After Abdominal Colectomy - NCBI

ANNALS OF SURGERY Vol. 225, No. 2, 202-207 © 1997 Lippincott-Raven Publishers

Rectal Cancer Risk in Hereditary Nonpolyposis Colorectal Cancer After Abdominal Colectomy Miguel A. Rodrrguez-Bigas, M.D.,* Hans F.A. Vasen, M.D., Ph.D,t Jukka Pekka-Mecklin, M.D.,4 Torben Myrh0j, M.D.,§ Paul Rozen, M.D.,II Lucio Bertario, M.D.,¶ Heikki J. Jarvinen, M.D.,# Jeremy R. Jass, M.D.,** Kazufumi Kunitomo, M.D., Ph.D.,tt Tadashi Nomizu, M.D.J t Deborah L. Driscoll, B.A.,* and the International Collaborative Group on HNPCC From the Division of Surgical Oncology, * Roswell Park Cancer Institute, Buffalo, New York; the Foundation for the Detection of Hereditary Tumors, t cdo Leyden University Hospital, Leyden, The Netherlands; the Department of Surgery, t JyvaskylI Central Hospital, Jyvaskyla, Finland; The Danish HNPCC Register, Department of Surgical Gastroenterology,§ Hvidovre Hospital, Hvidovre, Denmark; the Department of Gastroenterology, I Tel-Aviv Medical Center, Ichilov Hospital, Tel Aviv, Israel; the Instituto Nazionale per lo, Studio e Ia Cura del Tumori, ¶ Milan, Italy; the Second Department of Surgery, # University Central Hospital, Helsinki, Finland; the Department of Pathology,** University of Auckland School of Medicine, Auckland, New Zealand; Tezuka Hospital, tt Tokushima, Japan; and Hoshi General Hospital, 14 Kornyama, Japan

Objective The authors analyzed the incidence of rectal cancer in patients with hereditary nonpolyposis colorectal cancer (HNPCC) after an abdominal colectomy.

Summary Background Data The treatment of choice for a newly diagnosed patient with HNPCC with colon cancer is an abdominal colectomy. The incidence of rectal cancer after abdominal colectomy in HNPCC is not known.

Materials and Methods A questionnaire was mailed to all International Collaborative Group on HNPCC members to identify patients in whom rectal cancer developed after total, subtotal, or completion colectomy. Statistics were performed using the log-rank test, Kaplan-Meier method, and Cox's proportional hazards model.

Results Rectal cancer developed in 8 (1 1 %) of 71 patients a median of 158 months (range, 38282 months) from their primary procedure. Of these eight patients, adenomas in the rectal mucosa developed in five at risk either before (4) or synchronous (1) with the diagnosis of rectal cancer. At the time of diagnosis of rectal cancer, six of eight patients were being observed. Age at first procedure and whether the patient was under surveillance were the only significant variables (p < 0.05) in the multivariate analysis in terms of rectal cancer risk. The risk of developing rectal cancer was estimated to be 3% every 3 years after abdominal colectomy for the first 12 years.

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Rectal Cancer Risk in HNPCC

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Conclusions The risk of rectal cancer in patients with HNPCC after an abdominal colectomy is approximately 12% at 12 years. Age at first surgical procedure and surveillance correlated with rectal cancer risk. Aggressive endoscopic surveillance of the rectum should be performed after abdominal colectomy.

It has been estimated that hereditary nonpolyposis colorectal cancer (HNPCC) comprises < 1% to 6% of the total colorectal cancer burden.'-6 The majority of the neoplasms in HNPCC occur proximal to the splenic flexure.47-9 As opposed to sporadic colorectal cancer, patients with HNPCC have a higher incidence of synchronous and metachronous colonic lesions.47-9 The incidence of a metachronous colorectal carcinoma developing as calculated by life-table analysis has been reported to be 40% at 10 years.7 10 Because of the increased risk of a metachronous colon cancer developing, unless there are mitigating factors, the treatment of choice for a patient with HNPCC with colon cancer is a total abdominal colectomy (TAC) or a subtotal abdominal colectomy (STC) with ileorectal anastomosis. However, because there were no clinical or molecular markers of this disease until recently, the majority of the patients treated underwent less than a TAC and STC. The risk of having rectal cancer develop after a TAC or a STC in patients with HNPCC is unknown. Because until recently most patients with HNPCC were treated with less than a TAC, no single institution has had enough experience and follow-up after this procedure. Therefore, it was decided to perform a retrospective study with members of the International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer (ICG-HNPCC) to assess the risk of rectal cancer after TAC or STC, either as a primary procedure or as a completion procedure in patients with HNPCC.

