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Endoscopic and Surgical Management of
Hereditary Nonpolyposis Colorectal Cancer
Rebeccah B. Baucom, M.D. 1Paul E. Wise, M.D. 1
1Section of Surgical Sciences, Vanderbilt University Medical Center,
Nashville, Tennessee.
Clin Colon Rectal Surg 2012;25:90–96.
Address for correspondence and reprint requests Paul E. Wise, M.D.,
Section of Surgical Sciences, Vanderbilt University Medical Center
D5248 Medical Center North, Nashville, TN 37232-2543
(e-mail: paul.e.wise@vanderbilt.edu).
Objectives: On completion of this article, the reader should
be able to: (1) summarize the screening and postoperative
colonoscopic/endoscopic surveillance recommendations for
colorectal cancer in patients with HNPCC/Lynch syndrome;
(2) describe the surgical options and their justification for the
treatment of colon cancer in patients with HNPCC/Lynch
syndrome; (3) describe the surgical options and their justifi-
cation for the treatment of rectal cancer in patients with
HNPCC/Lynch syndrome; and (4) summarize the chemopre-
vention options for patients with HNPCC/Lynch syndrome.
Hereditary nonpolyposis colorectal cancer (HNPCC), or
Lynch syndrome, is the most common form of hereditary
colorectal cancer (CRC), accounting for 3 to 5% of all CRCs.1,2
Many affected families have a germline mutation in DNA
mismatch repair (MMR) genes including MLH1,MSH2,MSH6,
or PMS2. As more is learned about the genetics of this
syndrome, surveillance and management decisions become
more complex. Particular controversy surrounds the role of
prophylactic colectomy, time interval between screening
colonoscopies, and extent of resection in individuals with
colorectal cancer (CRC). This review discusses the manage-
ment related to CRC in individuals affected with HNPCC or
Lynch syndrome, including screening and surveillance rec-
ommendations, surgical interventions, and considerations of
chemoprevention.
For the purpose of this review, the terms HNPCC and Lynch
syndrome will not be used interchangeably. HNPCC will be
Keywords
►HNPCC
►hereditary
nonpolyposis
colorectal cancer
►Lynch syndrome
►colon cancer
►colorectal cancer
►hereditary cancer
syndrome
Abstract Hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome is a disease
characterized by autosomal dominant clustering of colorectal cancer (CRC) as well as
other cancers. It is critical for clinicians and surgeons caring for patients with HNPCC to
be familiar with their management related to CRC. Based on retrospective studies,
screening colonoscopy is recommended every 1 to 2 years beginning at age 20 to 25, or
10 years younger than the earliest CRC in the family (whichever is earlier). HNPCC
patients with colon cancer should be considered for total abdominal colectomy rather
than a more limited segmental colon resection due to the increased risk of metachro-
nous neoplasia associated with the condition. Rectal cancer in HNPCC has not been well
studied, but discussions with the patient regarding surgical management should weigh
the risks of metachronous CRC with the morbidity and quality of life issues associated
with proctocolectomy. Regardless of the procedure, a patient with HNPCC requires
close postoperative endoscopic surveillance of any remaining at-risk mucosa. Interms of
chemoprevention, aspirin has been shown to be effective in preventing colorectal
neoplasia in prospective trials and should be considered in patients who do not have a
contraindication to the drug. Trials for other chemopreventative agents in HNPCC are
ongoing. As more is learned about particular genotype–phenotype correlations with
Lynch syndrome, this will likely affect surgical decision making. Despite all of these
efforts in the management of patients with HNPCC or Lynch syndrome, incident CRCs
still occur, thus reinforcing the need for further studies to better understand the optimal
management of these patients.
Issue Theme Hereditary Colon and
Rectal Cancer; Guest Editor, Jaime L.
Bohl, M.D.
Copyright © 2012 by Thieme Medical
Publishers, Inc., 333 Seventh Avenue,
New York, NY 10001, USA.
Tel: +1(212) 584-4662.
DOI http://dx.doi.org/
10.1055/s-0032-1313779.
ISSN 1531-0043.
