Primary Crohn's Disease of the Appendix Report of 14 cases and Review of the Literature S. SAMUEL YANG, M.D., PETER GIBSON, M.D., RICHARD S. McCAUGHEY, M.D., FEDERICO A. ARCARI, M.D., JAY BERNSTEIN, M.D.
Fourteen patients with primary Crohn's disease of the
appendix have been seen in a 12 year period. These patients represent 12.8% of the total number undergoing surgical resection because of Crohn's disease. Twenty-three cases of appendiceal Crohn's disease have been previously reported in the literature. A correct preoperative diagnosis is rarely made; the usual diagnosis is that of acute appendicitis or appendiceal abscess. The removed appendix in twelve of our 14 cases had marked thickening of the wall with transmural fibrosis and often with granulomatous inflammation. The enlarged appendix had an external appearance similar to that of ileal Crohn's disease, and we consider a correct surgical diagnosis might be possible with better awareness of its existence. The diagnosis might be suspected earlier when the clinical course of apparent appendicitis is protracted or atypical. Contrary to the previous estimation of high recurrence rate, this series and the cumulative evidence in the literature show a relatively low rate at 14%. The feared fistula formation following the removal of the appendix has not been seen in either our series or the literature. These patients, however, merit long-term follow-up.
A PPENDICITIS DUE TO CROHN'S DISEASE may be an isolated abnormality, but its presence may occasionally indicate concurrent disease or future involvement of the intestine. The process is usually characterized by marked enlargement with transmural fibrosis, muscular hypertrophy and chronic inflammation; noncaseating granulomata are frequently present. Fourteen patients diagnosed as having Crohn's disease of the appendix have been seen in the 12 year period from 1966 to 1977 in a 700 bed general hospital. Most of the patients were considered clinically and at laparotomy to have acute appendicitis or appendiceal abscess. Twenty-three previously reported cases in the English literaturea 2,4,5,7,9 -13,15,17-19.21,22,25,26 are reviewed. We believe that this condition is not uncommon. Although its recognition is usually possible Reprint requests: S. Samuel Yang, M.D., The Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, Michigan 48072. Submitted for publication: August 4, 1978.
From the Departments of Anatomic Pathology, Surgery, Pediatric Section, and Internal Medicine, Gastroenterology Section, William Beaumont Hospital, Royal Oak, Michigan
and may be important to the intraoperative management, the diagnosis thus far has seldom been made clinically. The correct diagnosis also indicates that future long-term care of the patient is necessary. Materials and Methods From 1966 to the end of 1977, 14 appendices that were removed because of the clinical diagnosis of acute appendicitis or appendiceal abscess were diagnosed histopathologically as having Crohn's disease with transmural fibrosis, muscular hypertrophy, and chronic inflammation. Chronic inflammation associated with diverticulosis of the appendix was excluded from the study. Twelve of the 14 patients had at surgical exploration appendiceal enlargement and induration without clinically obvious abnormality on inspection of the intestine. Two appendices without enlargement had granulomatous inflammation of the appendix. Four patients underwent intestinal resection extending into the ileum and ascending colon, because of peritoneal fibrosis thought to be an extension of appediceal inflammation. One additional patient with similar peritoneal fibrosis had resection of terminal ileum and ascending colon after a frozen-section diagnosis of Crohn's disease. The patients in this study represented 12.8% of the total patients (109 cases) with Crohn's disease who had surgical resection of the bowel. The patients with a primary diagnosis of Crohn's disease elsewhere in the intestine and with concurrent, usually mild involvement of the appendix were not included in the study. All specimens on pathologic examination contained
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either severe transmural fibrosis and/or sarcoid-like granulomata. None was occluded proximally by tumor or other pathologic process. Clincal documents, descriptions of the surgical findings, and microscopic slides (H&E) were available in all cases. Ziehl-Neelsen and PAS stains were used to evaluate the granulomatous inflammation for microorganism. The patients were followed clinically from six months to 12 years and four months for postoperative complications and for recurrence of Crohn's disease in other areas. Twenty-three previously reported cases in the English literature with sufficient information were also reviewed. 1,2,4,5,7,911 -13,1517-19,2122,25,26 Probable cases were not included. Results Age
The age of our 14 patients ranged from 10 to 45 years (Table 1), with a mean of 21.1 years. The majority of the patients were in the second decade. The mean age of patients reported in the literature is slightly higher (25 years) with a peak incidence in the third decade. The oldest patient reported in the literature was 66 years (Table 1). Sex There were eight males and six females in the current series, approximately the same ratio as in the literature. The male-female ratio in the combined series was 1.5:1.
Clinical Findings The duration of the gastrointestinal symptoms varied from one day to three months in the two series. Only 24% (9/37) of the patients had courses of less than two days prior to surgery. Four of these nine patients with short clinical course, however, had chronic abdominal symptoms from several months to two years. The majority of the patients, 65% (24/37), had had abdominal symptoms more than five days before surgery. Five of these patients had had, in addition, chronic abdominal pain and discomfort for six months to 16 years. Two patients with a preoperative diagnosis of appendiceal abcess underwent appendectomy six weeks and seven weeks after initial diagnosis. Clinical Diagnosis (Table 1) Acute appendicitis was the preoperative diagnosis in 11 of 14 WBH cases and 11 of 17 cases in the literature with a preoperative diagnosis specified. Appendiceal
335
abscess was the diagnosis in the remaining three WBH cases and in three of the six remaining cases in the literature. Irritable colon, torsion of ovarian cyst and tubo-ovarian abscess were the remaining diagnoses in the latter series.
Surgical Procedure In five patients in the WBH series, the surgical resection extended to the ileum and cecum or ascending colon because of adhesions or a suspicion of tumor. Six patients in the literature also had extended surgical resection involving the ileum and cecum or colon. One additional patient had resection of right tube, ovary and cecum. One patient in each series had a sleeve of cecum removed. Only two patients, one in each of the two series, had a postoperative diagnosis of Crohn's disease after frozen-section examination at surgery. Another case in the literature had a surgical diagnosis of possible Crohn's disease of the appendix. In the remaining 34 patients, the Crohn's disease was not recognized at surgery.
