosa with maximum allowable propria, 63% epithelium. X 125.
normal range histologically. Even when the rectum itself was known to be involved, biopsy showed characteristic abnormalities in only 60%, and 35% were felt to be normal. Only 9% of patients with disease thought to be confined to the small bowel had any abnormality at all in the rectal biopsy.
Figure
2. Grade
II or mild nonspecific
inflammation
of rectal
amount
of chronic
inflammatory
Vol. 77, No. 4, Part 2
cells in lamina
Correlation of Histologic Grade Sigmoidoscopic Appearance
propria.
The mu-
with
The appearance of the rectosigmoid colon was classified by the gastroenterologist as normal, abnormal but atypical, or typical Crohn’s disease.
mucosa
with 52% lamina
propria.
48% epithelium.
X 125.
RECTAL
Figure
3. Grade
III or scvcrc
mucosal
inflammation
Table 4 shows the comparison of the sigmoidoscopic appearance with the rectal biopsy grade for all patients studied. Of the 349 patients, 223 (64%) had a normal sigmoidoscopy; of these 193 had a normal biopsy. Ten patients with a normal sigmoidoscopy had a grade III biopsy. An atypical abnormal rectosigmoid colon was seen in 69 patients (20%), 41 of
Figure
4. Grade III change with granulomas intlammation IS 1~s than in Figure
with 77% lamina
propria,
BIOPSY
IN CROHN’S
~3%~cpithrlium.
DISEASE
941
x 75
whom had a normal biopsy. In the group in which the sigmoidoscopy was reported by the gastroenterologist as typical of Crohn’s disease, 45% had a characteristic biopsy, and 45% were normal. Correlations between sigmoidoscopic appearance and rectal biopsy grade were then sought within subgroups according to the area of bowel involved.
and nonspecific: chronic inflammation 3. the proscmcc: of granulomas classifies
of mucosa the lesion
and suhmucosa. Although as grade 111. x 60.
the degree:
of
942
HILL
GASTROENTEROLOGY
ET AL.
Table 2. Clinical Characteristics Tested for Clinicopathological Correlations
These data for patients with involvement of colononly, small-bowel-only, and both organs are shown in Tables 5-7, respectively. Thirty-four of the 37 patients with colon-only disease had sigmoidoscopic findings reported. Fifteen of these had a normal sigmoidoscopy, and the rectal biopsy was also normal was seen in 1 case of these 15. in 13. A granuloma Six patients had the rectosigmoid colon judged abnormal-atypical on sigmoidoscopy; a grade III biopsy was obtained from 4 of these, of which 2 showed granulomas. Thirteen of the 37 patients with colon-only disease had the typical sigmoidoscopic appearance of Crohn’s disease. Of these, 6 had a normal biopsy and 2 showed granulomas. None of the patients with only the small bowel involved had a sigmoidoscopy judged to be typical of Crohn’s disease (Table 6). There were 110 patients in this subgroup and 96 (87%) had a normal sigmoidoscopy. Eighty-eight of these 96 had a normal biopsy also. In only one case was a granuloma found and this was in the presence of otherwise normal mucosa. Table 7 shows the subgroup with both organs involved. The incidence of rectal biopsy abnormality in this subgroup is intermediate between the subgroups of colon-only and small-bowel-only patients. Other
Crohn’s Disease Activity Index Appearance at sigmoidoscopy Proscncc: of anal fissurc/fistula Prc:sc:nce of diarrhea Prcstmce of lowor gastrointestinal Location of discasc Months since onsct Prior therapy
No correlation was found between the rectal biopsy grade and the following characteristics: Crohn’s Disease Activity Index value”; duration of disease; presence of anal fissure or fistula; diarrhea; rectal bleeding; or medication being taken at the time of biopsy. This was true for the entire group as well as those with small-bowel-only, colon-only, or both colon and small bowel involved.
