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2013
Frequency and Clinical Features of Multiple Tumors of
the Large Bowel in the General Population and in
Patients with Hereditary Colorectal Carcinoma
Rossella Fante, M.D."*
LUCa Roncucci, M.D.lV3
Carmela Di Gregorio, M.D."'
Maria Grazia Tamassia, P ~ . D . ' , ~
Lorena Losi, M.D."'
Piero Benatti, M.D."~
Monica Pedroni, P ~ . D . " ~
Antonio Percesepe, M.D."~
Stefan0 De Pietri, M.D."~
Maurizio Ponz de Leon, M . D . ' ~ ~
'
The Colorectal Cancer Study Group of the University of Modena, IModena, Italy.
Dipartirnento di Scienze Morfologiche e Medico Legali, Universitii di Modena, Modena, Italy.
Dipartirnento di Medicina lnterna Universita di
Modena, Modena, Italy.
This work has been supported by Grants from
the Italian Ministry of University and Technological Research (MIJRST, funds "60%" and
'"to%"), the Region Ernilia-Rornagna (Legge
1970, 15.03.1986); the Consiglio Nazionale deIle Ricerche (C.N.R., project A.C.R.O.); the
Associazione ltaliana per la Ricerca sul Cancro
(A.I.R.C., which supported, in part, Drs. Maria
Grazia Tarnassia and Monica Pedroni) and the
Provincia di Modena.
Address for reprints: Maurizio Ponz de Leon,
M.D., Dipartimento di Medicina Interna, Medicina Ill (I1 piano), Policlinico, via del Pozzo, 71,
41 100 Modena, Italy.
Received October 6, 1995; revision received
January 4, 1996; accepted January 24, 1996.
0 1996 American Cancer Society
BACKGROUND. Reports on the frequency of multiple carcinomas of the colon and
rectum have varied from 3-4% to more than 10% of all tumors of the large tiowel.
METHODS. We reviewed the files of a specialized colorectal cancer registry with
the following objectives: a) to determine the frequency of multiple tumors (synchronous or metachronous) in the general population: b) to compare these values
with those observed in patients with hereditary nonpolyposis colorectal carcinoma
(HNPCC);and c) to evaluate the clinical outcome of patients with multiple tumors
and the role of other clinical parameters in the development of these neoplasms.
RESULTS. From 1984 to 1992, 53 patients with multiple tumors (of 1298 registered
patients, 4%) had large bowel carcinoma; 33 (2.5%) were synchronous and 20
(1.5%)metachronous. The total number of multiple colorectal carcinomas was 95,
which was 7% of all registered colorectal carcinomas (1337 carcinomas in 1298
patients). Multiple tumors occurred significantly more often in patients with
HNPCC than in those with sporadic carcinomas ( P < 0.001); this increased prevalence was more marked for metachronous lesions, which occurred almost 4 times
more often in patients with HNPCC (5.8% vs. 1.3%; P < 0.001). The average interval
of time between the first and the second malignancy was 8.7 years; there was
no significant difference between hereditary and sporadic tumors. Patients with
synchronous tumors did not show appreciable differences in survival when compared with individuals who had single neoplasms. In contrast, a poor clinical
outcome was observed in patients with metachronous tumors after the development of the second carcinoma. Finally, polypoid adenomas of the large bowel
were found significantly more often in patients with multiple primary tumors than
in those with a single tumor.
CONCLUSIONS. These results emphasize the importance of preoperative pancolonoscopy for the identification of possible synchronous tumors (both benign and
malignant) and long-lasting endoscopic follow-up for the detection of recurrent
or metachronous lesions. The conclusions are even more pertinent for patients
with HNPCC, whose risk of metachronous tumors is significantly higher than that
of patients with sporadic carcinoma. Cancer 1996; 77:2013-21.
0 1996 American Cancer Society.
KEYWORDS colon, rectum, HNPCC, synchronous, metachronous, tumor.