Pathology (Table I) Most of the appendices were markedly enlarged and firm on external examination. Marked thickening of the wall with transmural fibrosis is evident grossly (Fig. 1). Eleven of the 14 appendices (79%) in the WBH series had a diameter larger than 1.7 cm. The remaining three appendices measured 1.2, 0.7 and 0.5 cm respectively. The gross findings among the previously reported patients were similar. All but one of the 14 (93%) appendices with measurements had a diameter larger than 1.5 cm. The one without enlargement was 0.6 cm. The appendiceal enlargement was mostly diffuse, only one
FIG. 1. Appendix of Case 7 with the lumen opened longitudinally. Abnormal mucosa and markedly thickened wall due to transmural fibrosis and muscular hypertrophy are evident.
336
YANG AND OTHERS
Ann. Surg. * March 1979
TABLE 1.
No.
Patients
Age/ Sex
Preop. Dx.
1
66-70
25 M AA
2
66-1272
27 F
3
66-2077
4
Extent of surgery
Surgical Dx.
Diameter Granuof A loma
AA
A
2
+
AA
T*
I-Ce, A
2
+
17 F
AA
AA
A
2.5
-
69-6450
14 F
AA?
AA r/o T
I-Ce, A
2
+
5
70-9517
17 F
AA
AA
A
1.2
+
6
72-9057
19 M AAb
Crohn*
I-Ac, A
2
-
7
73-12923
11 M AA
AA
A, Ce*
1.7
+
8
74-3146
18 F
Cecitis
A
0.5
+
9
74-12323
45 M AA
AA
I-AC, A
4
-
10
76-1578
19 F
AAb
I-AC, A
2
+
11
76-17973
14 M AA
AA
A
2.5
+
12 13
76-18063 77-16156
43 M AA 10 M AA
AA Chr A A AA A
1.7 1.8*
+
14
77-18329
16 F
AAbt
0.7
+
3
+
3 1.5
+ +
5
+
2.5
+
AA
AAb3
AAb*
A
Concurrent Dis.
Follow-up
Remarks
Negative sigmoidoscopy up to 20 cm at 2 yr., complained of spastic colon. Asymptomatic at 121/3 yr. EdemaofCe Negative UGI, SBS, BaE *Carcinoid or and sigmoidoscopy ulp to carcinoma 22 cln at 81/6 yr., abdominal pain several yrs. Asymptomatic at 121/6i yr. No evidence of disease at 7 yr. when she had tubal ligation. Asymptomatic at 121/2 yr. Negative UGI, SBS, BaE at 123 & 5 yr., occasional diarrhea. Normal chest x-ray at 6 yr. Good health at 8I/6 yr. with occasional diarrhea. Resection of I-Ac for CD 1 mo. postop. Asymptomatic at 42A yr. I, AC Asymptomatic and negative *By froz. sect. sigmoidoscopy up to 25 cm Granulomas at 6½2 yr. in I Ce Negative UGI, SBS at 1 yr. * 1.2 cm sleeve -for RLQ pain & tenfderness., Asymptomatic at 41/2 yr. Toxic mega- Total colectomy for typical *Bx-Chr. colon* CD 4 yr. postop. Proctitis I Negative BaE at 1 yr. Asymptorliatic at 31/2 yr. Asymptomatic at 5 mo. & I, Ce 21/3 Pr. Normal chest x-ray at 1 1/6 yr.
Lysis of intestinal adhesions at 2 wk. Normal UGI, at 6½2 mb. Acute gastritis at 11/ yr. No chr. problem. Asymptomatic at 10 mo. Asymptomatic at 6 mo. *Distal ½2 se,gment enldg. *CD considAsymptomatic at 6 mo. ered. tHealed
Meyerding 21 M et al. 16. Hollings 24 M AA 12 F AA 17 Fallis 15
91
T AA + T or Chr. A
18
Hall et al.
32
19
Ring
39 F
20
Cohen et al.
27 M Irritt. colon r/o T
21 22
37 F Ewenetal. 26 M AA
AA
Crohn*
Part'l colon I-AC, A
-
1.5 1.5
+ +
Edema Ce Ileocecal valve
Negative x-rays at 3 wk. & 9 mo. Asymptomatic at 1 yr. X-ray of GI negative. Negative sigmoidoscopy at 1 yr. CD of rectum by biopsy at 3 mo. X-ray negative. No evidence *By froz. sect. of disease at 5 yr.
I,Ce I Postop. wound abscess for 2 mo. Normal BaE & chest x-ray at
23
66
F
AA
1.5
+
1
yr.
CD in I-AC by BaE at 4 yr. Chest x-ray negative.
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o
CROHN'S DISEASE OF THE APPENDIX
No. 3
337
Table 1. (Continued)
No.
Patients
24
Age/ Sex
Preop. Dx.
21 F
Torsion ov. cyst
25
Hobson et al.
26 27 28
Geerkeen et al. Threatt et al.
16 M AA,? perf. 19 M AA
Surgical Dx.
Extent of surgery
Diameter Granuloma of A
L. ov. cyst*
0.6
+
Perf. + Ab
2
+
Perf. + Ab
3
+
17 M AA
A
+
21 M AAb
I-Ce, A
+
AAb
I-RC, A
+
29
20 F
30
26 F
*
Concurrent Dis.
Follow-up
Remarks
Colicky pain after 4 mo. *Appendix thickened & UGI, BaE negative. Negcongested ative laparotomy at 2 yr. CD of I-AC by BaE at 2½3 yr. Negative postop. BaE. Asymptomatic at 1½/2 yr. Pelvic abscess drained at 8 da. Negative postop. BaE. Asymptomnatic at 2½2 yr. UGI, BaE negative at 2 mo. Asymptomatic at 7 mo. Asymptomatic at 3 yr. Diarrhea for 6 mo. Asymptomatic at 25I6 yr. *Proximal Asymptomatic at 10 mo. segment
-
enlgd. 31 32 33 34 35 36 37
MacEachern Weiss et al. Wlodarski et al. Green et al.
20 F
Tubo-ov. Ab 21 M AAb
Ce, A, Rt. tube,ov.
