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J Surg Res 2020; 3 (1): 020-030 DOI: 10.26502/jsr.10020051
Journal of Surgery and Research 20
Review Article
Hereditary Nonpolyposis Colorectal Cancer (HNPCC): From
Diagnosis to Surgical Management of the Main Hereditary Form of
Colorectal Cancer: A Review
Guido Mantovani*, Michela De Angelis, Corrado Asteria, Francesco Di Lecce, Paolo
Mazza, Luca Vicenzi, Luigi Boccia
Department of General Surgery, Ospedale Carlo Poma, Mantua, Italy
*Corresponding Author: Guido Mantovani, Department of General Surgery, Ospedale Carlo Poma, Mantua,
Italy, Tel: +39 0376 201246; Fa x: +39 0376 201907; E- mail: guido.mantovani@asst-mantova.it
Received: 22 January 2020; Accepted: 06 February 2020; Published: 26 February 2020
Citation: Guido Mantovani, Michela De Angelis, Corrado Asteria, Francesco Di Lecce, Paolo Mazza, Luca
Vicenzi, Luigi Boccia. Hereditary Nonpolyposis Colorectal Cancer (HNPCC): From Diagnosis to Surgical
Management of the Main Hereditary Form of Colorectal Cancer: A Review. Journal of Surgery and Research 3
(2020): 020-030.
Abstract
Colorectal cancer (CRC) is the third most common
cancer worldwide, the 5% of CRC are hereditary.
Among hereditary forms of CRC the most frequent is
Hereditary Nonpolyposis Colorectal Cancer (HNPCC).
HNPCC is an autosomal dominant genetic disease.
Molecular basis of HNPCC are linked to genetic
alterations, involving several mismatch repair (MMR)
genes. Diagnosis of HNPCC is frequently difficult:
HNPCC diagnosis process starts from family medical
history and genetic counselling and continue with
molecular diagnosis and genetic tests which often
identify MMR genes mutation. In HNPCC the role of
screening is irreplaceable for prevention and early
diagnosis of CRC and extracolic cancer, such as
endometrium, ovary, urothelium, stomach, small bowel,
pancreas, brain, biliary ducts neoplasms. Surgical
management of HNPCC is significantly different
between colonic and rectal cancer. The main problem in
surgical approach for HNPCC patients is related to the
possibility of developing metachronous colorectal
cancer. The choice is always between extensive and
segmental resection. The aim of this study is to give
some practical indications to surgeons for the
management of HNPCC patients.
J Surg Res 2020; 3 (1): 020-030 DOI: 10.26502/jsr.10020051
Journal of Surgery and Research 21
Keywords: Hereditary Nonpolyposis Colorectal
Cancer; Microsatellite Instability; Colorectal Cancer;
Screening
1. Background
CRC is the third most common cancer worldwide, with
more than 1 million of cases and 600.000 deaths per
year [1]. About 85% of CRCs are sporadics, that is
CRCs in which there is neither family history nor
inherited mutation predisposing to CRC; approximately
10% of CRC are familial, this form may be due to the
presence of gene mutations, predisposing to CRC or to
environmental factors exposition, that may lead to an
increased risk of developing CRC. The remaining 5% of
CRC is hereditary. Among hereditary forms of CRC the
most frequent is HNPCC, accounting for 3-4% of
CRCs. HNPCC, as the name suggests, is not
characterized by the appearance of polyps in the
gastrointestinal tract, differently from Familial
Adenomatous Polyposis (FAP), Peutz-Jeghers
Syndrome and other polypoid forms of CRC. The
distinction of HNPCC from sporadic CRC is not always
obvious, rather sometimes it is very difficult and cannot
prescind from a careful family medical history. The aim
of this study is to describe clinical aspects, genetic and
molecular features, diagnostic management, screening
and surgical approach of HNPCC, giving some practical
indications to surgeons for the management of this
hereditary disease often difficult to recognize.