90
defined clinically as an autosomal dominantly inherited
disease character ized by early-onset cancers, most commo nly
CRC, endometrial and ovarian2,3 as defined by the Amster-
dam, Amsterdam-like, and/or the Bethesda clinical criteria
(described earlier in this edition of Clinics). Lynch syndrome
includes those patients and their family members with a
known germline mutation in an MMR gene, or those who
meet the HNPCC clinical criteria and have microsatellite
unstable tumors but have not had genetic testing for a
germline MMR mutation.4,5 “Familial colorectal cancer type
X”is a term recently used to describe families that meet
Amsterdam criteria, but without an MMR gene mutation.2,6
Colorectal Cancer Screening in HNPCC
The CRC that occurs in HNPCC typically develops from ade-
nomas just as CRC does in sporadic cases, however, they pass
through the adenoma to carcinoma transformation sequence
more quickly than the 8 to 15 years that it takes to occur in
sporadic CRC. This leads to a younger age at diagnosis of CRC
in HNPCC (mean of 45 years old) and a need for a shortened
screening interval.7These CRCs are also more likely to be
right-sided (60–70%), and are associated with high risk of
synchronous (18%) and metachronous (11–45%) tu-
mors.1,2,8,9 Therefore, it is imperative that the entire well-
prepped colon is evaluated during screening and that screen-
ing colonoscopy begin earlier than in individuals with aver-
age CRC risk (i.e., earlier than age 50).
The goal of screening is to detect a nd remove premalignant
lesions and to prevent cancer-related morbidity and mortali-
ty. One prospective controlled trial demonstrated a statisti-
cally significant 63% decrease in development of CRC from
11.9% to 4.5% (P¼0.03) in members of 22 families with
HNPCC who underwent surveillance with colonoscopy or
barium enema plus sigmoidoscopy every 3 years (n¼133)
compared with families with HNPCC who underwent no
screening (n¼118).10 Mortality differences were not signif-
icant in the study (12 control deaths vs 6 case deaths,
P¼0.08). A 15-year follow-up study of this same patient
cohort demonstrated both the 63% decrease in CRC incidence
with screening as well as decreased CRC-associated mortality
in those patients who underwent screening compared with
those who did not.11 In the subset of Lynch syndrome patients
in this study, CRC incidence rates also dropped significantly
from 41% to 18% (P¼0.02), but cancers continued to develop
despite their screening regimen. Of note, the CRCs were
diagnosed at an earlier stage (and therefore more often
amenable to curative operative intervention) in patients
undergoing screening as compared with those who were
not being screened who were diagnosed with CRC based on
symptoms.
Because of the continued CRC incidence in HNPCC despite
the 3-year screening, most authors have recommended more
frequent screening. Vasen et al demonstrated that in 745
patients with Lynch syndrome who underwent screening at a
mean interval of every 16 months during the years between
1995 and 2009, 4.4% developed CRC while under sur veillance,
with most cases occurring after age 40. The risk of developing
CRC at 10 years was reduced to 6% with this shorter interval
when compared with a 10% risk at 10 years with screening
every 2 to 3 years. Interestingly, they also looked at screening
in patients with familial CRC t ype X and showed that their risk
of developing CRC under surveillance was significantly lower
and occurred in older individuals when compared with Lynch
syndrome patients. The authors concluded that individuals
with Lynch syndrome should undergo screening every 1 to
2 years beginning at 20 to 25 years of age, and that a less
intensive colonoscopic surveillance program might be appro-
priate in patients who meet Amsterdam criteria but do not
have a demonstrated MMR mutation.6Alterations in screen-
ing intervals between Lynch syndrome patients versus those
with HNPCC have not been studied in a prospective fashion,
however; therefore, most authors recommend colonoscopy
every 1 to 2 years beginning at age 20 to 25, or 10 years
younger than the first diagnosis in the family (whichever is
first), then yearly after age 40 for patients with either HNPCC
or Lynch syndrome.2,7,12
Adjunctive technologies beyond standard colonoscopy
may increase the identification of neoplasia during screening
of HNPCC patients and may impact CRC mortality rates in
these patients. Technologies such as dye-spray or chromoen-
doscopy,13 as well as narrow band imaging have shown
promise in better-identifying adenomas when used for
screening HNPCC patients.14,15 Because these technologies
are not yet widely available, they are not considered the
standard of care in the screening of those with HNPCC. Even
increased magnification and slow withdrawal times during