Brown et al. Meyer
19 M
I-Tr, C, A
AA
+
26 M AA
+
24 F
24 M
Murphy et 18 M AA al.
Carcinoid I-Ce, A ? Crohn
+
1.5
+
2
+
6
-
Ce*, A
+
GI series negative at 3 wk., asymptomatic at 1 yr. Asymptomatic at 7 mo.
Tube, ov. Ce
Asymptomatic at 1½2 yr.
Negative UGI, SBS, BaE at 6 mo. Aymptomatic at 1½/2 yr. BaE & proctoscopy normal at 1½V2 yr. Asymptomatic at 5 yr. Negative GI tract x-ray. Negativepostop.UGI,SBS, *Sleeve BaE. Asymptomatic at 6 mo.
Footnote symbols refer to the remarks for that particular case number. Key: AA, Acute appendicitis; T, Tumor; Ce, Cecum; UGI, Upper GI series; CD, Crohn's disease; AAb, Appendiceal abscess;
A, Appendix; AC, Ascending colon; SBS, Small bowel series; Ov., Ovarian; I, Ileum; TrC, Transverse colon; BaE, Barium enema.
each in the WBH series and in the literature displayed a segmental enlargement. On microscopic examination, the enlargement and induration were due to transmural fibrosis, muscular hypertrophy and chronic inflammation (Fig. 2). Sarcoid-like granulomata (Fig. 3) were demonstrated in 11 of 14 appendices (79%) in the WBH series; stains for microorganisms were negative. Granulomata were demonstrated in the terminal ileum in one of the remaining three patients. Microscopic descriptions of the 23 previously reported cases indicated that granulomata were present in 20 (87%). All three appendices without significant enlargement in the combined series had granulomata. Seventeen patients in the combined series had regional lymph nodes available for evaluation, and granulomata were seen in 13 of them (76%). All of these 13 patients had granulomata in the appendix. No calcification was demonstrated either in the regional lymph nodes or bowels in both series.
Other pathologic findings of the appendix included crypt abscess in two of WBH patients, fissure and fistula in eight and abscess in seven of combined series. The appendix was considered perforated in two occasions.
Follow-up (Table I) Among our patients, a 17-year-old boy required surgery one month after the appendectomy for Crohn's disease of the ileocecal region and ascending colon. There is a possibility that the extra-appendiceal Crohn's disease had been present at the time of appendectomy, because the patient did not do well in the interim. After the second surgery, the patient has been asymptomatic for 4 2/3 years. Another patient, an 18-year-old girl, developed toxic megacolon immediately following the appendectomy. Therapy with Azulfidine® and corticosteroid was followed by a two year remission. Abdominal pain and diarrhea recurred, and total colectomy was carried out four years after surgery. The
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YANG AND OTHERS
338
developed fistula from the operative site. There has not been mortality in either the WBH series or the patients in the literature. Discussion
i J .--'.4.g : (:w
FIG. 2. A representative cross-section of appendix (Case 1), showing transmural fibrosis, muscular hypertrophy, and chronic inflammatory infiltration with multiple lymphoid aggregates. H&E stain (x4.4).
colon contained typical Crohn's disease with segmental, transmural granulomatous inflammation. One additional patient, who had extended resection of the ileum and cecum at age 14, had had occasional intermittent diarrhea (once every 2-3 months) up to 8 5/6 years of follow-up and was suspected of having recurrent disease. Roentgenograms of the entire intestine at 1 2/3 years and five years were, however, negative. The remaining 11 patients have been asymptomatic with follow-up periods ranging from six months to 12 1/3 years. Five patients had had more than four years follow-up. Follow-up results were similar among the previously reported 23 patients. Three patients developed Crohn's disease elsewhere after three months, 2 ½13 years and four years respectively. Seventeen of the remaining 20 patients had follow-up from six months to five years. Only two patients among these had follow-up more than four years. Follow-up information is not available in three patients. None of the patients in either series
FIG. 3. Submucosal sarcojf-like granulomata, composed of epithelioid histiocytes and multinucleated giant-cells (Case 10). H&E stain (x 120).
Retrospective analysis of the morphologic features of Crohn's disease of the appendix shows that gross diagnosis at surgery is possible in majority of the patients. This assumption is derived from the observation that most of the affected appendices in both WBH series (79%) and in the literature (93%) have been markedly enlarged and indurated (Fig. 1), much like mural thickening and induration in typical ileal Crohn's disease. However, the correct diagnosis has seldom been made surgically despite multiple case reports in the recent literature. 1,2,4,5,7,9,11-13,15,17-19,21,22,25,26 There are two immediate clinical implications of Crohn's disease of the appendix. The first is the possibility of concurrent Crohn's disease elsewhere in the gastrointestinal system, which seems to have been present though mild in approximately 25% of patients. The second is the risk of recurrence, which occurred in approximately 14% (including the case with occasional mild recurrent diarrhea). No late recurrence has been noted despite a follow-up of more than five years for six patients in the combined series. It is of interest that the postoperative recurrence rate among these patients is much lower than in those patients with intestinal Crohn's disease after primary excisional surgery (14% vs 34 to 58%).3 10 The rate is comparable, however, to that of colonic Crohn's disease (16%).6 The recurrence rate remains approximately the same when the patients with intercurrent disease are excluded or when the cases are limited to those with more than two or four years follow-up. If the two patients who had recurrences at one month and three months are considered as having had concurrent disease, then the recurrence rate is even lower than 10%. The risk of recurrence appears therefore to be small if intercurrent disease is carefully excluded at the time of surgery. The finding differs from the previous pessimistic observation.20 None of the patients developed a fistula from the operation site, a fact that has been noticed previously in the literature.9,12'19,20,22,25 The absence of postoperative fistula might indicate that appendiceal Crohn's disease is a mild form of the disease. The presence of lymphocytic cytotoxic effects on colonic tissue in patients with Crohn's disease24 and the hypothesis that Crohn's disease is a disease of lymphoid tissue"4 might explain the similarity of the reactions in the appendix and the ileum, both of which contain abundant lymphoid tissue. The colonic wall,
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CROHN'S DISEASE OF THE APPENDIX
on the other hand, does not become severely thickened in Crohn's disease8 and it contains less lymphoid tissue. The reader should be reminded that even though the appendiceal Crohn's disease is morphologically similar to the ileal disease, the clinical behaviors including the recurrence rate is similar to the colonic disease which is considered milder. The sarcoid-like reaction of lymphoid tissue is considered the most reliable feature of Crohn's disease although its presence is not essential for the diagnosis. The granulomata are indistinguishable from those in sarcoidosis, and the relationship of Crohn's disease and sarcoidosis is uncertain. Intestinal sarcoidosis is extremely rare, although 50% of patients with Crohn's disease may have positive Kveim tests.4 19 The case of appendiceal sarcoidosis reported by McLeod and colleagues had systemic disease as well.16 Other conditions that should be considered in the differential diagnosis, including tuberculosis, actinomycosis, parasitic infestation, foreign body reaction, and infection with Yersinia pseudotuberculosis, have been considered distinguishable histopathologically.23 One should not hesitate to make a diagnosis of Crohn's disease of the appendix when there is typical transmural chronic inflammation. However, diverticulitis of the appendix should be especially excluded, because the appendices are indurated and fibrotic with chronic inflammation. The differential diagnosis includes also occlusion of the proximal appendiceal lumen by tumor and mucocele. Crohn's disease may be suspected preoperatively when the clinical course of apparent appendicitis is protracted beyond five days or when the patient appears to have recurrent disease.