M
ultiple tumors are particularly frequent in some types of cancer that
may be associated with a relatively good prognosis, such as colorectal, breast, and head and neck carcinomas. The reasons whereby a
subgroup of patients develop more than one neoplasm remain unclear,
and in this respect multiple tumors represent a biologic challenge for
oncologists and cancer researchers. By definition, two or more tumors
occurring simultaneously (in the same organ or in different tissue:s) are
2014
CANCER May 15,1996 / Volume 77 / Number 10
designated as synchronous, whereas tumors occurring at
various intervals of time are known as metachronous.
Multiple tumors (both synchronous and metachronous) are rather frequent in the large bowel, in which
In
they may represent up to 10% of all malignancie~.’-~
the large intestine, the occurrence of multiple neoplasms
may have practical implications because the type of surgical operation can be influenced by the presence, or the
risk, of synchronous or metachronous lesions. In hereditary nonpolyposis colorectal carcinoma (HNPCC or
Lynch syndrome), for instance, multiple malignancies of
the large bowel are particularly freq~ent,’,~
and this has
led various investigators to propose subtotal colectomy
with ileorectal anastomosis as the most appropriate surgical approach, due to the high risk of a second or third
tum~r.~,~
Most of the clinical data on multiple colorectal tumors are drawn from surgical
whereas relatively
little information has been obtained from populationbased
In 1984, a specialized colorectal cancer
registry was instituted in the Health Care District of Modena, with the principal objective of investigating neoplastic familiarity of the registered patients and of identifying families with HNPCC.’ lo The main purposes of the
present investigation were: a) to determine the frequency
of multiple tumors of the large bowel in the general population; b) to compare the observed values with those seen
in HNPCC; and c) to assess the clinical outcome of patients with multiple tumors and the possible role of other
clinical parameters (i.e., adenomatous polyps) in the development of these neoplasms.
MATERIALS AND METHODS
The Colorectal Cancer Registry
Details of the general organization of the Registry have
already been
Briefly, Health Care District
16 of the Region Emilia-Romagna includes Modena and
10 surrounding communities for a total of 265,227 inhabitants at the 1991 census (there were 263,487 inhabitants
at the 1981 census, thus indicating a certain stability of
the resident population); the population density is 450
persons per square kilometer. The territory is entirely flat
and should be considered almost completely urban (the
working population involved in agriculture is less than
6% of the total). The area is highly industrialized with
one of the highest incomes per person in Italy. Initially,
patients were directly contacted and interviewed during
their hospitalization; in the subsequent years, the registration was performed by consulting clinical charts, usually within 1-2 years from the diagnosis.
Staging System and Definition of Multiple Tumors
Tumors were staged with the TNM classification, which
closely corresponds with Dukes staging into four main
TABLE 1
Crude incidence (Annual Rates per 100,000),Age-Adjusted Incidence
(on the European and World Population) and Cumulative Risk (0-74
Years per 1000) of Colorectal Cancer in the Health Care District of
Modena, 1984-1992
Age-adjusted
incidence
ICDa
Crude
incidence
Men
Colon
Rectum
153.0-9
154.0-9
24.9
Women
Colon
153.0-9
Rectum
154.0-9
36.8
33.9
18.0
Cumulative
Europe
World
risk (0-74)
31.3
21.5
20.6
14.7
23.3
18.5
22.4
14.9
8.7
8.8
12.1
17.2
lnternarional Classification of Disease, 9th Revisiou
~1asses.I~
Histologic diagnoses such as in situ carcinoma,
severe dysplasia, or neoplastic foci were not considered
as cancer (and thus were not registered), unless there
was an extension of the tumor through the muscularis
mucosae.”rl3
A total of 1337 carcinomas of the large bowel were
registered in 1298 patients during the period 1984- 1992;
among these, there were 53 patients with multiple colorectal malignancies (33 synchronous and 20 metachronous). Epidemiologic data concerning cancer registration
(crude and age-adjusted incidence rates, cumulative
risks) are shown in Table 1. Multiple tumors were defined
as the occurrence of two independent carcinomas developed simultaneously (synchronous) or at different times
(metachronous) in the various large bowel tracts. Local
recurrences (such as malignant tumors developed on the
suture line or, more generally, in the site of previous surgery or in the perirectal fat) were not classified as multiple
lesions. Data on adenomas were obtained from the
pathologic, operative, and endoscopic records.