Discussion We have reviewed the histologic findings on rectal biopsies of 349 patients with previously
Table
3. Location
of Disease
by X-ray
Compared
bleeding
established Crohn’s disease, and correlated the findings with certain clinical characteristics of these patients. We cannot answer the question whether rectal biopsy is useful in diagnosis, because we started with diagnosed cases. However, we would speculate that in undiagnosed cases, a single rectal biopsy would be likely to provide a low yield of diagnostic information, since biopsies in known cases do not usually provide diagnostic information. The results of this study indicate that under ordinary conditions of medical practice, a single rectal biopsy provides diagnostic information only when the colon is involved enough to produce either typical or atypical barium enema appearance, or the sigmoidoscopy reveals typical Crohn’s disease or at least abnormal mucosa. Even when typical ulcerated lesions of the rectosigmoid were present, biopsy was not distinctly abnormal in 44% of such instances. This finding may have resulted from failure to biopsy the most abnormal-appearing area of a lesion, from location of the lesion above the peritoneal reflection where biopsy was judged hazardous, or from a true discrepancy between degree of sigmoidoscopic and histologic abnormality. When disease is radiographically confined to the small intestine or the sigmoidoscopy is normal, diagnostic information is obtained rarely by a single rectal biopsy. It is possible that this low yield could be increased by intensive cooperation between endoscopist and pathologist, multiple biopsies, deeper biopsies, and
Correlations
coded
Vol. 77,No. 4, Part 2
with Rectal
Biopsy
Grade
III
I
II
Colon, with rectum Colon, rectum sparod Small bowel only Both organs
7 13 100 140
1 1 9 24
Total
260 (75)”
35
Location
of diwasc:
I’The numbers
in parentheses
equal percent
of total number
of patients.
(10)
Total (I. II. III)
Without granulomas
With granulomas
6 2 0 23
6 1 1 15
20 17 110 202
31 (8)
23 (7)
349
( 100)
October
Table
RECTAL
1979
4. Appearance of Sigmoidoscopy Compared Rectal Biopsy Grade for All 349 Patients
with
Table
in the
Study
BIOPSY
IN CROHN’S
943
6. Appearance of Sigmoidoscopy Compared Rectal Biopsy Grade in 110 Patients with “Small-Bowel-Only” Involved
with
Grade
Grade Appearancr: at sigmoidoscopy
DISEASE
I
II
III
193
20
10
223 (64)”
41 26
II 5
17 26
69 (20) 57(16)
Total
Appearance of sigmoidoscopy
I
II
III
Total
88 I2 0
7 2 ll
1 I) 0
Y6 (87)“ 14(13)
~____ Normal Abnormal, but not typical of Crohn’s disease Typical Crohn’s disease
Normal Abnormal, atypical Typical Crohn’s disease ” The numbers
” The numbers
in parentheses
equal percent
in parentheses
equal percent
of total group.
of total.
serial sections. This study examined the results and implications of .a single biopsy, the most commonly performed and least hazardous tissue sampling procedure. Although the nondiagnostic findings that we termed nonspecific, are not found in normal control it is not clear how these nonspecific patients,“’ changes are helpful in a diagnostic way. It has not been shown, for instance, that these nonspecific changes would help differentiate Crohn’s disease from certain cases of shigellosis, ulcerative colitis, or other inflammatory conditions of the colon.” We would conclude that routine single rectal biopsy is of limited usefulness in Crohn’s disease, generally providing a small amount of positive information in a small proportion of cases. This conclusion is somewhat at variance with the conclusions of several other observers7~“‘~‘2.‘3 who have supported rectal biopsy as a regular procedure for diagnosis or prognosis. Although there is some variation among reports in the percentages of cases reported as revealing diagnostic or nonspecific changes, the differences in conclusion may not reflect major differences in data. Our study indicates that in only 5% of patients with disease confined to the small bowel will routine rectal biopsy of the edge of a rectal valve yield diagnostically useful information (Table 6). This low yield does not seem to justify routine use of a potentially hazardous procedure in this group of patients. (Hemorrhage requiring tranfusion or hospitalization occurred after a
minimum of 0.7% of rectal biopsies done in the NCCDS.) Rectal biopsy may be more useful in defining the nature and extent of observable rectal disease, as when colonic surgery is contemplated. Even here the yield of diagnostic information seems low (Table 7). It must be emphasized that our biopsies were obtained by a large number of physicians under widely varying clinical circumstances and processed in many labs using different l.echniques; this does not reflect the experience of a single center specializing in the study of this disease.‘” Sigmoidostopic observations and biopsies in this study were performed by more than 50 different physicians and the resultant descriptions and biopsy techniques were inevitably diverse. This may account for some of the lack of correlation of clinical with cndoscopic and histologic findings. However, since a common biopsy protocol was followed, it is unlikely that this variability invalidates the major findings of the study. We do not suggest that rectal biopsy under carefully controlled conditions with advanced or experimental techniques be abandoned; this kind of study may lead to further understanding of the nature of the disease, and indeed to specific diagnostic or therapeutic modalities as yet undiscovered. Meanwhile, we find extremely limited diagnostic use of random single biopsy of the apparently uninvolved colon. We do agree with others who report that yield of diagnostic data is much more likely when the colon is known to be involved,“,” or when
Table
Tab/e
5. Appearance of Sigmoidoscopy Compared with Rectal Biopsy Grade in 34 Patients with “ColonOnly” Involved
7. Appearance of Sigmoidoscopy Compared with Rectal Biopsy Crude in 200 Patients with “Small Bowel and Colon” InvoIvotl
Gradt: Appearanw of sigmoidoscopy Normal Abnormal, atypical Typical Crohn’s disease ” The numbers
in parentheses
(;radl!
