Rectal cancer in hereditary nonpolyposis colorectal cancer

James S. Lee, M.D., Nicholas J. Petrelli, M.D., Miguel A. Rodriguez-Bigas, M.D.*Department of Surgery, Roswell Park Cancer Institute and State University of New York at Buffalo, Elm and Carlton Streets, Buffalo,

New York 14263, USA

Manuscript received July 25, 2000; revised manuscript November 7, 2000

Abstract

Background: Hereditary nonpolyposis colorectal cancer (HNPCC) accounts for approximately 2% to 5% of all colorectal cancers. Rectalcancer in HNPCC is not well characterized.Methods: A retrospective medical record review of HNPCC patients with colorectal cancer diagnosis from December 1948 to December1999 was performed in an attempt to elucidate the natural history of rectal cancer in HNPCC. Group A consisted of patients diagnosed withrectal cancer as the index colorectal cancer. Group B consisted of patients diagnosed with rectal cancer as a metachronous colorectal cancer.Results:Twenty-five of 104 patients developed rectal cancer in our HNPCC registry. There were 18 patients in group A with a median ageat diagnosis of rectal cancer of 48 years (range 24 to 79) and 7 patients in group B diagnosed at a median age of 58 years (range 45 to 68).Three of 18 patients (17%) in group A developed metachronous colon cancers at a median of 203 months (range 27 to 373) from the indexrectal cancer. Rectal cancer in group B was diagnosed at a median 245 months (range 51 to 564) from the index colorectal cancer diagnosis.Conclusions: Rectal cancer in HNPCC is not uncommon. The presentation of rectal carcinoma should not obviate the evaluation forHNPCC in suspected cases. © 2001 Excerpta Medica, Inc. All rights reserved.

Keywords:Rectal cancer; Colorectal cancer; Hereditary nonpolyposis colorectal cancer; HNPCC; Hereditary cancer syndromes

It is estimated that in 2001 there will be 135,400 new casesof colorectal cancer in the United States and 56,700 colo-rectal cancer deaths [1]. The majority of colorectal cancersare sporadic whereas approximately 10% represent familialsyndromes [2]. Hereditary nonpolyposis colorectal cancer(HNPCC) is the most common of these syndromes account-ing for 2% to 5% of all hereditary colorectal cancers [3–5].

HNPCC is characterized by early age onset of colorectalcancer, right-sided predominance, excess synchronous andmetachronous colonic neoplasms, and extracolonic neo-plasms such as endometrial, gastric, renal pelvis, and smallbowel cancers [6–8] The current diagnosis of HNPCC isbased on a high suspicion and detailed family history and onmolecular genetics, namely germline mismatch gene repairmutations.

The occurrence of rectal cancer in HNPCC althoughrecognized is not well studied. Because of the high occur-rence of synchronous and metachronous neoplasms, thesurgical management of HNPCC patients with newly diag-

nosed colon cancer is total abdominal colectomy and ileo-rectal anastamosis. This procedure, however, leaves therectum intact and at risk for cancer. The risk of rectal cancerfollowing total or subtotal colectomy in HNPCC has beenreported to be 12% at 12 years [9], which is similar to theincidence of rectal cancer following total abdominal colec-tomy and ileorectal anastamosis for familial adenomatouspolyposis (13.3% at 10 years) [10]. The purpose of thepresent study was to better delineate the natural history ofrectal cancer in an HNPCC registry.

Patients and methods

A retrospective medical records review was undertakenof HNPCC patients with documented rectal cancer betweenDecember 1948 and December 1999. The study populationwas selected from patients with documented pathology inthe Roswell Park Cancer Institute (RPCI) HNPCC registry.This registry includes those patients who have documentedgermline mutations in mismatch repair genes, meet theAmsterdam criteria, or have a strong clinical history sug-gestive of HNPCC. Clinically, 5 patients had extracolonic

* Corresponding author. Tel.:11-716-845-5815; fax:11-716-845-8980.

E-mail address:Miguel.Rodriguez-Bigas@roswellpark.org.