colonoscopy, however, have shown increases in adenoma
identification in Lynch syndrome up to 55% over standard
colonoscopy. This was equivalent to the improvement in
detection rates with chromoendoscopy.13,15,16
Surgical Management of Colorectal Cancer in
HNPCC
Colon Cancer in HNPCC
Surgery for HNPCC can be either therapeutic or prophylactic
with therapeutic resections for colon cancer being the most
common indication for surgery. Once colon cancer is diag-
nosed, surgical options include segmental resection (removal
of just the affected portion of colon such as a right or left
hemicolectomy) versus total abdominal colectomy (TAC)
with ileorectal anastomosis (removing the entire colon and
anastomosing the terminal ileum to the upper rectum or
rectosigmoid). A TAC in the setting of colon cancer is both
therapeutic and prophylactic because it involves removing
the portion of the colon affected by the cancer as well as the
remainder of the colon which harbors risk of metachronous
neoplasia.2Most authors agree that TAC is the favored option
for a patient with Lynch syndrome and colon cancer due to
the high risk of metachronous neoplasia in the remaining
colon if a segmental resection is performed.1,17–19 However,
no prospective trials have been done to demonstrate a true
survival benefit for TAC versus segmental resection.
In retrospective studies, the risk of developing a meta-
chronous colon cancer after partial colectomy ranges from 11
Clinics in Colon and Rectal Surgery Vol. 25 No. 2/2012
Endoscopic and Surgical Management of Hereditary Nonpolyposis Colorectal Cancer Baucom, Wise 91
to 45% over 8 to 13 years (►Table 1).1,2,8,18 Parr y et al assessed
the risk of metachronous CRC in 382 Lynch syndrome pat ients
from the Colon Cancer Family Registry who underwent TAC
versus segmental resection as treatment for their first CRC.
Interestingly, only 50 of the 382 patients studied (13%)
underwent the more extensive colon resection for their first
colon cancer, while the remaining 332 patients (87%) under-
went segmental resection. The incidence of metachronous
CRC (i.e., rectal cancer) in those undergoing TAC was zero,
whereas 22% (74/332 patients) of those who underwent
segmental resection developed a metachronous cancer at a
mean follow-up of 9 years. The cumulative risk of metachro-
nous CRC was 16% at 10 years, 41% at 20 years, and 62% at
30 years after segmental resection. Nearly 80% of the patients
who developed these lesions were undergoing surveillance
colonoscopy every 1 to 2 years. Notably, the greater th e extent
of the segmental resection for colon cancer, th e lower the risk
of metachronous cancer development (31% risk reduction for
every 10 cm resected). Although most metachronous CRCs
after segmental resection were stage I and II, 18% (10/57)
were stage III, and over half of those patients diagnosed with
stage III disease were undergoing screening endoscopy every
1 to 2 years. There was no survival difference at 5 or 10 years
between the patients who had undergone segmental resec-
tion versus more extensive resection. At 5 years, 98% of
patients from both groups were alive (P¼0.8); at 10 years,
98% of those who underwent extensive colectomy and 97% of
those who underwent segmental resection were alive
(P¼0.7).18
Another retrospective study, published by Natarajan et al,
looked at metachronous CRC rates, reoperation rates, and
survival in 37 Lynch syndrome patients (MLH1 and MSH2
MMR carriers only) who had undergone TAC for their first
cancer or as prophylaxis versus 69 age, sex, and MMR gene
mutation-matched controls who had undergone segmental
resection (or no operation to match as controls versus the
prophylactic colectomy cas es). A median follow-up of 12 years
was achieved, and even with equivalent endoscopic surveil-
lance in both groups, results favored extended operation: The
rate of metachronous cancer was 6% versus 26% (P<0.006),
reoperation rate was 16% versus 37% (P<0.04), and death
was 7% versus 12% (P¼NS), respectively, when comparing
TAC versus segmental resection.8
Other studies have used retrospective risk data to use
mathematical models to aid operative decision making in
HNPCC. One such Markov model predicts an increased life
expectancy of 2.3 years if a colon cancer diagnosed in a Lynch
syndrome patient at the age of 27 years is treated by TAC as
compared with performing a segmental colectomy. One
important consideration, though, is that the median age of
persons with CRC under surveillance programs for HNPCC is
around 45 years. Using this model, the estimated increased
life expectancy for a 47 year old undergoing total colectomy is
only one year.18,20 Therefore, some have argued that this
recommendation for more extended resection should be
reconsidered given the increased morbidity associated with
TAC compared with segmental resection.