Identification and Main Features of HNPCC
In addition to personal data, an accurate genealogic tree
was traced for each registered patient, in which the main
causes of morbidity and mortality of first-degree relatives
were recorded. Pedigrees were further analyzed for the
presence of six clinical criteria (vertical transmission, familial aggregation, multiple primaries, early age of onset,
right colonic localization, and mucinous histologic type),
all indicative of an increased susceptibility to hereditary
colorectal ~ a r c i n o m a , when
~ , ’ ~ two or more criteria were
present in the “nuclear pedigree,” this was extended to
second- and third-degree relatives. Finally, we evaluated
whether or not these expanded family trees met the minimum requisites for the definition of HNPCC (the so-
Frequency of Multiple TumorslFante et al.
2015
TABLE 2
Main Clinical Features of Patients with Multiple Tumors Registered in the Period 1984-1992
Mean Age (?SD)
Sex (MF)
Associated
adenomas (%)
5-year survival (%)
Synchronous (No = 33)
Metachronous (No = 20)
68.7 ? 11.3
63.2 ? 9.5
1.2
43
39.4
0.8
55
1" = 85
2"d = 15.7
Registered patients (no =: 1245)
68 5 9.7
1.1
21
41.Zb
Histologic
verification (%)
100
90
94.4
-
SD: standard detiation; M: male; F: female.
'This value l1.2451 was obtain1:d by subtracting the number of individuals with multiple tumors (53) from the overall number of registered patients.
Survival refers only to the 39;' patients registered in 1984-86.
called "Amsterdam criteria") . 1 6 The details of this original
procedure for the identification of the Lynch syndrome
have already been described in previous
During the period 19134-1990,28 HNPCC families were identified, for a total of 139 patients affected by (or dead as
a result of) colorectal malignancies.
TABLE 3
Assessment of Survival
HNPCC (NO = 139)
8b
Registered patients (No = 12591% 30
All registered patients were prospectively followed-up
through a strict collaboration between pathologists, oncologists, surgeons, and endoscopists. Patients unable to
return for study as controls were usually contacted by
telephone, so that their status and the reasons for the
poor compliance could be ascertained. Causes of death
were verified by clinical charts, pathologic reports, or
death certificates. Five-year survival could be estimated
for all patients registered between 1984-86.'"." However,
all patients with multiple carcinomas (or their close relatives) in the 1984--1992series were contacted so that their
status could be assessed. Thus, for most patients, a complete 5-year follow-up could be traced, whereas this was
necessarily limited to 3 or 2 years, respectively, for patients registered in 1991 or 1992.
Statistical Analysis
The statistical significance of differences in the occurrence of multiple tumors between the two investigated
series (registered patients and HNPCC families) was assessed with chi-square tests, using the Yates correction
when appropriate. Survival was assessed with KaplanMeier estimate^."^^*^
RESULTS
During the 9-year period 1984-1992, 53 patients with
multiple tumors were observed out of 1298 registered individuals (4%).Thirty-three patients (2.5%)had synchronous lesions and 20 (1.5%) had metachronous cancers,
of these, 14 developed the first malignancy before the
registration period (the second, of course, was always diagnosed be.tween 1984 and 1992).Table 2 summarizes the
Multiple Tumors Registered in Hereditary Nonpolyposis
Colorectal Carcinoma
Synchronous
Metachronous
Total
No.
%
No.
%
No.
%
-
5.8
8'
2.4
16
5.8
1.3
16d
46
11.5
3.6
HNPCC: hereditaly nonpolyposis colorectal carcinoma.
'This value (1259) was obtained by subtracting the number of patients with a clinical diagnosis of
HNPCC (no = 39) from the total number of registered patients (i.e., those with sporadic malignancies)
(n =1298).
1' = 3; not significant Jvs. registered patients).
' x 2 = 13.2;P < 0.001 (vs. registered patients).
2' = 13.1; P < 0.001 (vs. registered patients).
main clinicopathologic features of patients with multiple
tumors; it is worth noting the significantly increased occurrence of adenomatous lesions (either in patients with
synchronous or metachronous tumors) when compared
with patients affected by a single malignancy. The total
number of multiple neoplasms in the registration period
was 95 (in 53 patients), equal to 7% of all colorectal carcinomas (n = 1337).