MATERIALS AND METHODS A survey form was mailed to members of the ICGHNPCC to identify eligible HNPCC patients who had undergone a total or a subtotal colectomy. Eligibility was considered if the patients met the Amsterdam criteria defined as follows: 1) at least three relatives with colorectal cancer, one of whom was a first-degree relative of the other two (familial adenomatous polyposis excluded); 2) at least two successive generations affected; and 3) one of the individuals diagnosed with colorectal cancer before age 50.11 Patients who had prior colon surgery before a Address reprint requests to Miguel A. Rodriguez-Bigas, M.D., Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 142630001. Accepted for publication February 5, 1996.

completion TAC or STC also were eligible. Variables examined included gender; age at first procedure; type of procedure (first surgery); number of colorectal cancers at first procedure; TNM stage'2; Dukes' stage'3 of the primary at the time of first procedure; presence or absence of adenomas; and surveillance after the first procedure. Of 63 surveys mailed to members of the ICG-HNPCC, there were 19 responses. Surveys were completed on 94 patients. However, 23 patients were excluded for the following reasons: rectal cancer developing after less than TAC or STC (14), no follow-up (6), surgery not specified (1), no age noted at diagnosis (1), and inability to determine whether the rectal cancer was primary or metastatic (1). The remaining 71 patients form the basis of this report. Estimated survival distribution and risk estimates were calculated by the method of Kaplan-Meier."4 Time was defined as months from total, subtotal, or completion abdominal colectomy. The latter defined as the time of the surgical procedure where an abdominal colectomy was performed in patients treated previously by segmental resections. Tests of significance with respect to survival distributions were based on the log-rank test.'5 Cox's proportional hazards model was used for the multivariate analysis.

RESULTS Seventy-one individuals in 44 families were identified. There were 46 men (65%) and 25 women (35%). The median age at the time of the first surgical procedure was 38 years (range, 19-70 years). Table 1 lists the types of surgical procedures performed in these patients. Fortythree patients (61%) underwent a total or a subtotal colectomy at the time of the first procedure. Forty-one (95%) of the 43 patients had at least 1 carcinoma at the time of the TAC or STC. At least 17 of the remaining 28 patients had a carcinoma at the time of completion colectomy. Information is missing on 10 patients, whereas 1 patient had adenomas at the time of colectomy. In 44 (77%) of 57 patients where the site of the tumor was known, at least 1 neoplasm was proximal to the splenic flexure. Table 2 lists the degree of differentiation, tumor staging at the time of TAC, STC, or completion colectomy. Adenomas were present in 29 patients (41%) either before, at the time, or after TAC, STC, or completion colectomy. In 17 patients (24%), no reliable information was avail-

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Rodriguez-Bigas and Others

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Table 3. TIMING AND OCCURRENCE OF ADENOMAS

Table 1. SURGICAL PROCEDURES PERFORMED IN 71 PATIENTS WITH HEREDITARY NONPOLYPOSIS COLORECTAL CANCER No. (%) First surgical procedure TAC STC Other Surgical procedures before TAC, STC 1 2 3 Final surgical procedure TAC STC

Surg. February 1997

18 (25.4) 25 (35.2) 28 (39.4) 17 (61) 9 (32)

2(7) 39 (55) 32 (45)

No. of

Temporal Relationship to TAC, STC, and Completion Colectomy

Patients

Synchronous Synchronous (unknown before procedure)* Synchronous and before procedure Metachronous Metachronous (unknown before procedure)* Metachronous and before procedure None metachronous (unknown before procedure)* No adenomas at any time Total

15 8 1 2 1 2 17 25 71

TAC = total abdominal colectomy; STC = subtotal colectomy. * Unknown before procedure = no information before TAC, STC, or completion colectomy.

TAC = total abdominal colectomy; STC = subtotal colectomy.

able about the occurrence of adenomas before TAC, STC, or completion colectomy. Adenomas did not develop at any time in 25 patients (35%). Table 3 lists the timing and occurrence of adenomas.

Table 2. DEGREE OF DIFFERENTIATION, TNM, AND DUKES' STAGE OF 78 COLON CANCERS IN 71 PATIENTS AT THE TIME OF TOTAL ABDOMINAL COLECTOMY, SUBTOTAL COLECTOMY, AND COMPLETION COLECTOMY No. Differentiation Well differentiated Moderately differentiated Poorly differentiated Mucin producing Signet ring cell type Unknown TNM stage 0