Acknowledgment We greatly appreciate the help of Doctors Paul T. Lahti, Daniel Scholes, John W. Murphy, Richard Galpin, and Anne Kuhn, and Mrs. Barbara Sommerfield and others in the follow-up of patients.
References 1. Brown, W. K. and Peters, R. W.: Crohn's Disease of the Appendix Presenting as Lower Intestinal Hemorrhage and Cecal Mass. Am. J. Gastroenterol., 65:349, 1976. 2. Cohen, W. N. and Denbesten, L.: Crohn's Disease with Predominant Involvement of the Appendix. Am. J. Roentgenol.,
110:361, 1970.
339
3. DeDombal, F. T., Burton, I. and Goligher, J. C.: Recurrence of Crohn's Disease After Primary Excisional Surgery. Gut, 12:519, 1971. 4. Ewen, S. W. B., Anderson, J., Galloway, J. M. D., et al.: Crohn's Disease Initially Confined to the Appendix. Gastroenterology, 60:853, 1971. 5. Fallis, J. C.: Granulomatous Appendicitis: A Case Report. Can. J. Surg., 11:449, 1968. 6. Farmer, R. G., Hawk, W. A. and Turnbull, R. B., Jr.: Clinical Patterns in Crohn's Disease: A Statistical Study of 615 Cases. Gastroenterology, 68:627, 1975. 7. Geerken, R. G. and Gibbons, R. B.: Isolated Crohn's Disease of the Appendix: Case Report. Milit. Med., 139:215, 1974. 8. Glotzer, D. J., Gardener, R. C., Goldman, H., et al.: Comparative Features and Course of Ulcerative and Granulomatous Colitis. N. Engl. J. Med., 282:582, 1970. 9. Green, G. I., Broadrick, G. L. and Collins, J. L.: Crohn's Disease of the Appendix Presenting as Acute Appendicitis. Am. J. Gastroenterol., 65:74, 1976. 10. Greenstein, A. J., Sachar, D. B., Pasternack, B. S.. and Janowitz, H. D.: Reoperation and Recurrence in Crohn's Colitis and Ileocolitis. Crude and Cumulative Rates. N. Engl. J. Med., 293:685, 1975. 11. Hall, J. H. and Hellier, M. D.: Crohn's Disease of the Appendix Presenting as Acute Appendicitis. Br. J. Surg., 56:390, 1969. 12. Hobson, R. W., II, Howard, E. W., Tuttle, J. R. and Jenis, E. H.: Crohn's Disease of the Appendix. Am. Surg., 39:349, 1973. 13. Hollings, R. M.: Crohn's Disease of the Appendix. Med. J. Aust., 1:693, 1964. 14. Lockart-Mummery, H. E. and Morson, B. C.: Crohn's Disease (Regional Enteritis) of the Large Intestine and its Distinction from Ulcerative Colitis. Gut, 1:87, 1960. 15. MacEachern, A. G.: Crohn's Disease of the Appendix. J. R. Coll. Surg. Edinb., 20:320, 1975. 16. McLeod, I. B., Jenkins, A. M. and Gill, W.: Sarcoidosis Involvingthe Vermiform Appendix. J. R. Coll. Surg. Edinb., 10:319, 1965. 17. Meyer, J. H.: Regional Enteritis (Crohn's Disease) Limited to the Appendix. Int. Surg., 61:532, 1976. 18. Meyerding, E. V. and Bertram, H. F.: Nonspecific Granulomatous Inflammation (Crohn's Disease) of the Appendix. A Case Report. Surgery, 34:891, 1953. 19. Murphy, J. J. and O'Conner, J. B.: Crohn's Disease of the Appendix. Ir. Med. J., 70:229, 1977. 20. Nugent, F. W.: Crohn's Disease of the Appendix. Am. J. Gastroenterol., 65:83, 1976. 21. Ring, A. M.: Isolated Regional Enteritis of the Appendix. Int. Surg., 54:290, 1970. 22. Threatt, B. and Appelman, H.: Crohn's Disease of the Appendix Presenting as Acute Appendicitis. Report of 3 Cases with a Review of the Literature. Radiology, 110:313, 1974. 23. Wang, T. K., Tolnai, G., Campbell, J. S., et al.: Crohn's Disease of the Appendix. Can. Med. Assoc. J., 106:233, 1972. 24. Ward, M.: The Pathogenesis of Crohn's Disease. Lancet, ii: 903, 1977. 25. Weiss, Y. and Durst, A. L.: Crohn's Disease of the Appendix. Presentation of a Case with Review of the Literature. Am. J. Gastroenterol., 63:333, 1975. 26. Wlodarski, F. M. and Trainer, T. D.: Granulomatous Oophoritis and Salpingitis Associated with Crohn's Disease of the Appendix. Am. J. Obstet. Gynecol., 122:527, 1975.