Although the recommendations have supported TAC with
ileorectal anastomosis, still most of the first CRCs in HNPCC
are treated by segmental colectomy, even in patients from
Amsterdam-criteria positive families and some with known
MMR mutations. For example, one study from the Cleveland
Clinic looking at operative trends in patients with Lynch
syndrome found that only 1 6 of 33 patients (48%) with HNPCC
and CRC at their own institution underwent TAC as their first
operation. In other clinics across the United States, however,
only 7 of 60 persons (12%) with HNPCC or Lynch syndrome
with CRC underwent total colectomy.21 The exact reasons for
favoring segmental resections in practice, even when ac-
knowledging the high risk of metachronous CRCs, are not
known. Some of the patients may have been diagnosed with
Lynch syndrome only after their segmental colectomy based
on postoperative tumor testing, which underscores the im-
portance of preoperative family history and genetic assess-
ment/counseling (and consideration of preoperative tumor
testing, see below). The decision related to extent of resec tion
also likely relates to patient and surgeon concerns over
changes in bowel habits and increased surgical risks related
Table 1 Total Colectomy versus Segmental Resection in HNPCC: Metachronous Colorectal Cancer Formation
Study Segmental Colectomy Total Colectomy PValue
Kalady et al1Number of patients 253 43
Patients with endoscopic surveillance 221 (87%) 38 (88%) N/A
Average time from index surgery to 2
nd
CRC, months 69 227 N/A
Patients with metachronous CRC 55 (25%) 3 (8%)
Natarajan et al8Number of patients 69 37
Time range from index surgery to 2
nd
CRC, months 6–160 16–175 <.006
Total number of second CRCs 23 (33%) 4 (11%) N/A
Parry et al18 Number of patients 332 50
Metachronous CRCs (over 8–9 years of f/u) 74 (22%) 0 (0%) <.001
Endoscopic frequency, months (mean) Q20 months Q16 months 0.16
CRC, colorectal cancer; f/u, follow-up; N/A, not available/reported.
Clinics in Colon and Rectal Surgery Vol. 25 No. 2/2012
Endoscopic and Surgical Management of Hereditary Nonpolyposis Colorectal Cancer Baucom, Wise92
to TAC/ileorectal anastomosis versus segmen tal resection s, as
well as lack of understanding of the metachronous CRC risks
related to HNPCC, even when the condition is recognized
preoperatively. Of course, segmental resection may be appro-
priately favored over TAC in those instances where patients
may have more significant comorbidities, fecal incontinence,
and/or decreased life expectancy (thus minimizing the bene-
fit of preventing a metachronous CRC given that the risk is
16% at 10 years18). Unfortunately, with no prospective
studies to prove the appropriate extent of resection in HNPCC
or Lynch syndrome, most experts would recommend more
extended resection in those patients for whom it is a safe
operative option.
Proponents of segmental resection argue that the HNPCC
patient's quality of life should be given greater consideration,
particularly if over the age of 40, given the relatively small
predicted increase in life expectancy with more extensive
resection.20,22 Quality of life after TAC versus segmental
colectomy was not evaluated in the study mentioned above
by Parry et al, and very little data looking at quality of life
exists in the literature. One small study from Cleveland Clinic
(abstract only) compared 22 patients who underwent TAC
and ileorectal anastomosis with 22 control patients who
underwent right or left hemicolectomy. At 2 years, frequency
of bowel movements was four per day for patients after TAC
and two per day for those who underwent segmental resec-
tion. This was not associated with any difference in conti-
nence, nor was there a difference in qualit y of life as measured
by the SF-36.2,18 Quality of life is an area that needs further
study before accurate conclusions can be drawn comparing
segmental resection and TAC in HNPCC.