1

II

23 21 9

IV Unknown Dukes' stage A B

1

23*

C

2 49 12

D Unknown

14t

20 patients with 23 cancers. t 13 patients with 14 cancers. *

12 25 9 4 2 26

1

Rectal cancer developed in eight patients (11%) at a median of 158 months (range, 38-282 months) after the primary procedure. Four patients had a STC as the primary procedure at a median of 148.5 months (range, 38256 months) before the diagnosis of the rectal cancer, one patient had a TAC 65 months before diagnosis, and three patients had less than a TAC or a STC at a median of 165 months (range, 150-282 months) before diagnosis. The median age at diagnosis of rectal cancer was 51 years (range, 46-73 years), whereas the median age at the first procedure in these patients was 38 years (range, 28-70 years). Table 4 lists the characteristics of the neoplasms in patients in whom rectal cancer developed. Six of eight patients were being observed after TAC, STC, or completion colectomy. In five of the six patients being observed, the interval between the last examination and the diagnosis of the rectal cancer was known. It varied between 6 months and 24 months before the diagnosis of rectal cancer. The only patient who presented with advanced disease was not being observed. Five of seven patients had adenomas in the rectum. In one patient, the information was missing. Four patients had rectal adenomas before the diagnosis of rectal cancer. In one patient, a rectal adenoma was diagnosed synchronously. Seven of the eight patients in whom rectal cancer developed had adenomas (colon, two patients; rectum, four patients; colon and rectum, one patient) diagnosed either before or at the time of diagnosis of rectal cancer. All eight patients had at least one carcinoma at the time of TAC, STC, or completion colectomy. The median follow-up in seven of the eight patients with rectal cancer was 85 months (range, 5-2 16 months). One patient was lost to follow-up immediately after the diagnosis of a Dukes' stage B moderately differentiated rectal cancer. Five of the seven patients with follow-up have died. Two of these deaths have been


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Table 4. NEOPLASMS IN PATIENTS WITH RECTAL CANCER First Procedure

Patient No.

Cancer

1

Cecum T2NO Asc, Desc T3N1 Splenic T2NO Asc, Tr, Desc T3NO Desc* T2NO Asc T3NO Tr Dukes' A Tr Dukes' B

(%) risk 100

/

Rectal Stump

Cancer

Adenoma

Tr (TA)

T2NO

VA (S)

None

T2NO

TVA (P)

Adenoma

205

10

34 41

43 45 49 65 71

Klr) Klnnon I'4IJIi1TlIII'4L

A^ [Pi VA F)

None

T4NxM1

None

Yest

Ti NO

None

Rectum (TA)

T2NO

TA (P)

Tr (VA)

Dukes' B

Yes (P)

Sigmoid (TVA)

Dukes' B

N/A

ASC = ascending colon; Tr = transverse colon; Desc = descending colon; TA = tubular adenoma; TVA = tubulovillous adenoma; VA = villous adenoma; S = synchronous; P = prior to the diagnosis of rectal cancer; N/A = not available. * This was the fourth procedure of this patient; 2 previous for cancers and 1 for adenoma. t One procedure before completion colectomy (histology unknown).

related to colorectal cancer. One patient died 5 months after the diagnosis of a stage IV rectal cancer. The other patient died 29 months after the diagnosis of a stage II (Dukes' stage B) rectal cancer. As listed in Table 5, only age at the time of the first surgical procedure and whether the patient was being observed were significant in the

Table 5. UNIVARIATE AND MULTIVARIATE ANALYSIS ON THE RISK OF RECTAL CANCER* p Value Univariate

Multivariate

Gender Age at first surgical procedure First procedure (type) No. of colorectal cancers at first procedure Dukes' stage Adenoma Extracolonic cancer Surveillance

0.24

0.78

0.09 0.002

0.03 0.34

0.01 0.07 0.52 0.43 0.05

0.23 0.23 0.08 0.92 0.04

Considered significant at p < 0.05.

T

1v

38

I/ 72

108

144 Mort

180

216

252

288

afterTACQSTC

Figure 1. Estimated cumulative risk of having rectal cancer develop after total abdominal colectomy/subtotal abdominal colectomy/completion colectomy. TAC = total abdominal colectomy; STC = subtotal abdominal colectomy.

multivariate analysis. The presence or absence of adenomas showed a trend toward significance. Sixty-three (89%) of 71 of the patients did not have rectal cancer develop on follow-up after their first procedure. The median follow-up of the rectal mucosa in these patients was 108 months (range, 5-480 months). Figures 1 and 2 illustrate the estimated risks of having rectal cancer develop after abdominal colectomy and after the first surgery, respectively. The risk is based on the number of patients at the beginning of each interval.

DISCUSSION The incidence of rectal cancer in patients with HNPCC has not been reported. In fact, little is known about rectal cancer in this group of patients. Attention has been focused on the right-sided predominance of colorectal cancers in affected individuals. Because of this and the lack of recognition of this syndrome, the majority of the affected individuals have been treated with less than a TAC

ris

100

Variable

*

'A

10

36

72

108

144 180 Mot afer surgery

216

252

288

Figure 2. Estimated cumulative risk of having rectal cancer develop after the first surgical procedure.

