Download clinical characteristics of taiwanese hereditary non

S.C. Wei, M.H. Wang, M.C. Shieh, et al
CLINICAL CHARACTERISTICS OF
TAIWANESE HEREDITARY NON-POLYPOSIS
COLORECTAL CANCER KINDREDS
Shu-Chen Wei, Ming-Hsi Wang, Min-Chung Shieh, Cheng-Yi Wang, and Jau-Min Wong
Background and purpose: The prevalence of colorectal cancer in Taiwan has increased
gradually in recent years. Around 5% to 15% of colorectal cancer is hereditary, and
hereditary nonpolyposis colorectal cancer (HNPCC) is the most common form of
hereditary colorectal cancer. This study aimed to determine the clinical characteristics of Taiwanese HNPCC kindreds.
Patients and methods: We reviewed the chart records of all HNPCC kindreds followedup in our hospital during the period from 1996 to 1999. Their clinical characteristics
were recorded and analyzed.
Results: There were 10 families, including a total of 202 persons, who met the
Amsterdam criteria for HNPCC. Fifty-two persons in these families had a diagnosis
of cancer, including 26 women and 26 men. There were 40 colorectal cancers, five
endometrial cancers, five gastric cancers, two ovarian cancers, two hepatocellular
carcinomas, and one each of lung cancer, breast cancer, thyroid cancer, and
pancreatic cancer (six patients had two cancers). The mean age at cancer diagnosis
was 42.1 years. Among the 12 occurrences in 11 colorectal cancer patients with
complete clinical and pathological findings, most cancers (67%) were located
proximal to the splenic flexure (right-side colon). One patient had metachronous
colorectal cancer.
Conclusions: This is the first report of the general clinical characteristics of Taiwanese
HNPCC. The clinical characteristics of HNPCC in Taiwan were similar to those
in Western countries. The genetic bases of Taiwanese HNPCC patients remain to
be determined.
Colorectal cancer is one of the most common forms of
neoplasm in Western countries and its incidence is
increasing [1]. The incidence of colorectal cancer
increased during the period from 1987 to 1997 in
Taiwan, replacing gastric cancer as the third leading
cause of death from cancer during this period. The
annual number of deaths from colorectal cancer also
increased from 1,400 persons/year to 2,855 persons/
year during this 10-year period [2]. It is reasonable to
expect that colorectal cancer incidence will continue
to increase in the future in Taiwan.
Hereditary nonpolyposis colorectal cancer
(HNPCC) was first described nearly 100 years ago
[3, 4]. However, its pathogenesis remained elusive
until recently, when the disease was shown to be inher-
(J Formos Med Assoc
2002;101:206–9)
Key words:
HNPCC
Taiwanese
ited in mandelian fashion and linked to mismatch
repair (MMR) genes on chromosomes 2, 3, or 7 [5–13].
Five genes (hMSH2, hMLH1, hPMS1, hPMS2, and
hMSH6) that apparently participate in mismatch
repair in humans have been identified [7–15], and
defects in these genes lead to a genetic instability in
which short repeated sequences (microsatellites) are
characteristically altered [16–18]. Caretaker genes serve
to maintain genetic stability, and if one of these genes
undergoes mutation, the rate of mutation increases
significantly. This instability is believed to result in a
rapid accumulation of somatic mutation once tumorigenesis is initiated [11]. Individuals in families with
HNPCC have an increased incidence of colorectal
cancer (70%) and endometrial cancer as well as an
Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
Received: 13 July 2001.
Revised: 20 September 2001.
Accepted: 6 November 2001.
Reprint requests and correspondence to: Dr. Jau-Min Wong, Associate Professor, Department of Internal Medicine, National
Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, Taiwan.
