Crohn's Disease and Carcinoma: Increasing Justification for Surveillance? Thomas J. Stahl, M.D., David J. Schoetz Jr., M.D., Patricia L. Roberts, M.D., John A. Coller, M.D., John J. Murray, M.D., Mark L. Silverman, M.D., Malcolm C. Veidenheimer, M.D. From the Department of Colon and Rectal Surgery and the Department of Anatomic Pathology, Lahey Clinic Medical CenteL Burlington, Massachusetts Carcinoma of the colon that arises in patients with Crohn's disease is being reported with increasing frequency. To help clarify the nature of this association, records of 25 patients with Crohn's disease and colorectal carcinoma seen from 1957 through 1989 were reviewed. One patient had leiomyosareoma of the rectum, and two patients had the onset of Crohn's disease after the diagnosis and treatment of colorectal carcinoma. Therefore, 22 patients were available for complete retrospective analysis. The median age at diagnosis of Crohn's disease was 37 years (range, 15-67 years), and the median age at diagnosis of carcinoma was 54.5 years (range, 32-76 years). The median duration of symptoms preceding the discovery of colorectal carcinoma was 18.5 years (range, 0-32 years), Carcinoma arose in colonic segments with known Crohn's disease in 77 percent of patients, and six patients (27 percent) had associated colonic mucosal dysplasia. One lesion was classified as Dukes A, nine lesions were Dukes B, five lesions were Dukes C, and seven lesions were Dukes D. Patients with an onset of Crohn's disease before the age of 40 years had primarily Dukes C or D lesions and consequently poor survival. Most patients presented with nonspecific signs and symptoms, with nothing to distinguish the activity of the Crohn's disease from the presence of colorectal neoplasm. Younger patients with long-standing Crohn's disease should be considered for colonic surveillance to permit earlier diagnosis and treatment of potential colorectal carcinoma. [Key words: Crohn's disease; Colon carcinoma; Surveillance; Colorectal carcinoma] Stahl TJ, Schoetz DJ Jr, Roberts PL, Coller JA, Murray JJ, Silverman ML, Veidenheimer MC. Crohn's disease and carcinoma: increasing justification for surveillance? Dis Colon Rectum 1992;35:850-856. or the last 30 years, the relationship b e t w e e n Crohn's disease and colorectal carcinoma has evolved from the tenet that n o relationship existed to the currently held belief that the risk of carcin o m a d e v e l o p i n g in patients with Crohn's disease
F
Read at the meeting of The American Society of Colon and Rectal Surgeons, Boston, Massachusetts, May 12 to 17, 1991. Dr. Stahl's present address is Department of Surgery, Georgetown University Hospital, Washington, D.C. 20007. Address reprint requests to Dr. Schoetz: Department of Colon and Rectal Surgery, LaheyClinic Medical Center, 41 Mall Road, Burlington, Massachusetts 01805. 850
is greater than that in the general population. Concomitantly, as the recognition of Crohn's colitis as a distinct entity from ulcerative colitis has broadened, the n u m b e r of reported cases of colorectal carcinoma in patients with Crohn's disease has risen. However, several u n r e s o l v e d issues remain with regard to the association of C r o h n ' s disease and colorectal carcinoma. First, accurate assessment of the incidence of colorectal carcinoma in patients with Crohn's disease is not known, primarily because of difficulties in defining the core cohort of patients. Each institution has a u n i q u e population that is influenced by g e o g r a p h y and referral patterns. A population-based study of this association is n e e d e d to address the true incidence definitively, and it has yet to be undertaken. Second, as the n u m b e r of r e p o r t e d cases of colorectal carcinoma in patients with Crohn's disease increases, a growing n u m b e r of clinicians and surgeons cite colonic surveillance examinations as worthwhile, in k e e p i n g with the logic of such m e t h o d s as n o w applied to ulcerative colitis. Controversy stems from features of Crohn's colitis that are u n i q u e from ulcerative colitis and s u p p o s e d l y make surveillance less reliable. Third, because so few patients have colorectal carcinoma in association with Crohn's disease, the characterization of thfs illness is not complete. To add insight into this problem, we report o n patients with colorectal carcinoma in association with Crohn's disease w h o were treated at the Lahey Clinic over a 33-year period.