The surveillance required in patients with HNPCC after
resection for colon cancer has not been studied, so they are
based on the screening recommendations for HNPCC. After
TAC, surveillance of the remaining rectum (rigid or flexible
proctoscopy) should be performed at least annually, and this
can usually be performed after enema preparation and
without the need for sedation. After segmental colectomy,
any remaining mucosa must be evaluated every 1 to 2 years,
which means a standard bowel preparation will be required
as well as sedation, leading to time away from work as well as
the risk of dehydration or electrolyte abnormalities. It must
be underscored that even perfect compliance with surveil-
lance (or screening) recommendations does not prevent a
patient from developing metachronous CRC, as supported by
the retrospective screening studies as well as the studies
assessing the extent of resection mentioned above. Patients
and physicians must have an appropriate understanding
about screening and surveillance and the benefits of earlier
detection as well as decreased, but not zero, incidence of
metachronous CRC with screening. Furthermore, surgical
decision making should also take into account likely compli-
ance with future surveillance. One study evaluated the
screening behavior among individuals at high risk for CRC,
and they concluded t hat at least one in four individuals at high
risk will deviate significantly from recommended frequency
of screening.23 If there is any question about compliance, TAC
should be favored over segmental colectomy.
In summary, TAC should be considered in patients with
HNPCC or Lynch syndrome who develop CRC. This recom-
mendation is based upon the increased risk of metachronous
CRC in these patients, which has been repeatedly demon-
strated to be quite high in retrospective studies. No studies
have demonstrated a statistically significant difference in
survival between segmental colectomy and TAC, however.
Further studies are n eeded to more adequatelyassess possibl e
differences in quality of life, taking into account surveillance
as well as bowel function.
Prophylactic Colectomy in HNPCC
Prophylactic colectomy in Lynch syndrome (i.e., in patients
who have been found to have an MMR mutation but have not
developed CRC) is not currently recommended and is not
frequently performed. This is in part due to the incomplete
penetrance of the disease phenotype as not all patients with a
known gene mutation develop CRC; affected individuals have
a 60 to 80% lifetime risk for developing CRC, depending on the
MMR mutation.2,12 Some authors have suggested that pro-
phylactic colectomy could be considered and offered in Lynch
syndrome patients under certain circumstances: in those
patients who have a colon that is technically difficult to
evaluate with colonoscopy, those who cannot or will not
comply with screening recommendations, those with severe
psychological distress due to fear of developing CRC, families
with early onset or severe penetrance of the CRC phenotype,
and females who are already undergoing hysterectomy for
uterine cancer.2Based on study subsets of small retrospective
studies (e.g., eight patients in the Natarajan et al study who
underwent prophylactic colectomy—none of whom devel-
oped a metachronous CRC), it appears that prophylactic
colectomy may be a safe and effective means to prevent the
development of colon cancer. Additionally, no data exists to
support prophylactic completion colectomy after segmental
colectomy for colon cancer in a patient found later to have
Lynch syndrome. In this instance, surveillance is continued
every 1 to 2 years, and TAC may be considered if the patient
develops a metachronous CRC.