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0002-9610/01/$ – see front matter © 2001 Excerpta Medica, Inc. All rights reserved.PII: S0002-9610(01)00568-2

cancers only, whereas 89 patients had colorectal cancersdocumented by pathology reports, physician clinic notes, ordeath certificates. There were 10 patients at risk of HNPCCin this cohort of patients. Group A consisted of patientsdiagnosed with rectal cancer as the index colorectal cancer.Group B consisted of patients diagnosed with rectal canceras a metachronous rectal cancer.

Staging was defined according to the American JointCommittee on Cancer (AJCC) staging system [11]. Meta-chronous cancers were defined as those cancers diagnosedmore than 12 months from the index cancer. Synchronouscancers were staged with respect to the most advancedlesion and metachronous lesions were staged with respect tostage at each event. Patients were followed up until death bypatient or family reports, medical records, autopsy reports,or death certificates. This study was approved by the Insti-tutional Review Board.

Results

Eighty-nine patients in the registry had a total of 139documented colorectal adenocarcinoma. Twenty-five of the89 (28%) patients were diagnosed with rectal adenocarci-noma. The median age at diagnosis of rectal cancer was 50years (range 24 to 79). There were 6 women (24%) and 19men (76%). Twenty-one of the 25 (84%) patients with rectaladenocarcinoma met the Amsterdam criteria for HNPCC[12]. The remaining 4 patients (16%) had germline muta-tions in hMLH1 or hMSH2. Eight of 25 (30%) patients weredocumented to have mutations in mismatch repair genes, 3in hMSH2 and 5 in hMLH1. Genetic testing has not beenperformed on the other 17 patients. Table 1 illustrates thedemographics, stage, and follow-up of groups A and B.

In 18 patients (72%), rectal cancer was the index colo-rectal cancer (group A). The median age of diagnosis ofrectal cancers in group A patients was 48 years (range 24 to79). There were 4 women and 14 men. Fourteen patientshad rectal cancer as their only colorectal cancer. Threepatients developed metachronous colon cancer diagnosed at

a median of 203 months (range 27 to 373). One patient hadsynchronous cecal and rectal carcinomas. This patient hadadvanced disease at presentation and died of liver metasta-ses.

Five patients in group A developed cancer at other ex-tracolonic sites. The median follow-up after the diagnosis ofrectal cancer was 63 months (range 0 to 558). At the time oflast follow-up, 1 patient (6%) was alive with disease, 9patients (50%) alive without disease, 4 patients (22%) diedwith disease, 2 patients (11%) died without evidence ofdisease, and 2 patients (11%) were lost to follow-up. Fig. 1shows a graphic representation of the time course, colonic,and extracolonic neoplasms of group A in our study.

Seven of 25 patients (28%) developed rectal cancer afterthe diagnosis of colon cancer (group B). There were 5 menand 2 women. The median age at diagnosis was 58 years(range 45 to 68). Rectal cancer was diagnosed in thesepatients at a median of 180 months (range 42 to 523) fromthe index colon cancer diagnosis. Six of the 7 patients hadsegmental resections prior to the diagnosis of metachronousrectal cancer, whereas 1 patient had a subtotal colectomy asthe initial procedure. Rectal cancer was diagnosed as thesecond colorectal cancer in 4 of 7 patients, the third colo-rectal cancer in 2 patients, and the fourth colorectal cancerin 1 patient. Four patients had extracolonic neoplasms, 2 ofwhich developed before the index colorectal cancer. Ingroup B, the median follow-up was 245 months (range 51 to564). At the time of last follow-up, no patients were alivewith disease, 4 patients (57%) were alive without disease, 2patients (29%) died with disease, and 1 patient (14%) diedwithout evidence of disease. Fig. 2 shows a graphic repre-sentation of the time course, colonic, and extracolonic neo-plasms of group B in our study.

Comments

Right-sided colorectal cancer predominance is one of thecharacteristics of HNPCC patients. Nevertheless, there is asmall, yet significant incidence of left-sided carcinomas.The incidence of right-sided lesions has been reported ashigh as 70% [7]. However, as patients treated with less thanabdominal colectomy are followed up, the difference de-creases. At our institution we reported a 60% incidence ofright-sided neoplasms at presentation, but on subsequentfollow-up, the incidence was 52% right-sided versus 48%left-sided carcinomas [13].

The natural history of rectal cancer in HNPCC patients islargely unreported. The incidence of rectal cancer in ourstudy was 24%. More importantly, we report that 1 in 5patients with HNPCC develops rectal cancer as their indexcolorectal cancer.