MATERIALS A N D
METHODS
The records of patients having the simultaneous diagnoses of Crohn's disease and carcinoma of the colon or rectum from 1957 t h r o u g h 1989 were
Vol. 35, No. 9
ANAL INCONTINENCE AND ANORECTAL MANOMETRY
reviewed. From this review, 25 patients were identified. The diagnosis of Crohn's disease was predicated on the basis of clinical behavior, endoscopic and radiographic findings, results of biopsy, macroscopic appearance of the bowel at surgery, and pathologic findings of the surgical specimen. On the few occasions when pathologic findings of the resected specimen were not diagnostic, the patient was included based on the strong clinical impressions of the treating physicians along with standard macroscopic characteristics of the disease found at surgery (fat wrapping, thickened bowel with shortened mesentery, and formation of fistulas). Onset of Crohn's disease was determined to be when the patient first noted symptoms. No systematic surveillance program for patients with Crohn's disease was or is in effect at the Lahey Clinic. A comparative group of 1,719 patients treated at the Lahey Clinic for carcinoma of the colon during 1962 through 1980 was also included for comparison. Data for these patients were taken from two studies from the Lahey Clinic *'z for 1962 through 1976 and from information in the Lahey Clinic Cancer Registry abstracts for 1977 through 1980. Mann-Whitney rank sum analyses were used for statistical analysis.
851
Table 1. Comparative Patient Characteristics
Characteristics Number of patients Male Female Median age at diagnosis of carcinoma Median age at diagnosis of Crohn's disease
Crohn's Disease and Carcinoma
Colon Carcinoma 1962-1980
22 8 (36%) 14 (64%) 55 yr
1,719 941 (55%) 778 (45%) 63 yr
39 yr
6
~a 2
I
5
1
I
I
I
J
I
15
20
25
30
35
C r o h n ' s to c a n c e r i n t e r v a l ( y r s )
Figure 1. Interval from symptomatic onset of Crohn's disease to the diagnosis of colorectal carcinoma for all 22 patients. 7
-1
6
-4 5 |
[] Crohn'~ D• , 40 yrs 9 Crohn's Dx , 40 yea
RESULTS Of the 25 patients in our study, one patient had Crohn's colitis and leiomyosarcoma of the rectum. Two patients had carcinoma of the colon diagnosed and treated before the diagnosis of Crohn's disease was made. These three patients are excluded from the study, leaving 22 patients for discussion. The general characteristics of these patients are presented in Table 1. The median interval between the onset of symptoms of Crohn's disease and the diagnosis of carcinoma of the colon was 18.5 years (range, 0-32 years). The number of patients in each five-year interval is represented in Figure 1. Of note is the number of patients who presented with carcinoma within five years of the diagnosis of Crohn's disease, with one patient who presented with the two illnesses simultaneously. The interval pattern of Crohn's disease to carcinoma differed when the 22 patients were further categorized by the age at onset of Crohn's disease. The number of patients diagnosed with colorectal carcinoma in 10-year intervals is shown in Figure 2. Half of the patients
~
2
10 20 3o Crohn's to cancer interval
40
(yrs) Figure 2. Interval from symptomatic onset of Crohn's disease to the diagnosis of colorectal carcinoma categorized by onset of Crohn's disease before (darkened bars; n -12) and after (open bars; n = 10) the age of 40 years. with the onset of Crohn's disease after the age of 40 years had less than 10 years of Crohn's disease before carcinoma was diagnosed, whereas, for patients with the onset of Crohn's disease before the age of 40 years, 10 of 12 patients (83 percent) had 10 years or more of Crohn's disease before carcinoma was diagnosed. Most cases occurred in the latter part of the study period. From 1957 through 1970, two patients were diagnosed; from 1971 through 1980, five patients were diagnosed; and from 1981 through 1989, 15 patients were diagnosed.