2. Introduction
HNPCC is an autosomal dominant genetic disease, with
medium-high penetrance degree (30-70%) [2]. HNPCC
is associated to increased risk of developing colorectal
cancer (CRC) and other tumours (ovarian, gastric,
urinary, cutaneous) in young age. The worldwide
incidence of CRC related to HNPCC is 3-4 % of overall
CRC, about 30.700 new cases every year [3], while the
worldwide incidence of CRC is about 1.000.000 new
cases every year. In HNPCC definition, it’s necessary to
differentiate type I, the form associated only to
development of colorectal cancer, from type II, in which
there are extracolonic tumours associated to CRC, such
as endometrial, ovarian, uterine, gastric, urinary and
biliary.
3. Genetic Features
Molecular basis of HNPCC are linked to genetic
alterations, involving several MMR genes. MMR is a
multienzimatic complex, involved in the repair of DNA
replication errors. These mutations regard the following
genes: MLH1 [4], MSH2 [5], MSH6 [6], PMS2 [7],
MLH3 [8] and EPCAM. EPCAM-gene is not implied in
MMR, but it seems to inactivate his adjacent gene
MSH2. Among all, MLH1 and MSH2 are the most
frequently mutated, with an incidence of 50% and 40 %,
respectively, whilst MSH6 mutations are present in
approximately 10% of HNPCC families. PMS2, that has
recently been identified, has an incidence from 2,2% to
5% [9]. The microsatellite sequences (Ms) are the DNA
regions in which these errors accumulate more easily.
Abnormalities of Ms are found in 85-95% of tumours
associated with HNPCC and in 15-25% of sporadic
colorectal cancer [10]. The most frequently observed
genotype is mutation in genes MLH1 or MSH2, which
is associated with "typical" tumour manifestations: early
onset (mean age 44 years), colorectal cancer in proximal
colon, poorly differentiated (G3), mucinous histology,
presence of tumour ring-infiltrating lymphocytes and
high MSI (MSI-H, with more than 30-40%
microsatellite instability sequences) [11]. Germline
mutations in MSH6, PMS2, MLH3, instead, manifest
themselves by "atypical" tumour phenotypes, related to
onset, penetrance and instability degree of MSI.
Particularly, germline mutations in MSH6 seem to be
associated with increased risk of developing
endometrial cancer (lifetime risk is estimated to be 26%
at age 70 years and 44% at age 80 years) [12], whilst
J Surg Res 2020; 3 (1): 020-030 DOI: 10.26502/jsr.10020051
Journal of Surgery and Research 22
germline mutations of PMS2 seems to be related to
Turcot syndrome [13]. The lifetime risk of CRC
according to HNPCC mutation carriers, in male and
female, is summarized in Table 1.
4. Clinical Aspects and Classifications
Different criteria were developed to classify patients
with HNPCC, Amsterdam criteria I (1991) [16] and
Amsterdam criteria II (1998) [17], Revised Bethesda
Guidelines (2004) [18] were developed to classify
patients with HNPCC. Amsterdam Criteria II and
Revised Bethesda Guidelines are reported in Table 2
and Table 3. Both Amsterdam and Bethesda criteria are
often complex to apply and are burdened with estimated
values of specificity (only 51% for Bethesda criteria)
and sensibility (only 65% for Amsterdam criteria II).
Mutation Carrier
Lifetime Risk of CRC (males)
Lifetime risk of CRC (females)
MLH1 and MSH2 [14]
68.7%
52%
MSH6 [12]
22%
10%
PMS2 [15]
20%
15%
Table 1: Lifetime Risk of CRC in HNPCC-related Mutation Carrier.
Table 2: Amsterdam II Criteria.
