Rectal cancer in hereditary nonpolyposis colorectal cancer

doi:10.1016/S0002-9610(01)00568-2

The American Journal of Surgery

Volume 181, Issue 3, March 2001, Pages 207-210

https://doi.org/10.1016/S0002-9610(01)00568-2 Get rights and content

Abstract

Background: Hereditary nonpolyposis colorectal cancer (HNPCC) accounts for approximately 2% to 5% of all colorectal cancers. Rectal cancer in HNPCC is not well characterized.

Methods: A retrospective medical record review of HNPCC patients with colorectal cancer diagnosis from December 1948 to December 1999 was performed in an attempt to elucidate the natural history of rectal cancer in HNPCC. Group A consisted of patients diagnosed with rectal 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 age at 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 index rectal 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 for HNPCC in suspected cases.

Section snippets

Patients and methods

A retrospective medical records review was undertaken of HNPCC patients with documented rectal cancer between December 1948 and December 1999. The study population was selected from patients with documented pathology in the Roswell Park Cancer Institute (RPCI) HNPCC registry. This registry includes those patients who have documented germline mutations in mismatch repair genes, meet the Amsterdam criteria, or have a strong clinical history suggestive of HNPCC. Clinically, 5 patients had

Results

Eighty-nine patients in the registry had a total of 139 documented colorectal adenocarcinoma. Twenty-five of the 89 (28%) patients were diagnosed with rectal adenocarcinoma. The median age at diagnosis of rectal cancer was 50 years (range 24 to 79). There were 6 women (24%) and 19 men (76%). Twenty-one of the 25 (84%) patients with rectal adenocarcinoma met the Amsterdam criteria for HNPCC [12]. The remaining 4 patients (16%) had germline mutations in hMLH1 or hMSH2. Eight of 25 (30%) patients

Comments

Right-sided colorectal cancer predominance is one of the characteristics of HNPCC patients. Nevertheless, there is a small, yet significant incidence of left-sided carcinomas. The incidence of right-sided lesions has been reported as high as 70% [7]. However, as patients treated with less than abdominal colectomy are followed up, the difference decreases. At our institution we reported a 60% incidence of right-sided neoplasms at presentation, but on subsequent follow-up, the incidence was 52%

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Colorectal cancer (CRC) results from a series of complex, multistep genetic and molecular events causing uncontrolled cell growth. The underlying changes within the cells define distinct but somewhat overlapping tumor phenotypes. There are at least three well-defined pathways leading to CRC: chromosomal instability, microsatellite instability, and DNA hypermethylation. These pathways are present in cancers that develop via somatic mutations or within hereditary syndromes. The changes are manifest in both sporadic cancers and in hereditary syndromes. A relatively small proportion of CRCs develop as a consequence of a highly penetrant germline mutation in one gene, resulting in a familial cancer syndrome. The tumors that develop in these syndromes then follow the same evolutionary paths as sporadic tumors, but the risk for cancer is greatly elevated, forms at an early age, and is associated with multiple and metachronous colorectal and extracolonic cancers. The hereditary CRC syndromes are broadly classified as polyposis (adenomatous, hamartomatous, or mixed) or nonpolyposis syndromes (including hereditary nonpolyposis CRC, Lynch syndrome, and familial CRC type X). Each of these syndromes is associated with specific gene mutations that determine the clinical phenotype and define the cancer risk. This chapter provides an overview of the underlying changes in colorectal carcinogenesis and the hereditary CRC syndromes.
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While the risk for metachronous colon cancer after proctectomy for rectal cancer may be less than that following a colon cancer resection in the setting of LS, it is still a clinically significant risk. One study from Roswell Park Cancer Institute reported that 18% patients who met Amsterdam criteria or had a germline MMR mutation and underwent proctectomy for rectal cancer developed a metachronous cancer at a median 203 month follow up.27 Another retrospective study from Germany reported that 54% (6/11) of patients with HNPCC developed metachronous colon cancer after proctectomy (median follow-up 7.4 years).36
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Colorectal Cancer (CRC) is the third most prevalent cancer in men and women. Up to 15% of CRCs display microsatellite instability (MSI). MSI is reflective of a deficient mismatch repair (MMR) system and is most commonly caused by hypermethylation of the MLH1 promoter. However, it may also be due to autosomal dominant constitutional mutations in DNA MMR, termed Lynch Syndrome. MSI may be diagnosed via polymerase chain reaction (PCR) or alternatively, immunohistochemistry (IHC) can identify MMR deficiency (dMMR). Many institutions now advocate universal tumor screening of CRC via either PCR for MSI or IHC for dMMR to guide Lynch Syndrome testing. The association of sporadic MSI with methylation of the MLH1 promoter and an activating BRAF mutation may offer further exclusion criteria for genetic testing. Aside from screening for Lynch syndrome, MMR testing is important because of its prognostic and therapeutic implications. Several studies have shown MSI CRCs exhibit different clinicopathological features and prognosis compared to microsatellite-stable (MSS) CRCs. For example, response to conventional chemotherapy has been reported to be less in MSI tumours. More recently, MSI tumours have been shown to be responsive to immune-checkpoint inhibition providing a novel therapeutic strategy. This provides a rationale for routine testing for MSI or dMMR in CRC.
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In a study from the Roswell Park Cancer Institute, 18 patients either meeting the Amsterdam criteria or with a documented germline MMR mutation presented with an index rectal cancer and were treated by proctectomy without colectomy. One patient died of advanced disease, and 3 of 17 patients (18%) developed metachronous cancer at a median of 203 months after the initial surgery [41]. A report from Germany described 6 of 11 patients with HNPCC (54%) developing metachronous colon cancer at a median of 7.4 years after proctectomy [42].
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Scientific paperRectal cancer in hereditary nonpolyposis colorectal cancer

Abstract

Section snippets

Patients and methods

Results

Comments

Gastroenterology

Common inheritance of susceptibility to colonic adenomatous polyps and associated colorectal cancers

N Engl J Med

Hereditary colorectal cancer in the general populationfrom cancer registration to molecular diagnosis

Gut

Hereditary nonpolyposis colorectal cancer

Scand J Gastroenterol

Incidence of HNPCC in a population based study of 1137 consecutive cases of colorectal cancer

Br J Surg

Recognition and treatment of patients with hereditary non polyposis colon cancer (Lynch syndromes I and II)

Ann Surg

Scientific paper
Rectal cancer in hereditary nonpolyposis colorectal cancer