STAHL E T AL
852
The number of patients with Crohn's disease seen at the Lahey Clinic during the same 33-year interval was 2,987, which includes patients with Crohn's disease in all locations. Annual incidence rates for the development of colorectal carcinoma are presented in Table 2, with a rate in excess of that which would be expected for patients seen from 1981 through 1989. The presenting symptoms of carcinoma of the colon were nonspecific. The dominant symptoms are listed in Table 3. Location of Carcinoma and Relationship to Involvement w i t h Crohn's D i s e a s e The locations of the carcinomas are presented in Table 4. Two patients had two synchronous carcinomas each, for a total of 24 carcinomas of the colon. The locations of 1,719 colon carcinomas treated at the Lahey Clinic during 1962 through 1980 are presented for comparison, The extent of Crohn's disease is summarized in Table 5. The number of patients whose colon carcinoma arose in an area of the colon known to have been involved with Crohn's disease was 17 (77 percent). Four of the carcinomas arose in areas of stricture (18 percent), and severe mucosal dysplasia was found in the colon of six patients (27 percent). Table 2. Annual Incidence Rates Time
Number of Carcinomas
Number of Patients with Crohn's Disease
Annual Incidence
1957-1989 1957-1980 1981-1989
22 7 15
2,987 1,603 1,384
22/100,000 26/100,000 120/100,000
Annual incidence rate for general population is 42/ 100,000. a Table 3. Presenting Symptoms Symptoms None Pain or mass Flare inflammatory bowel disease symptoms Blood in stool or anemia Obstruction Rectal bleeding Change in bowel habits Toxic colitis Unknown
Number of Patients 5 4 4 3 2 1 1 1 1
Dis Colon Rectum, September 1992
Table 4. Comparative Distribution of Colorectal Carcinomas
Location
Ascending colon Transverse colont Descending colon Sigmoid colon Rectum
Crohn's Disease and Carcinoma*
Colon Carcinoma 1962-1980
(%)
(%)
10 (42) 4 (17) 1 (4) 5 (21) 4 (17)
329 (19) 158 (9) 83 (5) 493 (29) 656 (38)
* Includes two patients with synchronous carcinomas. ? Includes hepatic and splenic flexures. Table 5. Distribution of Crohn's Disease Location
Number of Patients
Ileocolonic Ileocecal Pancolonic Descending colon Ascending colon Distal ileum
10 4 3 3 1 1
Stage a n d D i f f e r e n t i a t i o n The stages of the carcinomas are listed in Table 6. The pathologic differentiation of the tumors was as follows: well differentiated in two patients, moderately differentiated in eight patients, and poorly differentiated in nine patients; it was not specified in the pathologic report in three patients. Seven mucinous carcinomas (32 percent) were found, and three signet-ring cell carcinomas were present.
Survival Survival was determined for 18 patients who were observed for five or more years. The remaining four patients had no evidence of disease at 11 to 30 months. Survival data are summarized in Table 7. The only comparative difference in survival involves patients with Crohn's disease with Dukes C lesions who tended to have a poorer survival than patients with colorectal carcinoma in the comparative cohort at the same stage,
Early
vs.
Late Onset of Crohn's D i s e a s e
The characteristics of the clinical presentation and subsequent colorectal carcinoma were distinctly different when patients whose onset of Crohn's disease occurred before the age of 40 years
CROHN'S DISEASE AND CANCER
Vol. 35, No. 9 Table 6.
Table 8. Onset of Crohn's Disease
Comparative Cancer Stages Dukes Stage
Crohn's Disease and Carcinoma (%)
Colon Carcinoma 1962-1980 (%)
A
1 (5) 9 (41) 5 (23) 7 (32)
309(18) 629 (37) 400 {23) 372 (22)
B
C D
Table 7.