Revised Bethesda Guidelines (one or more of the following criteria must be met)
CRC before the age of 50 years
Synchronous or metachronous CRC or other HNPCC-related tumours*, regardless of age
CRC with MSI –H morphology** before the age of 60 years
CRC (regardless of age) and a first-degree relative with CRC or an HNPCC-related tumours before the age
of 50 years
CRC (regardless of age) and two or more first or second-degree relatives diagnosed with CRC or an
HNPCC-related tumours (regardless of age)
*HNPCC-related tumours colorectal, endometrial, stomach, ovarian, pancreas, ureter and renal pelvis, biliary tract
and brain (usually glioblastoma as seen in Turcot syndrome) tumours, sebaceous gland adenomas and
keratoachantomas in Muir-Torre syndrome and carcinomas of the small bowel; **Presence of tumour- infiltrating
lymphocytes, Crohn’s like lymphocytic reaction, mucinous/signet-ring cell differentiation, or medullary growth
pattern.
Table 3: Revised Bethesda Guidelines.
Amsterdam II Criteria (all criteria must be met)
Three or more relatives with histologically confirmed CRC or cancer of the endometrium, small bowel,
ureter, or renal pelvis, one affected relative being a first-degree relative of the other two; FAP should be
excluded
Two or more successive generations are affected
At least one relative was diagnosed before the age of 50 years
J Surg Res 2020; 3 (1): 020-030 DOI: 10.26502/jsr.10020051
Journal of Surgery and Research 23
5. Diagnosis
The HNPCC diagnosis process starts from a clinical
suspicion, such as early onset of CRC (<50 years),
familial history of CRC or the occurrence of multiple
primary tumours, that fall into the category of cancer-
related HNPCC type II, in at least two relatives (until
the third generation), especially before the age of 50
years.
First step: family medical history and genetic
counselling. Family history’s analysis requires a direct
interview of patients or their closest relatives. The
anamnesis should be able to reconstruct a
comprehensive genealogical tree, which dates back at
least to the third generation [19], to assess whether the
disease is in their family or acquired and whether the
patient matches the Amsterdam Criteria II or Revised
Bethesda Guidelines (both or one of these criteria).
Patients who meet these criteria will be submitted to
specific screening, described below. If both Amsterdam
and Bethesda criteria are not respected, patients will
undergo classic CRC screening.
Second step: molecular diagnosis and genetic tests. If
Amsterdam or Bethesda criteria are satisfied assessment
of Ms of the tumour and immunohistochemical (IHC)
investigations will be required. The order of molecular
and genetic tests required is explained in Figure 1. The
first step is the analysis of tumour phenotype, through
the execution of IHC and Ms investigations on tumour
DNA, searching for high instability (MSI-H), that
interests at least 30% of analysed loci. If microsatellite
sequences and IHC assessments are not diagnostic, i.e.
microsatellite stability (MSS), or low MSI (MSI-L), or
no loss of protein on IHC, patients will undergo classic
CRC screening. If there is MSI-H and loss of expression
on IHC, patients will be submitted to the second step,
that consists in specific genetic tests, to identify
germline mutations in MLH1, MSH2, MSH6, PMS2,
summarized in Figure 1. These genetic tests are very
expensive and, so it’s important a closely selection of
the population to submit to these tests.
The presence of MSI in the tumour by itself is not
enough to diagnose HNPCC because 10-15% of
sporadic CRCs exhibit MSI. MSI in non-LS CRCs is
usually caused by hypermethylation of the MLH1 gene.
This acquired epigenetic inactivation of MLH1 is
typically associated with mutations in the BRAF gene
(specifically the V600E mutation), which has been
described in about 35% of sporadic MSI-H CRCs.
Therefore, identification of hypermethylation of MLH1
and/or BRAF V600E is an indication that a patient does
not have the HNPCC germline mutation.