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Rodriguez-Bigas and Others

or an STC. This probably is because the majority of the patients affected with this condition were not recognized as members of HNPCC kindred. Therefore, no single group has had enough experience in the follow-up of the rectum in these patients. The limitations of our study include its retrospective nature, which is to be expected in such a disease, and in that, not all members in the ICG-HNPCC participated. Even so, important information was obtained. There is a definite risk of rectal cancer after total or subtotal colectomy in these patients. In fact, the risk is approximately 12% (confidence interval, 1-21) at 12 years after abdominal colectomy. This incidence is similar to the incidence of rectal cancer after TAC in familial adenomatous polyposis-affected individuals.'6 However, because of the small number of patients in our study, the risk increases markedly at subsequent years. In the multivariate analysis, only age at the first procedure and whether the patient was being observed were significant. The former finding is only logical. That is, the rectal mucosa in these patients is at risk; therefore, the longer the mucosa remains at risk, the higher the chance of a carcinoma developing. The latter may just be a bias because as these patients are closely observed over longer periods, rectal cancers will be diagnosed. However, six of the eight patients in whom rectal cancer developed after an abdominal colectomy were being observed. Furthermore, the only one who presented with advanced disease was not being observed and died of the disease. The other patient who died of rectal cancer was being observed at the time of rectal cancer diagnosis. As shown by Jarvinen et al,'7 patients with HNPCC who were being observed had a reduced risk of having colorectal cancer develop and were diagnosed with earlier stage colorectal cancer as compared with affected individuals not being observed. Whether those findings will result in an improvement in survival still is not known.'7 The other variable that was not significant, but showed a trend toward significance, was the presence or absence of adenomas. Five of the eight patients in whom rectal cancer developed after TAC or STC had adenomas in the rectal stump either synchronously or before the development of the rectal cancer. This latter finding has important implications because it already has been shown that the incidence of colorectal cancer is decreased in nonHNPCC patients who have undergone polypectomy at the time of colonoscopy.'8 Furthermore, it appears that the adenoma carcinoma sequence is accelerated in HNPCCaffected individuals as compared with sporadic patients.'9 Thus, because there is a definite risk of having rectal cancer develop after an abdominal colectomy in HNPCCaffected individuals and adenomas appear to be more aggressive in terms of progressing into a carcinoma, the frequency of endoscopic examinations of the rectum in these patients should be no less than annually after 10

Ann. Surg. * February 1997

years at risk. Even an interval of 6 months may be reasonable because in two patients, carcinoma of the rectum developed 6 and 10 months after their last endoscopic examinations. In the former patient, a rectal adenoma had been removed 6 months before the development of rectal cancer. Flexible sigmoidoscopy makes this a reasonable program. It must be emphasized that observation of the rectum after abdominal colectomy should be performed every 1 to 2 years. However, prospective studies such as the one by Jarvinen et al.'7 should be done to evaluate this. We still do not know the true incidence of rectal cancer in patients with HNPCC. A collaborative study is being conducted among members of the ICG-HNPCC to identify rectal cancers diagnosed before and after abdominal colectomy. We have no information in terms of mismatch repair genes mutations in these patients. What is known is that there is a definite risk of rectal cancer after abdominal colectomy and that continued surveillance should be done in HNPCC-affected individuals after abdominal colectomy. Chemoprevention studies should be considered in these patients.

Acknowledgments The following International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer members participated in the questionnaire: D. Timothy Bishop, Ph.D., Imperial Cancer Research Fund, Leeds West Yorkshire, England; Klaus Shlaefer, M.P.H., German Cancer Research Center, Heidelberg, Germany; Stanley R. Hamilton, M.D., Johns Hopkins University, Baltimore, Maryland; Jose A. Bufill, M.D., Elkhart Clinic, Elkhart, Indiana; Gabriela M6slein, M.D., Dusseldorf Registry for Hereditary Colorectal Cancer, Dusseldorf, Germany; Hartley S. Stern, M.D., University of Ottawa, Ottawa, Canada; Remy Meier, M.D., Kantonsspital Liestal, Liestal, Switzerland; and Guiseppe Cristoffaro, M.D., Hereditary Gastrointestinal Cancer Prevention Center, Brindisi, Italy: James St. John, M.D., Royal Melbourne Hospital, Victoria, Australia; Patrice Watson, Ph.D., Creighton University, Omaha, Nebraska, and Raul Cutait, M.D., Sao Paulo, Brazil.

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