Fourteen patients with primary Crohn's disease of the
appendix have been seen in a 12 year period. These patients represent 12.8% of the total number undergoing surgical resection because of Crohn's disease. Twenty-three cases of appendiceal Crohn's disease have been previously reported in the literature. A correct preoperative diagnosis is rarely made; the usual diagnosis is that of acute appendicitis or appendiceal abscess. The removed appendix in twelve of our 14 cases had marked thickening of the wall with transmural fibrosis and often with granulomatous inflammation. The enlarged appendix had an external appearance similar to that of ileal Crohn's disease, and we consider a correct surgical diagnosis might be possible with better awareness of its existence. The diagnosis might be suspected earlier when the clinical course of apparent appendicitis is protracted or atypical. Contrary to the previous estimation of high recurrence rate, this series and the cumulative evidence in the literature show a relatively low rate at 14%. The feared fistula formation following the removal of the appendix has not been seen in either our series or the literature. These patients, however, merit long-term follow-up.
A PPENDICITIS DUE TO CROHN'S DISEASE may be an isolated abnormality, but its presence may occasionally indicate concurrent disease or future involvement of the intestine. The process is usually characterized by marked enlargement with transmural fibrosis, muscular hypertrophy and chronic inflammation; noncaseating granulomata are frequently present. Fourteen patients diagnosed as having Crohn's disease of the appendix have been seen in the 12 year period from 1966 to 1977 in a 700 bed general hospital. Most of the patients were considered clinically and at laparotomy to have acute appendicitis or appendiceal abscess. Twenty-three previously reported cases in the English literaturea 2,4,5,7,9 -13,15,17-19.21,22,25,26 are reviewed. We believe that this condition is not uncommon. Although its recognition is usually possible Reprint requests: S. Samuel Yang, M.D., The Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, Michigan 48072. Submitted for publication: August 4, 1978.
From the Departments of Anatomic Pathology, Surgery, Pediatric Section, and Internal Medicine, Gastroenterology Section, William Beaumont Hospital, Royal Oak, Michigan
and may be important to the intraoperative management, the diagnosis thus far has seldom been made clinically. The correct diagnosis also indicates that future long-term care of the patient is necessary. Materials and Methods From 1966 to the end of 1977, 14 appendices that were removed because of the clinical diagnosis of acute appendicitis or appendiceal abscess were diagnosed histopathologically as having Crohn's disease with transmural fibrosis, muscular hypertrophy, and chronic inflammation. Chronic inflammation associated with diverticulosis of the appendix was excluded from the study. Twelve of the 14 patients had at surgical exploration appendiceal enlargement and induration without clinically obvious abnormality on inspection of the intestine. Two appendices without enlargement had granulomatous inflammation of the appendix. Four patients underwent intestinal resection extending into the ileum and ascending colon, because of peritoneal fibrosis thought to be an extension of appediceal inflammation. One additional patient with similar peritoneal fibrosis had resection of terminal ileum and ascending colon after a frozen-section diagnosis of Crohn's disease. The patients in this study represented 12.8% of the total patients (109 cases) with Crohn's disease who had surgical resection of the bowel. The patients with a primary diagnosis of Crohn's disease elsewhere in the intestine and with concurrent, usually mild involvement of the appendix were not included in the study. All specimens on pathologic examination contained
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either severe transmural fibrosis and/or sarcoid-like granulomata. None was occluded proximally by tumor or other pathologic process. Clincal documents, descriptions of the surgical findings, and microscopic slides (H&E) were available in all cases. Ziehl-Neelsen and PAS stains were used to evaluate the granulomatous inflammation for microorganism. The patients were followed clinically from six months to 12 years and four months for postoperative complications and for recurrence of Crohn's disease in other areas. Twenty-three previously reported cases in the English literature with sufficient information were also reviewed. 1,2,4,5,7,911 -13,1517-19,2122,25,26 Probable cases were not included. Results Age
The age of our 14 patients ranged from 10 to 45 years (Table 1), with a mean of 21.1 years. The majority of the patients were in the second decade. The mean age of patients reported in the literature is slightly higher (25 years) with a peak incidence in the third decade. The oldest patient reported in the literature was 66 years (Table 1). Sex There were eight males and six females in the current series, approximately the same ratio as in the literature. The male-female ratio in the combined series was 1.5:1.
Clinical Findings The duration of the gastrointestinal symptoms varied from one day to three months in the two series. Only 24% (9/37) of the patients had courses of less than two days prior to surgery. Four of these nine patients with short clinical course, however, had chronic abdominal symptoms from several months to two years. The majority of the patients, 65% (24/37), had had abdominal symptoms more than five days before surgery. Five of these patients had had, in addition, chronic abdominal pain and discomfort for six months to 16 years. Two patients with a preoperative diagnosis of appendiceal abcess underwent appendectomy six weeks and seven weeks after initial diagnosis. Clinical Diagnosis (Table 1) Acute appendicitis was the preoperative diagnosis in 11 of 14 WBH cases and 11 of 17 cases in the literature with a preoperative diagnosis specified. Appendiceal
335
abscess was the diagnosis in the remaining three WBH cases and in three of the six remaining cases in the literature. Irritable colon, torsion of ovarian cyst and tubo-ovarian abscess were the remaining diagnoses in the latter series.
Surgical Procedure In five patients in the WBH series, the surgical resection extended to the ileum and cecum or ascending colon because of adhesions or a suspicion of tumor. Six patients in the literature also had extended surgical resection involving the ileum and cecum or colon. One additional patient had resection of right tube, ovary and cecum. One patient in each series had a sleeve of cecum removed. Only two patients, one in each of the two series, had a postoperative diagnosis of Crohn's disease after frozen-section examination at surgery. Another case in the literature had a surgical diagnosis of possible Crohn's disease of the appendix. In the remaining 34 patients, the Crohn's disease was not recognized at surgery.