Rectal Cancer in HNPCC
Approximately 15% of those with Lynch syndrome will pres-
ent with rectal cancer as their index cancer2,24;itisunclear
how this should be treated as this has not been well-studied
in the setting of HNPCC and Lynch syndrome. In those for
whom rectal cancer is their index cancer, surgical options to
consider include segmental resection (e.g., low anterior re-
section [LAR] or abdominoperineal resection [APR]) or more
extended resection (i.e., total proctocolectomy with end
ileostomy or restorative ileal pouch-anal anastomosis). One
retrospective study by Lee et al looked at the incidence of
metachronous CRC in 18 patients who either met Amsterdam
criteria or had documented MMR mutation and presented
with an index rectal cancer. They were treated with segmen-
tal proctectomy (without colectomy), and 18% later devel-
oped a metachronous lesion at a median of 203 months after
their initial surgery.24 Data from Cleveland Clinic from 31
HNPCC patients who had undergone segmental proctectomy
Clinics in Colon and Rectal Surgery Vol. 25 No. 2/2012
Endoscopic and Surgical Management of Hereditary Nonpolyposis Colorectal Cancer Baucom, Wise 93
at a median follow-up of 106 months showed that 45% of
patients developed significant colonic neoplasia, either carci-
noma or high-risk adenoma.2G iven these high metachronous
colon cancer risks, some experts believe that proctocolec-
tomy should be offered as the initial operation for those
presenting with rectal cancer in the setting of HNPCC. If not,
the remainder of the colonic mucosa remains at risk which
requires strict compliance with an intensive, usually yearly,
surveillance program.2,24
Those patients with HNPCC or Lynch syndrome who have
undergone segmental resection or TAC, either for CRC or
prophylactically, are also at risk for developing a metachro-
nous rectal cancer. One retrospective study by Rodriguez-
Bigas found that rectal cancer developed in 11% of 71
patients who had undergone TAC or subtotal colectomy at
a median of 158 months after initial surgery. They deter-
mined that the risk of developing rectal cancer is around
12% at 12 years after colectomy.9Interestingly, this is the
same risk found after TAC in individuals with familial
adenomatous polyposis (FAP) which led to the recommen-
dation that individuals affected with FAP undergo total
proctocolectomy as the standard of care (with or without
ileal pouch anal anastomosis). The difference between
Lynch syndrome and FAP lies in the polyp burden and the
ability to adequately screen the remaining mucosa. In the
Rodriguez-Bigas study mentioned above, all but one patient
who developed rectal cancer were being closely followed in
surveillance programs. The time from most recent surveil-
lance endoscopy to the development of rectal cancer ranged
from 6 to 24 months. The one patient not active in surveil-
lance did present with an advanced stage tumor and died
from the disease. The authors concluded that frequency of
endoscopic examinations of the rectum in these patients
should be no less than annually after 10 years at risk and
should be considered as frequently as every 6 months.9
Again, surveillance does not prevent the development of
cancer, but in patients with Lynch syndrome, endoscopycan
decrease the incidence of cancers and detect cancers at an
earlier stage. No prospective data exist evaluating surveil-
lance of the rectum or optimal surgical treatment in this
patient population.
In all patients with HNPCC who develop rectal cancer, any
surgical treatment must take into account the tumor stage
and possible need for chemoradiation therapy. If a patient
presents with stage III or IV rectal cancer, the risk of death
from metastatic disease may be greater than the risk of
developing a metachronous cancer, and these patients should
be treated with more limited bowel resection (e.g., LAR or
APR) in an effort to preser ve bowel length and quality of life.2
Additionally, if a patient is to undergo creation of a colonic
pouch or restorative ileal pouch, any radiation should be
performed preoperatively to avoid radiating the pouch and
thus adversely impacting its function. As with segmental
resections for colon cancer, HNPCC pat ients with rectal cancer
who undergo segmental proctectomy (whether LAR or APR)
with or without chemoradiation and/or adjuvant chemother-
apy need to have continued close surveillance of the remain-
ing colon as discussed above.
Other Considerations
Genotype–Phenotype Correlations
The specific MMR gene mutations in Lynch syndrome may
also play a role in surgical decision making in the future as
more studies uncover the genotype–phenotype correlations
in this condition. Several studies show that the risk of CRC is
significantly higher in families with MLH1 and MSH2 muta-
tions when compared with mutations in PMS2 and MSH6,
although more data are needed to fully understand and
quantify these cancer r isks.18,25 As more is lear ned, a patient's
specific genotype may aid in counseling the patient to more
strongly consider TAC over segmental resection if CRC risk is
known to be particularly high for that patient's particular
gene mutation. The same may be t rue for segmental resection
if the CRC penetrance of the patient's gene mutation is found
to be much lower. Currently, however, this form of personal-
ized medicine cannot be advocated for the management of
Lynch syndrome without further supportive data from larger
genotype–phenotype studies that are currently ongoing (e.g.,
the International Mismatch Repair Consortium with over
10,000 gene mutation carriers from 3800 families).