The HNPCC series included 39 registered patients
(in 28 families) and 100 first- or second-degree relatives
affected by (or dead as a result of) colorectal malignancies. Multiple tumors occurred significantly more often
( P < 0.001) in patients with Lynch syndrome rather than
in those with sporadic tumors (n = 1259, the large majority of the registered patients) (Table 3). This increased
frequency was particularly evident for metachronous lesions, which occurred almost 4 times more often in patients with HNPCC (5.8%vs. 1.3%; P < 0.001).
Figure 1 shows the number of patients with multiple
tumors by year of registration. In the upper part of the
figure, on a different scale, the absolute number of colorectal carcinoma patients registered between 1984- 1992
CANCER May 15,1996 / Volume 77 / Number 10
2016
0Registered
HNPCC
120
1
)
I
I
I
I
I
I
I
I
I
'84
'85
'86
'87
'86
'89
'80
'91
'92
Year of registration
FIGURE 1. Patients with multiple tumors by year of registration. Upper
scale: total patients with colorectal carcinoma (n = 1298). Lower scale:
total patients with multiple tumors (synchronous and metachronous) (n
= 53) (4%; solid square); patients with synchronous lesions (n = 33)
(2.5%; solid triangle).
1-3
4-6
7-9
10-12 13-15
16-18
Timeinterval (yrs) between first and second malignancy
FIGURE 3. Interval of time between the first and the second malignancies
f
in patients with metachronous tumors. Registered patients are compared
with hereditary nonpolyposis colorectal carcinoma patients. The proportions are calculated within each of the two groups.
1
le0
I A
I
'84
I
I
I
I
I
'a5
'86
*a7
'80
'a9
I
'90
I
'91
I
'92
Year of registration
FIGURE 2. Proportion of metachronous tumors (lower scale), by year
of registration, among patients at risk of developing a second tumor (upper
scale: registered patients with Dukes A, B, or C neoplasms).
is reported. Only minor fluctuations were observed
around the average value of 4% of all registered colorectal
malignancies. For metachronous lesions, the population
at risk does not correspond to the registered patients,
because Dukes stage D and unstaged patients usually had
such a poor prognosis that the development of a second
malignancy was extremely unlikely. Figure 2 illustrates
the frequency of metachronous tumors, by year of registration, among patients at risk of developing a second
neoplasm ke., registered patients in Dukes Stages A, B,
or C). It should be noted, however, that the available data
allow only a partial definition of this estimate, because
they do not take into consideration patients who survived
a colorectal carcinoma diagnosed before 1984 (the first
year of registration).
The time interval between the first and the second
malignancy in patients with metachronous tumors is
shown in Figure 3. The average interval was approximately 9 years, virtually without any appreciable difference between hereditary and apparently sporadic neoplasms. The distribution of all multiple (n = 95) and nonmultiple (n = 1242) registered tumors in various tracts of
the large bowel (Fig. 4, panels A and B) revealed only
marginal differences between the two series. The results
of clinicopathologic staging are summarized in Table 4.
Synchronous lesions, first metachronous lesions, and single tumors were distributed similarly among the 4 main
Dukes categories; in contrast, in almost half of the cases
(9 of 201, the second metachronous tumor developed in
an advanced stage, which was usually beyond the limits
of a curative resection.
Five-year survival of patients with synchronous tumors was almost identical to that observed in common
Frequency of Multiple Tumors/Fante et al.
2017
DISCUSSION
6,4 %
A
O 96
0,9
S % U
4,690
4,656
FIGURE 4. Distribution of single (n = 1242; panel A) and of multiple
(n 95; panel 6)colorectal malignancies in the various tracts of the large
bowel.
malignancies of the large bowel (Fig. 5). In our series.
patients with metachronous tumors had an excellent survival after the first carcinoma (85%)at 5 years, Table 21,
whereas rhe prognosis was much poorer after the second
neoplasm (15.7% at 5 years [ P < 0.011, vs. first tumor by
the log rank test) (Fig. 6).
The results of the present study can he summarized as
follows.