206
J Formos Med Assoc 2002 • Vol 101 • No 3
Hereditary Non-Polyposis Colorectal Cancer in Taiwan
Results
Ten families with 202 persons met the Amsterdam
criteria and were included in this study. The Figure
shows an example family pedigree. Fifty-two persons in
these 10 families had a diagnosis of cancer, including
26 men and 26 women, and six of these had two types
J Formos Med Assoc 2002 • Vol 101 • No 3
Endometrial ca
▼
Ovarian ca,
rectal ca
▼
Colon ca
Rectal ca
Gastric ca
▼
To standardize the classification of HNPCC kindreds
and facilitate genetic linkage analysis, the International Collaborative Group on HNPCC, meeting in
Amsterdam in 1991, issued a set of phenotypic requirements for HNPCC families. The “Amsterdam Criteria”
stipulate that HNPCC families should include three
members with a histologically verified diagnosis of
colorectal cancer in two successive generations. One of
the three individuals must be a first-degree relative of
the other two, and one of the three affected individuals
must be diagnosed prior to 50 years of age [20].
We searched for families with members who met
the Amsterdam criteria and had been treated either at
the outpatient clinic or hospitalized during the period
from 1996 to 1999. The medical charts of these patients
were reviewed and data were collected on family history and clinical characteristics.
▼
Patients and Methods
Rectal ca
▼
increased risk for other tumors such as ovarian, gastric,
ureter, and small bowel cancer. Tumor progression is
also accelerated, and HNPCC patients therefore develop colorectal cancer at an average age of 42 years,
more than two decades earlier than the general population [3].
Identifying mutations in families allows identification
of mutation carriers who would benefit from screening
and surveillance. Determination of the microsatellite
instability (MSI) and MMR gene status is important in
these kindreds to enable genetic consultation and facilitate clinical follow-up. All HNPCC families should undergo a thorough genetic analysis to determine their
genetic background. A database of Taiwanese HNPCC
kindreds from all hospitals in Taiwan is needed to determine the clinical and genetic basis for Taiwanese HNPCC
kindreds. Although the incidence of colorectal cancer is
increasing in Taiwan, there has only been one case report
about HNPCC in Taiwan, which focused on the gynecologic field [19]. This is the first report about the general
clinical characteristics of Taiwanese HNPCC kindreds,
and their comparison to those from Western countries.
Colon ca,
gastric ca
▼
Figure. Hereditary nonpolyposis colorectal cancer (HNPCC) family
pedigrees show cancers in three generations. Seven persons in the
family already had cancer and at least three persons were in a firstdegree relationship.
of cancer. Most had colorectal cancer (40), and other
kinds of cancers included endometrial (5), ovarian
(2), gastric (5), pancreatic (1), lung (1), breast (1),
thyroid (1), and liver cancer (2). Among the 52 persons
with cancers, the age of cancer onset could be traced in
27 persons. The age at cancer diagnosis ranged from 19
to 64 years (mean, 42.1 yr). The demographic data of
these 10 HNPCC families is shown in the Table. One
patient had metachronous colorectal cancer during
the follow-up period. There were 170 persons who were
still under regular follow-up at the end of the study
period.
There were complete data on clinical characteristics
and pathologic results for 15 patients (10 women and five
men). Eleven patients had colorectal cancer, four had
endometrial cancer, two had gastric cancer, one had
ovarian cancer, and one had hepatocellular carcinoma
(four had two types of cancer). The most common initial
presentations of colorectal cancer included bowel habit
change (30.8%), body weight loss (30.8%), abdominal
pain (23.0%), and anemia (15.4%). Most occurrences of
colorectal cancer (eight of 12, 67%) were on the right side
of the colon. Eleven patients had Duke’s stage B to C
colorectal cancer. Only one patient had Duke’s stage A,
and her colorectal cancer was found and resected by
colonfibroscopy during a health check-up prompted by
the recent occurrence of cancer in her family.