Preoperative Tumor Testing
For those patients who present with CRC and a history
suspicious for HNPCC (early age of onset, right-sided cancer,
characteristic pathology, family history or personal history of
other HNPCC-associated tumors, etc.), the surgeon or endo-
scopist should have a low threshold for performing microsat-
ellite instability (MSI) testing or immunohistochemistry
studies for the protein products of the MMR genes on the
tumor itself to allow for subsequent focused genetic testing.
Although somewhat controversial, several institutions now
reflexively test all CRCs due to the high potential for identify-
ing Lynch syndrome patients even in the absence of these
clinical or pathologic high-risk features.26 Ideally, all tumor
and genetic testing would occur before surgery, if possible, to
guide surgical planning.27 This is especially true in rectal
cancer where neoadjuvant chemoradiation can affect the
accuracy of any tumor testing strategies, either due to lack
of sufficient tissue for testing or radiation-induced tissue
alterations diminishing the accuracy of any tumor tests.28–30
Unfortunately, the results of MSI testing or MMR gene testing
can take weeks to process, often longer than mo st patients are
willing to wait for surgical intervention for a CRC. Therefore,
an extensive discussion with a patient whose clinical picture
is suspicious for HNPCC is needed to ensure that they fully
understand the risks and benefits of segmental or extended
resection for colon or rectal cancer. This is especially true if
they elect to proceed with their operation prior to completion
of preoperative testing.
Chemoprevention
To prevent or delay the development of neoplasia in the colon
and rectum in the setting of HNPCC or Lynch syndrome, and
hopefully avoid the need for surgical intervention, there has
been an attempt to use medical therapy as chemopreventative
Clinics in Colon and Rectal Surgery Vol. 25 No. 2/2012
Endoscopic and Surgical Management of Hereditary Nonpolyposis Colorectal Cancer Baucom, Wise94
agents, much as they have been used in the setting of FAP (see
article on FAP in this issue of Clinics).7Unlike FAP, however,
fewer human trials have been conducted because of the
relative infrequency of developing adenomas in HNPCC,
the numbers of patients that are required for such trials,
and the lack of understanding of the impact of genotype–
phenotype correlations on the development of neoplasia
based on each patient's MMR gene mutation (assuming
they have been gene tested or they are positive for a muta-
tion).13 Much like in FAP, however, attempts at developing or
identifying chemoprevention agents seem appropriate given
the high risk circumstances for HNPCC patients. This allows
for more leeway when compared with chemopreventative
agents used in average risk individuals when looking at cost
of the agents, cost of trials to develop them, as well as safety
and efficacy of the agents.13
Preclinical studies in cell lines and mouse models have
been helpful to direct human chemoprevention trials, but
these models do not always mimic the human situation with
MMR deficiency.31 Most of the agents being studied were
identified as chemoprevention candidates based on observa-
tional studies of CRC risk in normal populations. These
include but are not limited to aspirin, nonsteroidal antiin-
flammatory drugs (NSAIDs), selective COX-2 inhibitors, and
supplements such as calcium/vitamin D. Even vaccines for
MSI tumors have been developed, and while in their preclini-
cal infancy, they are being tested in HNPCC models.31
Aspirin has been the best-studied drug in the setting of
HNPCC. Aspirin is thought to function by increasing MMR
protein production in MMR-deficient cells based on preclini-
cal models.31 The Colorectal Adenoma/Carcinoma Prevention
Program 2 (CAPP2) study of aspirin in Lynch syndrome is the
first and largest chemoprevention trial aimed at a genetic
condition. The trial recruited 937 Lynch syndrome and
HNPCC patients from 1999 to 2005 into a 2 2factorialtrial
of 600 mg aspirin and aspirin placebo as well as 30 g resistant
starch and starch placebo with the primary endpoint being
the development of CRC. Initial results showed no difference
in the treatments, l eading the authors to conclude, “The use of
aspirin, resistant starch, or both for up to 4 years has no effect
on the incidence of colorectal adenoma or carcinoma among
carriers of the Lynch syndrome.”32 Interestingly, however,
subsequent analyses showed that after a mean followup of
56 months, there was a statistically significant decrease in the
development of colorectal neoplasia (HR, 0.41; 95% CI, 0.19–
0.86; P¼0.02) in the 8 61 patients from the initial cohor t who
had been randomized to aspirin or placebo.33 The authors
concluded in the follow-up study that at least 2 years of daily
aspirin use by Lynch syndrome patients leads to a significant
decrease in the incidence of CRC and polyps (but not other
Lynch-associated cancers). They concluded in the follow-up
trial that “…aspirin is an effective chemopreventative agent
in hereditar y cancer with an effect equivalent to that achieved
with surveillance colonoscopy. The case for prescription of
aspirin to this high-risk group is clear.”33 The follow-up study
to CAPP2 will be CAPP3 that has started recruiting patients as
of late 2011 (http://www.capp3.org/). The aim of the study is
to determine the dose effect of aspirin on the development of
neoplasia in Lynch syndrome patients by recruiting 3000
MMR gene mutation carriers into three treatment groups at
varying doses of daily aspirin intake: 600 mg, 300 mg, and 75
to 100 mg.