Moslein et al [14] reported that rectal cancer was theindex cancer in 31% of unrelated HNPCC patients. This ishigher than the 20% incidence of rectal cancer as the index

Table 1Demographics, stage of rectal adenocarcinoma, and follow-up ofhereditary nonpolyposis colorectal cancer patients with rectal cancers

Group A Group B

Male 14 5Female 4 2Median age 48 years (24–79) 58 years (45–68)Stage 0 1/18 (5%) NoneStage I 6/18 (33%) 3/7 (43%)Stage II 2/18 (11%) 2/7 (29%)Stage III 5/18 (%) 1/7 (14%)Stage IV 1/18 (6%) 0Unknown stage 4/18 (22%) 0Median follow-up 91 months (6–458) 204 months (51–276)

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cancer in our cohort. In the study by Mo¨slein et al [14], 54%of the patients with rectal carcinoma as their first colorectalcancer developed a metachronous colonic cancer at a meaninterval of 7.4 years after the diagnosis of the index rectalcancer. Three patients (17%) in our study developed meta-

chronous colon carcinoma at a mean interval of 201 monthsfrom the diagnosis of the index rectal carcinoma.

Because of the increased incidence of synchronous andmetachronous colorectal neoplasms, abdominal colectomyhas been recommended as the procedure of choice in

Fig. 1. Time course and colonic and extracolonic neoplasms of patients diagnosed with rectal cancer as the index colorectal cancer (group A).Open diamondindicates colon and rectum;open triangle indicates extracolonic sites;open boxindicates dead, no disease;solid box indicates dead with disease;open circleindicates alive, no disease;solid circle indicates alive with disease; and? indicates lost to follow-up. A5 ascending colon; C5 cecum; D5 descendingcolon; NS5 not specified; K5 right colon; S5 sigmoid; SF5 splenic flexure; T5 transverse colon; X5 rectum; X1 5 synchronous cancers; B5 breast;C 5 cervix; D 5 duodenum; E5 endometrium; G5 gastric; I5 ileum; J5 jejunum; K 5 kidney; P5 prostate; S5 skin; SA 5 sebaceous adenoma;T 5 testicular; O5 ovarian.

Fig. 2. Time course and colonic and extracolonic neoplasms of patients diagnosed with rectal cancer as a metachronous rectal cancer (group B). Symbolsand abbreviations as in Fig. 1.

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HNPCC patients with colorectal cancer. However, the re-maining rectal mucosa is still at risk for cancer. In a studyby the International Collaborative Group on HNPCC, therectal cancer estimated cumulative risk was 12% at 12 yearsafter colectomy [10]. In this study 8 of 71 (11%) patientsdeveloped rectal cancer at a median of 158 months (range38 to 252) after the primary procedure. Five of 8 patientswho developed rectal cancer had previous adenomas in therectum (63%). Mo¨slein et al [14] reported that 6 of 29patients (20%) developed metachronous rectal cancers at amean interval of 25 years (range 5 to 41). Baba [15] re-ported a 6% incidence of metachronous rectal cancer inHNPCC patients in Japan. In our study, the majority of thepatients presented with rectal cancer as the index colorectalcarcinoma; however, the overall incidence of metachronousrectal cancer was 8%, which is similar to the Japaneseexperience.

Rectal carcinoma is not an uncommon presentation inHNPCC. The diagnosis of rectal carcinoma in an HNPCCpatient has clinical implications in terms of the procedure tobe performed whether it is sphincter preservation or radicalsurgery. Although there are no reports in the literature onileoanal pouch procedures in HNPCC patients, this shouldbe considered in patients who are candidates for sphincterpreservation at the time of rectal cancer diagnosis. In addi-tion, it is important for the clinician to recognize potentialHNPCC patients, especially those presenting with rectalcarcinoma as the index neoplasm, so that appropriate sur-gical recommendations and surveillance can be offered topatients and their families.

In summary, rectal adenocarcinoma can be the present-ing index tumor in HNPCC and is a common event. There-fore, the diagnosis of HNPCC should not be obviated be-cause of the presence of a rectal neoplasm. The familyhistory as well as the clinical and molecular characteristicsof the tumor should be evaluated.

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