Discussion
There are several hereditary diseases with an excess risk
of colorectal cancer, including familial adenomatous
polyposis (FAP) and HNPCC. HNPCC, which was first
described by Warthin in 1913 and named cancer family
207
S.C. Wei, M.H. Wang, M.C. Shieh, et al
Table. Demographic characteristics of the 10 hereditary non-polyposis colorectal cancer (HNPCC) kindreds
Kindred Total no. Cancer diagnosed
Site of cancer
No. under
persons (alive/dead)/
follow-up
(M/F)
Colon Stomach Ovary Endometrium Liver Pancreas Lung Breast Thyroid during
study
1
2
3
4
5
6
7
8
9
10
39
23
20
11
23
36
22
8
10
10
8
3
3
4
5
8
8
3
4
6
(3/5)/(4/4)
(0/3)/(2/1)
(2/1)/(1/2)
(2/2)/(2/2)
(2/3)/(3/2)
(5/3)/(2/6)
(3/5)/(4/4)
(2/1)/(1/2)
(1/3)/(3/1)
(3/3)/(4/2)
5
3
2
3
4
7
5
3
3
5
3
1
1
1
1
1
1
1
1
1
1
1
syndrome in the 1960s [21], is a disease with a definite
hereditary component [22]. Forty to sixty percent of
classical HNPCC families are found to harbor a germline mutation in one of the MMR genes [21, 22]. Prior
to the availability of molecular genetic diagnosis, the
diagnosis of HNPCC was based exclusively on the
family history of colon cancer and the following cardinal clinical features: an autosomal dominant mode
of inheritance of colorectal cancer; a paucity of
adenomatous colonic polyps, with number and site
distribution conforming to general population
expectations; gene penetrance of approximately 85%
to 90%; development of colorectal cancer in gene
carriers at an early age (around 45 yr); most (around
70%) colorectal cancers arising proximal to the splenic
flexure; multiple colorectal cancers, both synchronous
and metachronous are common; improved survival
relative to sporadic colorectal cancer [23, 24]; distinguishing pathologic features of colorectal cancer are
manifested, including an increased frequency of MSI;
and increased risk for malignancy at certain extracolonic
sites, especially the endometrium, and including the
ovary, stomach, small bowel, hepatobiliary tract,
pancreas, ureter, renal pelvis [25], brain, and breast
[26].
In comparing the clinical characteristics of our
Taiwanese HNPCC kindreds and the clinical features
described in the literature (reports from Western
countries), the characteristics were mostly similar but
with some differences in the following areas. First, the
mean age of cancer onset in our patients was 42.1 years,
earlier than the reported mean age of 45 years [24, 26].
Both were younger than the usual age of cancer onset
(around 60–65 yr for colorectal cancer, for example).
Second, although the tumor spectrum involved in our
208
1
1
1
1
33
19
19
9
20
33
16
7
7
7
patients (colorectal, stomach, endometrium, ovarian,
liver, pancreas, lung, breast, thyroid) was similar to
those of previous reports [25–27], there were no small
bowel or urinary tract cancers in our patients. Colorectal
cancer remained the most common cancer, followed
by gastric and endometrial cancers. Most colorectal
cancers, both in our study and those from Western
countries, developed in the right colon. There were
synchronous and metachronous cancers in both our
study and those from Western countries. Our HNPCC
patients had a better prognosis than non-HNPCC
colorectal cancer cases. Only two patients (one gastric
cancer, one colorectal cancer) died during the followup period.
We had only a few tissue blocks, so there was no
adequate evidence of whether our patients also had the
specific pathologic findings reported previously. The
genetic bases (including the MMR genes and MSI
status) of our HNPCC patients remain to be determined.
These questions will be answered when there is a
database of molecular diagnosis of HNPCC in Taiwan.
Collecting more Taiwanese HNPCC kindreds will help
to set up both clinical and genetic databases. Alertness
to the possibility of this disease (detailed family history
taking) is the only way to obtain an early diagnosis
when molecular database methods are not available.
Similar findings were reported by Chen et al in a study
of two families [19]. Our series had 10 families, which
is more representative. These results are the first report
of the general clinical characteristics of Taiwanese
HNPCC.
ACKNOWLEDGMENTS: This study was supported by a
grant from the National Science Council of the Republic of China (NSC-89-2315-B-002-028).
J Formos Med Assoc 2002 • Vol 101 • No 3
Hereditary Non-Polyposis Colorectal Cancer in Taiwan
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