Five-Year Survival by Stage Dukes Stage
and Carcinoma (%)
Colon Carcinoma 1962-1980 (%)
A* Bi C~: D
0 6/7 (86) 1/4 (25) 0/7
291/304 (96) 518/595 (87) 166/304 (55) 6/312 (2)
Crohn's Disease
* One patient with no evidence of disease at 12 months. 1 Two patients with no evidence of disease at 19 and 30 months. :[: One patient with no evidence of disease at 11 months.
were compared with patients whose onset of Crohn's disease occurred after this age. Some of these differences are noted in Table 8. The median duration of disease before the diagnosis of carcinoma was significantly longer for patients with early onset of Crohn's disease. The presenting stage of disease and survival were also notably different when these two groups were compared (Table 9). Half of the patients with the onset of Crohn's disease before the age of 40 years presented with Dukes D lesions, with a corresponding poor five-year survival. The only survivors in the group with early-onset Crohn's disease were patients whose carcinoma was a Dukes B lesion at diagnosis. DISCUSSION Although the initial description of granulomatous enteritis of the colon was made in 1934 by Colp, 4 it was not until the article by LockhartMummery and Morson 5 in 1960 that the clinical entity of Crohn's colitis was accepted as distinct from ulcerative colitis. Since then, the number of patients with Crohn's disease of the large intestine has grown consistently to the point that colonic involvement is present in 40 to 60 percent of all patients with Crohn's disease.
F
Read at the meeting of The American Society of Colon and Rectal Surgeons, Boston, Massachusetts, May 12 to 17, 1991. Dr. Stahl's present address is Department of Surgery, Georgetown University Hospital, Washington, D.C. 20007. Address reprint requests to Dr. Schoetz: Department of Colon and Rectal Surgery, LaheyClinic Medical Center, 41 Mall Road, Burlington, Massachusetts 01805. 850
is greater than that in the general population. Concomitantly, as the recognition of Crohn's colitis as a distinct entity from ulcerative colitis has broadened, the n u m b e r of reported cases of colorectal carcinoma in patients with Crohn's disease has risen. However, several u n r e s o l v e d issues remain with regard to the association of C r o h n ' s disease and colorectal carcinoma. First, accurate assessment of the incidence of colorectal carcinoma in patients with Crohn's disease is not known, primarily because of difficulties in defining the core cohort of patients. Each institution has a u n i q u e population that is influenced by g e o g r a p h y and referral patterns. A population-based study of this association is n e e d e d to address the true incidence definitively, and it has yet to be undertaken. Second, as the n u m b e r of r e p o r t e d cases of colorectal carcinoma in patients with Crohn's disease increases, a growing n u m b e r of clinicians and surgeons cite colonic surveillance examinations as worthwhile, in k e e p i n g with the logic of such m e t h o d s as n o w applied to ulcerative colitis. Controversy stems from features of Crohn's colitis that are u n i q u e from ulcerative colitis and s u p p o s e d l y make surveillance less reliable. Third, because so few patients have colorectal carcinoma in association with Crohn's disease, the characterization of thfs illness is not complete. To add insight into this problem, we report o n patients with colorectal carcinoma in association with Crohn's disease w h o were treated at the Lahey Clinic over a 33-year period.
MATERIALS A N D
METHODS
The records of patients having the simultaneous diagnoses of Crohn's disease and carcinoma of the colon or rectum from 1957 t h r o u g h 1989 were
Vol. 35, No. 9
ANAL INCONTINENCE AND ANORECTAL MANOMETRY
reviewed. From this review, 25 patients were identified. The diagnosis of Crohn's disease was predicated on the basis of clinical behavior, endoscopic and radiographic findings, results of biopsy, macroscopic appearance of the bowel at surgery, and pathologic findings of the surgical specimen. On the few occasions when pathologic findings of the resected specimen were not diagnostic, the patient was included based on the strong clinical impressions of the treating physicians along with standard macroscopic characteristics of the disease found at surgery (fat wrapping, thickened bowel with shortened mesentery, and formation of fistulas). Onset of Crohn's disease was determined to be when the patient first noted symptoms. No systematic surveillance program for patients with Crohn's disease was or is in effect at the Lahey Clinic. A comparative group of 1,719 patients treated at the Lahey Clinic for carcinoma of the colon during 1962 through 1980 was also included for comparison. Data for these patients were taken from two studies from the Lahey Clinic *'z for 1962 through 1976 and from information in the Lahey Clinic Cancer Registry abstracts for 1977 through 1980. Mann-Whitney rank sum analyses were used for statistical analysis.