Pathology (Table I) Most of the appendices were markedly enlarged and firm on external examination. Marked thickening of the wall with transmural fibrosis is evident grossly (Fig. 1). Eleven of the 14 appendices (79%) in the WBH series had a diameter larger than 1.7 cm. The remaining three appendices measured 1.2, 0.7 and 0.5 cm respectively. The gross findings among the previously reported patients were similar. All but one of the 14 (93%) appendices with measurements had a diameter larger than 1.5 cm. The one without enlargement was 0.6 cm. The appendiceal enlargement was mostly diffuse, only one
FIG. 1. Appendix of Case 7 with the lumen opened longitudinally. Abnormal mucosa and markedly thickened wall due to transmural fibrosis and muscular hypertrophy are evident.
336
YANG AND OTHERS
Ann. Surg. * March 1979
TABLE 1.
No.
Patients
Age/ Sex
Preop. Dx.
1
66-70
25 M AA
2
66-1272
27 F
3
66-2077
4
Extent of surgery
Surgical Dx.
Diameter Granuof A loma
AA
A
2
+
AA
T*
I-Ce, A
2
+
17 F
AA
AA
A
2.5
-
69-6450
14 F
AA?
AA r/o T
I-Ce, A
2
+
5
70-9517
17 F
AA
AA
A
1.2
+
6
72-9057
19 M AAb
Crohn*
I-Ac, A
2
-
7
73-12923
11 M AA
AA
A, Ce*
1.7
+
8
74-3146
18 F
Cecitis
A
0.5
+
9
74-12323
45 M AA
AA
I-AC, A
4
-
10
76-1578
19 F
AAb
I-AC, A
2
+
11
76-17973
14 M AA
AA
A
2.5
+
12 13
76-18063 77-16156
43 M AA 10 M AA
AA Chr A A AA A
1.7 1.8*
+
14
77-18329
16 F
AAbt
0.7
+
3
+
3 1.5
+ +
5
+
2.5
+
AA
AAb3
AAb*
A
Concurrent Dis.
Follow-up
Remarks
Negative sigmoidoscopy up to 20 cm at 2 yr., complained of spastic colon. Asymptomatic at 121/3 yr. EdemaofCe Negative UGI, SBS, BaE *Carcinoid or and sigmoidoscopy ulp to carcinoma 22 cln at 81/6 yr., abdominal pain several yrs. Asymptomatic at 121/6i yr. No evidence of disease at 7 yr. when she had tubal ligation. Asymptomatic at 121/2 yr. Negative UGI, SBS, BaE at 123 & 5 yr., occasional diarrhea. Normal chest x-ray at 6 yr. Good health at 8I/6 yr. with occasional diarrhea. Resection of I-Ac for CD 1 mo. postop. Asymptomatic at 42A yr. I, AC Asymptomatic and negative *By froz. sect. sigmoidoscopy up to 25 cm Granulomas at 6½2 yr. in I Ce Negative UGI, SBS at 1 yr. * 1.2 cm sleeve -for RLQ pain & tenfderness., Asymptomatic at 41/2 yr. Toxic mega- Total colectomy for typical *Bx-Chr. colon* CD 4 yr. postop. Proctitis I Negative BaE at 1 yr. Asymptorliatic at 31/2 yr. Asymptomatic at 5 mo. & I, Ce 21/3 Pr. Normal chest x-ray at 1 1/6 yr.
Lysis of intestinal adhesions at 2 wk. Normal UGI, at 6½2 mb. Acute gastritis at 11/ yr. No chr. problem. Asymptomatic at 10 mo. Asymptomatic at 6 mo. *Distal ½2 se,gment enldg. *CD considAsymptomatic at 6 mo. ered. tHealed
Meyerding 21 M et al. 16. Hollings 24 M AA 12 F AA 17 Fallis 15
91
T AA + T or Chr. A
18
Hall et al.
32
19
Ring
39 F
20
Cohen et al.
27 M Irritt. colon r/o T
21 22
37 F Ewenetal. 26 M AA
AA
Crohn*
Part'l colon I-AC, A
-
1.5 1.5
+ +
Edema Ce Ileocecal valve
Negative x-rays at 3 wk. & 9 mo. Asymptomatic at 1 yr. X-ray of GI negative. Negative sigmoidoscopy at 1 yr. CD of rectum by biopsy at 3 mo. X-ray negative. No evidence *By froz. sect. of disease at 5 yr.
I,Ce I Postop. wound abscess for 2 mo. Normal BaE & chest x-ray at
23
66
F
AA
1.5
+
1
yr.
CD in I-AC by BaE at 4 yr. Chest x-ray negative.
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o
CROHN'S DISEASE OF THE APPENDIX
No. 3
337
Table 1. (Continued)
No.
Patients
24
Age/ Sex
Preop. Dx.
21 F
Torsion ov. cyst
25
Hobson et al.
26 27 28
Geerkeen et al. Threatt et al.
16 M AA,? perf. 19 M AA
Surgical Dx.
Extent of surgery
Diameter Granuloma of A
L. ov. cyst*
0.6
+
Perf. + Ab
2
+
Perf. + Ab
3
+
17 M AA
A
+
21 M AAb
I-Ce, A
+
AAb
I-RC, A
+
29
20 F
30
26 F
*
Concurrent Dis.
Follow-up
Remarks
Colicky pain after 4 mo. *Appendix thickened & UGI, BaE negative. Negcongested ative laparotomy at 2 yr. CD of I-AC by BaE at 2½3 yr. Negative postop. BaE. Asymptomatic at 1½/2 yr. Pelvic abscess drained at 8 da. Negative postop. BaE. Asymptomnatic at 2½2 yr. UGI, BaE negative at 2 mo. Asymptomatic at 7 mo. Asymptomatic at 3 yr. Diarrhea for 6 mo. Asymptomatic at 25I6 yr. *Proximal Asymptomatic at 10 mo. segment
-
enlgd. 31 32 33 34 35 36 37
MacEachern Weiss et al. Wlodarski et al. Green et al.
20 F
Tubo-ov. Ab 21 M AAb
Ce, A, Rt. tube,ov.
Brown et al. Meyer
19 M
I-Tr, C, A
AA
+
26 M AA
+
24 F
24 M
Murphy et 18 M AA al.