I
II
III
Total
1:i
0
I I
2 4
15 (44)”
I 6 equal percent
6 of total.
6(l8) I3 (38)
Appcaranc~: of sigmoidoscopy Normal Abnormal, atypical Typical Crohn’s disease ” The numbers
in parentheses
1
II
III
Y3 29 19
13 -l h
F II IX
equal percent
of total group
Total 112 (56)” 47 (23) 43 (21)
944
HILL
ET AL.
the mucosa appears abnormal sigmoidoscopically,“~lo and that histological abnormalities in the colon COPrelate poorly with the severity of the disease.“.”
GASTROENTEROLOGY
8.
9.
Reference 1. Crohn 2. 3. 4. 5. 6.
7.
BB, Ginzburg L, Oppenheimer GD: Regional ileitis. A pathologic and clinical entity. JAMA 99:1323-1329, 1932 Colp R: A case of non-specific granuloma of the terminal ileum and cecum. Surg Clin North Am 14:443-449,1934 Cornes JS, Stecher M: Primary Crohn’s disease of the colon and rectum. Gut 2:189-201,196l Hawk WA, Turnbull RB Jr, Farmer RG: Regional enteritis of the colon. JAMA 201:738-746,1967 Lockhart-Mummery HE, Morson BC: Crohn’s disease of the large intestine. Gut 5:493-509.1964 Morson BC: The technique and interpretation of rectal biopsies in inflammatory bowel disease. In: Pathology Annual. Edited by SC Sommers. Englewood, Cliffs, N.J., Prentice-Hall, Inc., 1974, p 209-230 Goodman MJ, Skinner JM, Truelove SC: Abnormalities in the
10. 11. 12.
13.
14.
15.
Vol. 77, No. 4, Part 2
apparently normal bowel mucosa in Crohn’s disease. Lancet 1275~278,1976 Rotterdam H, Korelitz BI. Sommers SC: Microgranulomas in grossly normal rectal mucosa in Crohn’s disease. Am J Clin Path01 67:550-554,1977 Best WR, Becktel JM, Singleton JW, Kern F Jr: Development of a Crohn’s Disease Activity Index. Gastroenterology 70:439444,1978 Korelitz BI, Sommcrs SC: Rectal biopsy in patients with Crohn’s disease. JAMA 237:2742-2744,1977 Anderson FH. Bogoch A: Biopsies of large bowel in regional enteritis. Can Med Assoc J 98:150-153,1968 Dyer NH, Stansfeld AG, Dawson AM: The value of rectal biopsy in the diagnosis of Crohn’s disease. Stand J Gastroenterol5:491-496, 1970 Korelitz BI, Sommers SC: Differential diagnosis in ulcerative and granulomatous colitis by sigmoidoscopy, rectal biopsy and cell counts of rectal mucosa. Am J Gastroentcrol 61:460469,1974 Goodman MJ, Kirsner JB, Riddell RR: Usefulness of rectal biopsy in inflammatory bowel disease. Gastroenterology 72:952-956,1977 Gear EV Jr, Dobbins WO III: Rectal biopsy: A review of its diagnostic usefulness. Gastroenterology 55:522-544,1968