In a total group of 1298 patients registered for colorectal carcinoma during the period 1984-1992, 33 (2.5%)
had synchronous carcinomas and 20 (1.5%) metachronous lesions. The corresponding values in a series of 139
patients with hereditary colorectal carcinoma were 7 (5%)
and 8 (5.8%), respectively, (not significant, and P < 0 001,
respectively). In both series (registered patients and patients with HNI'CC), the average interval of time between
the index lesion and the second malignancy was approximately 8 years (range, 2- I6 years). Adenomatous polyps
were found significantly more often in patients with multiple tumors (both synchronous and metachronous) than
in those with a single tumor. The stage of metachronous
lesions in registered patients was generally less favorable
than the index lesions. Survival of patients with synchronous lcsions did not differ from that of individuals with
a single malignancy; in contrast, the development of a
metachronous tumor was more often associated with a
severe prognosis.
Although these findings may appear similar to some
of the previous studies on multiple tumors, at least two
original aspects of the present investigation should be
underscored. First, the data are derived from a populatioti-based registry; thus, the risk of a selection bias (as
it may occur in surgical series) should be minimized. Second, the results obtained in sporadic (i.e., nonfamilial)
colorectal malignancies have been compared with Those
of HNPCC, which represents an etiologically different
type of
Frequency of Synchronous Carcinomas
The frequency of synchronous colorectal cancers shows
ample fluctuations in the available literature. At one extreme, Cunliffe et al." found synchronous lesions in 18
of 193 investigated patients (9.3%); similarly, Ilvers et al.'"
reported simultaneous lesions in 21 of 320 of their patients (7%) and Slater et al." in 5.4%, nioreover, in a Swedish series," the frequency of synchronous tumors was
4.6%.At the other extreme, Welch'8 reported an incidence
o f synchronous lesions of the large bowel as low as 1.7%,
an estimate that is not far from the 2.5% incidence observed in the present investigation. In our opinion, this
variation in the frequency may be attributed to two main
reasons; the criteria used for the diagnosis of carcinoma
and differences in the selection of patients. Thus, in many
studies, a tumor was considered as a carcinoma only
when infiltrating the niuscularis mucosae,"'i~'"whereas in
otherszi this was not required, provided the atypical cells
had invaded through the basal membrane; moreover,
other authors'.'.'' did not provide sufficient details on the
diagnosis of carcinoma. 'l'he selection of patients was
2018
CANCER May 15,1996 / Volume 77 / Number 10
TABLE 4
Clinicopathologic(Dukes)Staging of Multiple Tumors
Dukes Staging
~~
~
Synchronousa(n = 33)
Metachronous first tumor [n = 20)
Metachronous second tumor (n = 201
Registered patients (n = 1245)
a
5
7
0
162
(15)
(35)
(0)
(13)
13
2
6
361
(39)
5
4
3
249
(10)
(30)
(29)
(15)
(201
8
4
(15)
(20)
9
411
1241
(20)
(45)
(33)
2
3
2
62
(6)
(15)
(10)
(5)
In synchronous lesions, staging of the mosi advantaged tumor was taken into consideration.
’NS = not staged.
‘Patients in whom no IvmDh nodes were found in the resected colorectal specimens.
100
100
00
80
A
c
-m
2
- 60
Q
80
.L
.L
5
5
u)
u)
40
40
20
20
0
0
I
I
I
I
I
I
0
12
24
36
40
60
I
0
I
I
I
I
I
12
24
36
40
60
Months
Months
FIGURE 5. Cancer specific, 5-year survival of all patients with colorectal
carcinoma registered between 1984-86 (n = 397; solid line) and of individuals with synchronous lesions (n = 33; dotted line).
similarly important; in most of the above mentioned
s t u d i e ~ , ~the
~ - ~frequency
’
of synchronous lesions was assessed in patients who underwent resection for colorectal
carcinoma, and this virtually limits the analysis to Dukes
Stage A, B, and C patients. When the estimate was evaluated in all diagnosed or registered patients (thus including Dukes Stage D, nonstaged patients and individuals
receiving only palliation), the frequency of synchronous
tumors was much lower, as seen in the study by Welch“
and in the present investigation. This is not surprising,
because it is rather obvious that the chances of finding
FIGURE 6. Cancer specific, 5-year-survival of patients with metachronous tumors (survival after the iirst tumor: dotted line; survival after the
second tumor: solid line).
a second malignancy are much higher when a resected
specimen is available (as in the case of a carcinoma infiltrating the submucosa [through the muscularis mucosal
in an apparently benign polyp). In conclusion, whatever
their exact frequency, synchronous colonic malignancies
are not rare, and a careful preoperative search of these
lesions should be made to provide optimal treatment.