NSAIDs, such as sulindac, have shown great promise in
chemoprevention trials in other hereditary syndromes, but
NSAIDs have been noted to increase cell proliferation and
even tumor development in Lynch syndrome mouse mod-
els.31 A placebo-controlled, crossover trial of sulindac in 22
patients with HNPCC showed statistically increased cell pro-
liferation in the right colon similar to the mouse model
findings; therefore, this agent has fallen out of favor in
HNPCC.34 Nitric oxide (NO)-donating NSAIDs for Lynch syn-
drome have shown promise based on their inhibition of MSI
with apparently low toxicity, whereas more selective COX-2
inhibitors (such as celecoxib) have unclear promise as che-
moprevention in HNPCC based on mixed expression of COX-2
in Lynch syndrome tumors (as opposed to high expression in
some sporadic adenomas).7,31,35 Human studies with COX-2
inhibitors in HNPCC are ongoing. Calcium has been consid-
ered as a chemopreventative agent as it is thought to bind
fatty acids and bile salts thus decreasing colonic irritation an d
cell proliferation. However, human studies with calcium have
shown no change in cell proliferation in the colon and rectum
of 30 patients with HNPCC when compared with placebo,36,37
so no trials are ongoing looking at calcium and HNPCC.
Currently, in addition to the use of daily aspirin in those
HNPCC patients without a contraindication to the drug, the
best CRC prevention modality in HNPCC is appropriate endo-
scopic screening for neoplasia.38,39 Other recommendations
such as maintaining a healthy lifestyle (e.g., avoiding smok-
ing, maintaining a healthy weight, etc.) seem intuitive, but
may have a beneficial effect in HNPCC patients just as it
appears to have in patients at risk for sporadic CRC. Chemo-
prevention agents may allow for increasing the interval for
screenings and postoperative surveillance in HNPCC, if not
avoiding them altogether, but this will require further con-
firmatory studies.
Conclusion
In conclusion, there is still much to be learned about the
management of patients with HNPCC and Lynch syndrom e. As
more is learned about particular genotype–phenotype cor-
relations, this will certainly affect surgical management and
decision making. Additionally, prospective data are needed to
better understand the optimal surgical treatment of patients
with Lynch syndrome or HNPCC who are diagnosed with
colon or rectal cancer. At this time, scr eening is recommended
every 1 to 2 years beginning at ages 20 to 25 or 10 years
younger than the first diagnosis of CRC (whichever comes
earlier). Patients who develop CRC should be considered for
total abdominal colectomy due to the increased risk of
metachronous lesions. Rectal cancer has not been well stud-
ied, but discussions with the patient should weigh the risks of
future metachronous CRC with the morbidity associated with
total proctocolectomy. Finally, it appears that aspirin may be
an effective chemopreventive agent in patients with HNPCC,
Clinics in Colon and Rectal Surgery Vol. 25 No. 2/2012
Endoscopic and Surgical Management of Hereditary Nonpolyposis Colorectal Cancer Baucom, Wise 95
and should be considered in patients who do not have a
contraindication to the drug.
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