851
Table 1. Comparative Patient Characteristics
Characteristics Number of patients Male Female Median age at diagnosis of carcinoma Median age at diagnosis of Crohn's disease
Crohn's Disease and Carcinoma
Colon Carcinoma 1962-1980
22 8 (36%) 14 (64%) 55 yr
1,719 941 (55%) 778 (45%) 63 yr
39 yr
6
~a 2
I
5
1
I
I
I
J
I
15
20
25
30
35
C r o h n ' s to c a n c e r i n t e r v a l ( y r s )
Figure 1. Interval from symptomatic onset of Crohn's disease to the diagnosis of colorectal carcinoma for all 22 patients. 7
-1
6
-4 5 |
[] Crohn'~ D• , 40 yrs 9 Crohn's Dx , 40 yea
RESULTS Of the 25 patients in our study, one patient had Crohn's colitis and leiomyosarcoma of the rectum. Two patients had carcinoma of the colon diagnosed and treated before the diagnosis of Crohn's disease was made. These three patients are excluded from the study, leaving 22 patients for discussion. The general characteristics of these patients are presented in Table 1. The median interval between the onset of symptoms of Crohn's disease and the diagnosis of carcinoma of the colon was 18.5 years (range, 0-32 years). The number of patients in each five-year interval is represented in Figure 1. Of note is the number of patients who presented with carcinoma within five years of the diagnosis of Crohn's disease, with one patient who presented with the two illnesses simultaneously. The interval pattern of Crohn's disease to carcinoma differed when the 22 patients were further categorized by the age at onset of Crohn's disease. The number of patients diagnosed with colorectal carcinoma in 10-year intervals is shown in Figure 2. Half of the patients
~
2
10 20 3o Crohn's to cancer interval
40
(yrs) Figure 2. Interval from symptomatic onset of Crohn's disease to the diagnosis of colorectal carcinoma categorized by onset of Crohn's disease before (darkened bars; n -12) and after (open bars; n = 10) the age of 40 years. with the onset of Crohn's disease after the age of 40 years had less than 10 years of Crohn's disease before carcinoma was diagnosed, whereas, for patients with the onset of Crohn's disease before the age of 40 years, 10 of 12 patients (83 percent) had 10 years or more of Crohn's disease before carcinoma was diagnosed. Most cases occurred in the latter part of the study period. From 1957 through 1970, two patients were diagnosed; from 1971 through 1980, five patients were diagnosed; and from 1981 through 1989, 15 patients were diagnosed.