Frequency of Metachronous Carcinomas
The incidence of metachronous colorectal carcinomas in
the literature ranges between 1-4% of all cases. Demeter
and Freeark3’ reported that patients being treated for
Frequency of Multiple TumorslFante et al.
metachronous lesions represented 1.6% of all patients
undergoing surgical treatment for colorectal cancer during the period 1978- 1989;similar results were previously
obtained by other authors either in ~ m a l l e ror~large?’
~,~~
series. In contrast, higher frequencies were found in other
investigation^.^"^^."" Moreover, Cali et al.3Lwere able to
calculate an annual incidence (0.35%per year) and a CUmulative incidence (6.3% at 18 years) for metachronous
tumors of the large bowel. The frequency observed in the
present study (1.5% of all registered patients) and the
mean interval between the first and the second malignancy (8.7 years; Fig. 3) are in accordance with most of
the previous reports.
It should be pointed out that establishing the frequency
of metachronous carcinomas is not as simple as for synchronous 1t:sions; nonetheless this estimate is of undoubted
clinical importance, because it may have profound implications not only for the treatment but also for the appropriate
follow-up of patients with colorectal malignancies. As already discussed for synchronous lesions, selection of patients is of fundamental importance; if one considers only
patients who have undergone s ~ r g e r y , ~and
~ , 3not
~ all diagnosed or registered colorectal cancers, the proportion of
patients with metachronous tumors tends to increase. This
is also clear frorn our observations: the 20 patients with
metachronous c.ancers detected between 1984 and 1992
represent 1..5% of all registered patients (1298) but 2.4% of
patients with Dukes Stage A,B, and C carcinomas (Fig. 2).
The criteria used by various authors for the definition of a
metachronous tumor (after the index lesion) are also a matter of concern, a reason for confusion, and a plausible explanation for differences among apparently similar investigations,””-:’3
Thus, for instance, despite strict rules or well detailed definitions, it is often difficultto distinguish between
a second primary tumor and a local recurrence, especially
when the second event occurs 3 or more years after the
index lesion. Finally,the frequency of metachronous tumors
might be influenced by the follow-up of patients who have
undergone surgery. In our institutions, endoscopic surveillance is at present strongly recommended for virtually all
patients who undergo resection for malignancies of the
large bowel; however, we do not know what proportion of
these patients actually return for endoscopic management;
in addition, there is no doubt that 10 years ago these suggestions were more vague and imprecise. In theory, if in an
ideal population all patients operated on for colorectal tumors were r e p !arly followed-up with lower endoscopies,
we would expect a higher detection of metachronous lesions (especiallyat an early stage),although a more optimistic view might also anticipate a reduction in their frequency
due to the removal of all adenomatous polyps.
Frequency of Multiple Tumors in HNPCC
The proclivity tci multiple tumors (not limited to the large
bowel, but frequently involving other organs, such as the
2019
uterus, stomach, ovary, and ureter) is one of the main
features of HNPCC. Thus, Mecklin and J a ~ i n e n re,~
ported that 29 of 81 of their patients (35%)who survived
at least 1 year after the index colorectal carcinoma subsequently developed metachronous lesions, corresponding
to a cumulative annual risk of 3.2%. In a large American
series of patients with hereditary colorectal cancer, Fitzgibbons et
found synchronous lesions in 18.1% and
metachronous carcinomas in 24.2% of patients. In addition, the authors estimated that the cumulative risk of
metachronous lesions at 10 years from the index tumor
was approximately 40%. Lower frequencies of multiple
lesions, however, were reported in other HNPCC series.34,35
The incidence of synchronous (5%) and of rnetachronous (5.8%)tumors observed in the present investigation is lower than those observed in the above mentioned studies. The reasons for this difference are unclear,
although it is likely that they reflect different criteria used
for the selection and definition of HNPCC families. Moreover, we should not forget that colorectal cancer is a very
common malignancy; consequently, it is possible that the
presence of phenocopies (i.e., sporadic cases occurring by
chance in a familywith genetically determined tumors) as
well as aspecific cancer aggregates might represent further confounding factors in establishing the frequency of
multiple primary tumors in HNPCC. Finally, even if lower
than previously reported estimates, the observed frequency of multiple colorectal malignancies in HNPCC
patients was significantly higher than that seen in patients with common sporadic tumors (expecially metachronous lesions), an observation that lends further support
to the peculiar susceptibility of HNPCC patients towards
the development of two or more primary tumors.