Carcinoid I-Ce, A ? Crohn
+
1.5
+
2
+
6
-
Ce*, A
+
GI series negative at 3 wk., asymptomatic at 1 yr. Asymptomatic at 7 mo.
Tube, ov. Ce
Asymptomatic at 1½2 yr.
Negative UGI, SBS, BaE at 6 mo. Aymptomatic at 1½/2 yr. BaE & proctoscopy normal at 1½V2 yr. Asymptomatic at 5 yr. Negative GI tract x-ray. Negativepostop.UGI,SBS, *Sleeve BaE. Asymptomatic at 6 mo.
Footnote symbols refer to the remarks for that particular case number. Key: AA, Acute appendicitis; T, Tumor; Ce, Cecum; UGI, Upper GI series; CD, Crohn's disease; AAb, Appendiceal abscess;
A, Appendix; AC, Ascending colon; SBS, Small bowel series; Ov., Ovarian; I, Ileum; TrC, Transverse colon; BaE, Barium enema.
each in the WBH series and in the literature displayed a segmental enlargement. On microscopic examination, the enlargement and induration were due to transmural fibrosis, muscular hypertrophy and chronic inflammation (Fig. 2). Sarcoid-like granulomata (Fig. 3) were demonstrated in 11 of 14 appendices (79%) in the WBH series; stains for microorganisms were negative. Granulomata were demonstrated in the terminal ileum in one of the remaining three patients. Microscopic descriptions of the 23 previously reported cases indicated that granulomata were present in 20 (87%). All three appendices without significant enlargement in the combined series had granulomata. Seventeen patients in the combined series had regional lymph nodes available for evaluation, and granulomata were seen in 13 of them (76%). All of these 13 patients had granulomata in the appendix. No calcification was demonstrated either in the regional lymph nodes or bowels in both series.
Other pathologic findings of the appendix included crypt abscess in two of WBH patients, fissure and fistula in eight and abscess in seven of combined series. The appendix was considered perforated in two occasions.
Follow-up (Table I) Among our patients, a 17-year-old boy required surgery one month after the appendectomy for Crohn's disease of the ileocecal region and ascending colon. There is a possibility that the extra-appendiceal Crohn's disease had been present at the time of appendectomy, because the patient did not do well in the interim. After the second surgery, the patient has been asymptomatic for 4 2/3 years. Another patient, an 18-year-old girl, developed toxic megacolon immediately following the appendectomy. Therapy with Azulfidine® and corticosteroid was followed by a two year remission. Abdominal pain and diarrhea recurred, and total colectomy was carried out four years after surgery. The
Ann. Surg. * March 1979
YANG AND OTHERS
338
developed fistula from the operative site. There has not been mortality in either the WBH series or the patients in the literature. Discussion
i J .--'.4.g : (:w
FIG. 2. A representative cross-section of appendix (Case 1), showing transmural fibrosis, muscular hypertrophy, and chronic inflammatory infiltration with multiple lymphoid aggregates. H&E stain (x4.4).
colon contained typical Crohn's disease with segmental, transmural granulomatous inflammation. One additional patient, who had extended resection of the ileum and cecum at age 14, had had occasional intermittent diarrhea (once every 2-3 months) up to 8 5/6 years of follow-up and was suspected of having recurrent disease. Roentgenograms of the entire intestine at 1 2/3 years and five years were, however, negative. The remaining 11 patients have been asymptomatic with follow-up periods ranging from six months to 12 1/3 years. Five patients had had more than four years follow-up. Follow-up results were similar among the previously reported 23 patients. Three patients developed Crohn's disease elsewhere after three months, 2 ½13 years and four years respectively. Seventeen of the remaining 20 patients had follow-up from six months to five years. Only two patients among these had follow-up more than four years. Follow-up information is not available in three patients. None of the patients in either series
FIG. 3. Submucosal sarcojf-like granulomata, composed of epithelioid histiocytes and multinucleated giant-cells (Case 10). H&E stain (x 120).
Retrospective analysis of the morphologic features of Crohn's disease of the appendix shows that gross diagnosis at surgery is possible in majority of the patients. This assumption is derived from the observation that most of the affected appendices in both WBH series (79%) and in the literature (93%) have been markedly enlarged and indurated (Fig. 1), much like mural thickening and induration in typical ileal Crohn's disease. However, the correct diagnosis has seldom been made surgically despite multiple case reports in the recent literature. 1,2,4,5,7,9,11-13,15,17-19,21,22,25,26 There are two immediate clinical implications of Crohn's disease of the appendix. The first is the possibility of concurrent Crohn's disease elsewhere in the gastrointestinal system, which seems to have been present though mild in approximately 25% of patients. The second is the risk of recurrence, which occurred in approximately 14% (including the case with occasional mild recurrent diarrhea). No late recurrence has been noted despite a follow-up of more than five years for six patients in the combined series. It is of interest that the postoperative recurrence rate among these patients is much lower than in those patients with intestinal Crohn's disease after primary excisional surgery (14% vs 34 to 58%).3 10 The rate is comparable, however, to that of colonic Crohn's disease (16%).6 The recurrence rate remains approximately the same when the patients with intercurrent disease are excluded or when the cases are limited to those with more than two or four years follow-up. If the two patients who had recurrences at one month and three months are considered as having had concurrent disease, then the recurrence rate is even lower than 10%. The risk of recurrence appears therefore to be small if intercurrent disease is carefully excluded at the time of surgery. The finding differs from the previous pessimistic observation.20 None of the patients developed a fistula from the operation site, a fact that has been noticed previously in the literature.9,12'19,20,22,25 The absence of postoperative fistula might indicate that appendiceal Crohn's disease is a mild form of the disease. The presence of lymphocytic cytotoxic effects on colonic tissue in patients with Crohn's disease24 and the hypothesis that Crohn's disease is a disease of lymphoid tissue"4 might explain the similarity of the reactions in the appendix and the ileum, both of which contain abundant lymphoid tissue. The colonic wall,
Vol. 189 . No. 3
CROHN'S DISEASE OF THE APPENDIX
on the other hand, does not become severely thickened in Crohn's disease8 and it contains less lymphoid tissue. The reader should be reminded that even though the appendiceal Crohn's disease is morphologically similar to the ileal disease, the clinical behaviors including the recurrence rate is similar to the colonic disease which is considered milder. The sarcoid-like reaction of lymphoid tissue is considered the most reliable feature of Crohn's disease although its presence is not essential for the diagnosis. The granulomata are indistinguishable from those in sarcoidosis, and the relationship of Crohn's disease and sarcoidosis is uncertain. Intestinal sarcoidosis is extremely rare, although 50% of patients with Crohn's disease may have positive Kveim tests.4 19 The case of appendiceal sarcoidosis reported by McLeod and colleagues had systemic disease as well.16 Other conditions that should be considered in the differential diagnosis, including tuberculosis, actinomycosis, parasitic infestation, foreign body reaction, and infection with Yersinia pseudotuberculosis, have been considered distinguishable histopathologically.23 One should not hesitate to make a diagnosis of Crohn's disease of the appendix when there is typical transmural chronic inflammation. However, diverticulitis of the appendix should be especially excluded, because the appendices are indurated and fibrotic with chronic inflammation. The differential diagnosis includes also occlusion of the proximal appendiceal lumen by tumor and mucocele. Crohn's disease may be suspected preoperatively when the clinical course of apparent appendicitis is protracted beyond five days or when the patient appears to have recurrent disease.