STAHL E T AL
852
The number of patients with Crohn's disease seen at the Lahey Clinic during the same 33-year interval was 2,987, which includes patients with Crohn's disease in all locations. Annual incidence rates for the development of colorectal carcinoma are presented in Table 2, with a rate in excess of that which would be expected for patients seen from 1981 through 1989. The presenting symptoms of carcinoma of the colon were nonspecific. The dominant symptoms are listed in Table 3. Location of Carcinoma and Relationship to Involvement w i t h Crohn's D i s e a s e The locations of the carcinomas are presented in Table 4. Two patients had two synchronous carcinomas each, for a total of 24 carcinomas of the colon. The locations of 1,719 colon carcinomas treated at the Lahey Clinic during 1962 through 1980 are presented for comparison, The extent of Crohn's disease is summarized in Table 5. The number of patients whose colon carcinoma arose in an area of the colon known to have been involved with Crohn's disease was 17 (77 percent). Four of the carcinomas arose in areas of stricture (18 percent), and severe mucosal dysplasia was found in the colon of six patients (27 percent). Table 2. Annual Incidence Rates Time
Number of Carcinomas
Number of Patients with Crohn's Disease
Annual Incidence
1957-1989 1957-1980 1981-1989
22 7 15
2,987 1,603 1,384
22/100,000 26/100,000 120/100,000
Annual incidence rate for general population is 42/ 100,000. a Table 3. Presenting Symptoms Symptoms None Pain or mass Flare inflammatory bowel disease symptoms Blood in stool or anemia Obstruction Rectal bleeding Change in bowel habits Toxic colitis Unknown
Number of Patients 5 4 4 3 2 1 1 1 1
Dis Colon Rectum, September 1992
Table 4. Comparative Distribution of Colorectal Carcinomas
Location
Ascending colon Transverse colont Descending colon Sigmoid colon Rectum
Crohn's Disease and Carcinoma*
Colon Carcinoma 1962-1980
(%)
(%)
10 (42) 4 (17) 1 (4) 5 (21) 4 (17)
329 (19) 158 (9) 83 (5) 493 (29) 656 (38)
* Includes two patients with synchronous carcinomas. ? Includes hepatic and splenic flexures. Table 5. Distribution of Crohn's Disease Location
Number of Patients
Ileocolonic Ileocecal Pancolonic Descending colon Ascending colon Distal ileum
10 4 3 3 1 1
Stage a n d D i f f e r e n t i a t i o n The stages of the carcinomas are listed in Table 6. The pathologic differentiation of the tumors was as follows: well differentiated in two patients, moderately differentiated in eight patients, and poorly differentiated in nine patients; it was not specified in the pathologic report in three patients. Seven mucinous carcinomas (32 percent) were found, and three signet-ring cell carcinomas were present.
Survival Survival was determined for 18 patients who were observed for five or more years. The remaining four patients had no evidence of disease at 11 to 30 months. Survival data are summarized in Table 7. The only comparative difference in survival involves patients with Crohn's disease with Dukes C lesions who tended to have a poorer survival than patients with colorectal carcinoma in the comparative cohort at the same stage,
Early
vs.
Late Onset of Crohn's D i s e a s e
The characteristics of the clinical presentation and subsequent colorectal carcinoma were distinctly different when patients whose onset of Crohn's disease occurred before the age of 40 years
CROHN'S DISEASE AND CANCER
Vol. 35, No. 9 Table 6.
Table 8. Onset of Crohn's Disease
Comparative Cancer Stages Dukes Stage
Crohn's Disease and Carcinoma (%)
Colon Carcinoma 1962-1980 (%)
A
1 (5) 9 (41) 5 (23) 7 (32)
309(18) 629 (37) 400 {23) 372 (22)
B
C D
Table 7.
Five-Year Survival by Stage Dukes Stage
and Carcinoma (%)
Colon Carcinoma 1962-1980 (%)
A* Bi C~: D
0 6/7 (86) 1/4 (25) 0/7
291/304 (96) 518/595 (87) 166/304 (55) 6/312 (2)
Crohn's Disease
* One patient with no evidence of disease at 12 months. 1 Two patients with no evidence of disease at 19 and 30 months. :[: One patient with no evidence of disease at 11 months.
were compared with patients whose onset of Crohn's disease occurred after this age. Some of these differences are noted in Table 8. The median duration of disease before the diagnosis of carcinoma was significantly longer for patients with early onset of Crohn's disease. The presenting stage of disease and survival were also notably different when these two groups were compared (Table 9). Half of the patients with the onset of Crohn's disease before the age of 40 years presented with Dukes D lesions, with a corresponding poor five-year survival. The only survivors in the group with early-onset Crohn's disease were patients whose carcinoma was a Dukes B lesion at diagnosis. DISCUSSION Although the initial description of granulomatous enteritis of the colon was made in 1934 by Colp, 4 it was not until the article by LockhartMummery and Morson 5 in 1960 that the clinical entity of Crohn's colitis was accepted as distinct from ulcerative colitis. Since then, the number of patients with Crohn's disease of the large intestine has grown consistently to the point that colonic involvement is present in 40 to 60 percent of all patients with Crohn's disease.