Clinical Features of Patients with Multiple Tumors
At least two clinical findings deserve some comments:
the frequency of associated colorectal adenomas and the
stage of metachronous lesions. Because adenoma.tous
polyps represent a precursor lesion of ~ancer,~’.~’
it is of
interest that our studies confirm that patients with multiple carcinomas are more likely to have associated polyps
(Table 2). Welchz8reported that 65% of synchronous tumors and 60% of metachronous lesions were accompanied by polyps; similar results were reported by other
i n v e ~ t i g a t o r s .Among
~ ~ ’ ~ ~ these, Evers et aLZ5found that
48% of their patients with synchronous tumors had benign adenomas larger than 1 cm in diameter compared
with an 18% occurrence rate in patients with a s:ingle
tumor. The frequent cohexistence of benign and malignant multiple colorectal lesions suggests the presence of
a generalized disorder of cell growth and differentiation
in the entire colorectal mucosa of some individuals who
are particularly prone to the development of neopliasms
2020
CANCER May 15,1996 / Volume 77 I Number 10
and who should be identified, and then managed, with
close endoscopic f o l l ~ w - u p . ~ ~
In the 20 patients with metachronous tumors in this
study, we found that the index lesion frequently showed
a more favorable stage when compared with the second
carcinoma. This is probably what one should expect simply on a logical basis, because if a patient survives after
a first malignancy for an average of almost 9 years (Fig.
3), this clearly indicates that the tumor was not in an
advanced stage; accordingly, various authors reported
that staging tended to be worse in metachronous lesions
when compared with the initial neoplasm^.^^^^' At variance with these results, other authors3' found that metachronous tumors were diagnosed at an earlier stage than
the index lesions; it is likely that in this series patients
underwent a closer endoscopic follow-up, leading to the
detection of an increased proportion of early stage tumors.
Practical Implications
The main practical implications concern treatment and
follow-up of patients with colorectal malignancies, and
should be addressed differently for sporadic versus hereditary tumors. With regard to patients with common
colorectal malignancies, our findings reinforce the usefulness of the current recommendations: 1) preoperative inspection of the entire large bowel to identify all
(benign and malignant) possible synchronous lesions;
2) appropriate surgery (right or left hemicolectomy with
close endoscopic follow-up or subtotal colectomy with
ileorectal anastomosis) with removal of all neoplastic
lesions; and 3) adequate endoscopic surveillance of patients who have undergone surgery virtually for the rest
of their lives. Due to the possible late development of
metachronous tumors (which occur rather often at an
advanced stage), there is a general agreement that patients with HNPCC (and their first-degree relatives)
should be managed with particular care, beginning
with endoscopic examinations (in unaffected individuals) at the age of 25 years, and then continuing at regular, usually biannual, intervals of time.17,L8~"9
The results
of the present study further support this policy. As for
the treatment of patients with HNPCC, subtotal colectomy with ileorectal anastomosis has repeatedly been
especially for the frequent development
of metachronous lesions. An alternative approach
might be standard hemicolectomy followed by close
surveillance of the remaining large bowel. By showing
a frequency of metachronous lesions much lower than
that of other investigation^,^'^ our data seem to favor
this latter possibility. However, prospective investigations are needed to evaluate which of the procedures
can be associated with a reduced mortality for colorectal carcinoma.
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