Acknowledgment We greatly appreciate the help of Doctors Paul T. Lahti, Daniel Scholes, John W. Murphy, Richard Galpin, and Anne Kuhn, and Mrs. Barbara Sommerfield and others in the follow-up of patients.
References 1. Brown, W. K. and Peters, R. W.: Crohn's Disease of the Appendix Presenting as Lower Intestinal Hemorrhage and Cecal Mass. Am. J. Gastroenterol., 65:349, 1976. 2. Cohen, W. N. and Denbesten, L.: Crohn's Disease with Predominant Involvement of the Appendix. Am. J. Roentgenol.,
110:361, 1970.
339
3. DeDombal, F. T., Burton, I. and Goligher, J. C.: Recurrence of Crohn's Disease After Primary Excisional Surgery. Gut, 12:519, 1971. 4. Ewen, S. W. B., Anderson, J., Galloway, J. M. D., et al.: Crohn's Disease Initially Confined to the Appendix. Gastroenterology, 60:853, 1971. 5. Fallis, J. C.: Granulomatous Appendicitis: A Case Report. Can. J. Surg., 11:449, 1968. 6. Farmer, R. G., Hawk, W. A. and Turnbull, R. B., Jr.: Clinical Patterns in Crohn's Disease: A Statistical Study of 615 Cases. Gastroenterology, 68:627, 1975. 7. Geerken, R. G. and Gibbons, R. B.: Isolated Crohn's Disease of the Appendix: Case Report. Milit. Med., 139:215, 1974. 8. Glotzer, D. J., Gardener, R. C., Goldman, H., et al.: Comparative Features and Course of Ulcerative and Granulomatous Colitis. N. Engl. J. Med., 282:582, 1970. 9. Green, G. I., Broadrick, G. L. and Collins, J. L.: Crohn's Disease of the Appendix Presenting as Acute Appendicitis. Am. J. Gastroenterol., 65:74, 1976. 10. Greenstein, A. J., Sachar, D. B., Pasternack, B. S.. and Janowitz, H. D.: Reoperation and Recurrence in Crohn's Colitis and Ileocolitis. Crude and Cumulative Rates. N. Engl. J. Med., 293:685, 1975. 11. Hall, J. H. and Hellier, M. D.: Crohn's Disease of the Appendix Presenting as Acute Appendicitis. Br. J. Surg., 56:390, 1969. 12. Hobson, R. W., II, Howard, E. W., Tuttle, J. R. and Jenis, E. H.: Crohn's Disease of the Appendix. Am. Surg., 39:349, 1973. 13. Hollings, R. M.: Crohn's Disease of the Appendix. Med. J. Aust., 1:693, 1964. 14. Lockart-Mummery, H. E. and Morson, B. C.: Crohn's Disease (Regional Enteritis) of the Large Intestine and its Distinction from Ulcerative Colitis. Gut, 1:87, 1960. 15. MacEachern, A. G.: Crohn's Disease of the Appendix. J. R. Coll. Surg. Edinb., 20:320, 1975. 16. McLeod, I. B., Jenkins, A. M. and Gill, W.: Sarcoidosis Involvingthe Vermiform Appendix. J. R. Coll. Surg. Edinb., 10:319, 1965. 17. Meyer, J. H.: Regional Enteritis (Crohn's Disease) Limited to the Appendix. Int. Surg., 61:532, 1976. 18. Meyerding, E. V. and Bertram, H. F.: Nonspecific Granulomatous Inflammation (Crohn's Disease) of the Appendix. A Case Report. Surgery, 34:891, 1953. 19. Murphy, J. J. and O'Conner, J. B.: Crohn's Disease of the Appendix. Ir. Med. J., 70:229, 1977. 20. Nugent, F. W.: Crohn's Disease of the Appendix. Am. J. Gastroenterol., 65:83, 1976. 21. Ring, A. M.: Isolated Regional Enteritis of the Appendix. Int. Surg., 54:290, 1970. 22. Threatt, B. and Appelman, H.: Crohn's Disease of the Appendix Presenting as Acute Appendicitis. Report of 3 Cases with a Review of the Literature. Radiology, 110:313, 1974. 23. Wang, T. K., Tolnai, G., Campbell, J. S., et al.: Crohn's Disease of the Appendix. Can. Med. Assoc. J., 106:233, 1972. 24. Ward, M.: The Pathogenesis of Crohn's Disease. Lancet, ii: 903, 1977. 25. Weiss, Y. and Durst, A. L.: Crohn's Disease of the Appendix. Presentation of a Case with Review of the Literature. Am. J. Gastroenterol., 63:333, 1975. 26. Wlodarski, F. M. and Trainer, T. D.: Granulomatous Oophoritis and Salpingitis Associated with Crohn's Disease of the Appendix. Am. J. Obstet. Gynecol., 122:527, 1975.