6. Screening
Patients with MMR genes mutations have more than
80% risk of developing colorectal cancer, compared to
5% of the general population, so this require close
monitoring. The recent guidelines indicate to submit
patients with MMR genes mutations to colonoscopy
every 1-2 years, starting from 20-25 years of age, or 2-5
years before the youngest case in family. There is still
no general consensus on the need to perform a
colonoscopy every year or every two years, anyway it
has been demonstrated its importance, in 2013, Vasen et
al. [20] reviewed studies that reported the outcomes of
colonoscopic surveillance in HNPCC before surgery,
and although cancers did arise, the vast majority were
early stage and death rates were very low. Practice
guidelines for colon surveillance of HNPCC patients are
summarized in Table 4. The risk of developing
extracolic cancer (endometrium, ovary, urothelium,
stomach, small bowel, pancreas, brain, biliary ducts) in
patients with MMR gene mutations is about 37.5%,
compared to 2% of general population [21]. This risk
increase in patients with MSH2 mutations and in
females. The district most affected is the endometrium
J Surg Res 2020; 3 (1): 020-030 DOI: 10.26502/jsr.10020051
Journal of Surgery and Research 24
(20-60%), while the ovary is the less one (9-12%).
Gynaecological screening is standardized and consists
of gynaecological examination, associated with trans-
vaginal ultrasound with endometrial sampling every
year from HNPCC is 1.6 to 19%, which is higher in
Asian countries; screening programs provide EGDS
every 1-3 years in patients with MMR genes mutations
[22]. There is not general consensus about urothelial
cancer (lifetime risk 28%), anyway the screening
includes chemical and cytological urine examination, if
necessary associated with abdominal ultrasound [23].
J Surg Res 2020; 3 (1): 020-030 DOI: 10.26502/jsr.10020051
Journal of Surgery and Research 25
*Early onset of CRC (<50 years), familial history of CRC or primary tumours, that fall into category of cancer
Yes
No
Clinical suspicion of HNPCC*
Amsterdam or Bethesda Criteria met
IHC and MSI analysis
Probably not HNPCC
MSI-H and loss of expression of
MSH2 or MSH6 only or both
MSH2/MSH6 on IHC
MSI-H and loss of expression of
MLH1 or PMS2 only or both
MLH1/PMS2 on IHC
MSS or MSI-L, no less of
proteins on IHC
Test for MLH1 promoter methylation and BRAF
p. V600e mutation
Test for MSH2 gene mutations
Hypermethylation of MLH1 and BRAF
mutation detected
Normal methylation of MLH1 and no BRAF
mutation detected
No mutation detected
Mutation detected
Test for EPCAM gene
mutations
CRC not due to MMR
defect
Test for MLH1 gene
mutation
No mutation detected
Mutation detected
Mutation detected
No mutation detected
Test for MSH6 gene mutations
Test for PMS2 gene mutations
No mutation detected
Mutation detected
No mutation detected
Mutation detected
HNPCC with unidentified mutation
HNPCC with identified mutation
J Surg Res 2020; 3 (1): 020-030 DOI: 10.26502/jsr.10020051
Journal of Surgery and Research 26
-related HNPCC type II (especially before 50 years or if more successive generations are affected).
Figure 1: Suggested algorithm for HNPCC diagnosis.
Organization
Age Screening Initiated
Frequency
Method
American Cancer Society
(2002) [24]
21 years
1-2 years until age of 40
years, then annually
Colonoscopy
GI Societies [25] (2003)a
20-25 years
1-2 years
Colonoscopy
Europe Mallorca Group
(2007) [26]
20-25 years
1-2 years since 80 years
Colonoscopy
NCCN (2014) [27]
20-25 years or 2-5 years
before the youngest age at
diagnosis in the family if it
is before age of 25 years
1-2 years
Colonoscopy
aGI Societies-American Academy of Family Practice, American College of Gastroenterology, American College of
Physicians-American Society of Internal Medicine, American College of Radiology, American Gastroenterological
Association, American Society of Colorectal Surgeons, and American Society for Gastrointestinal Endoscopy
Table 4: Practice Guidelines for Colon Surveillance of HNPCC patients.
7. Surgery
The main problem in surgical approach for HNPCC
patients is related to the possibility (that they have) of
developing metachronous colorectal cancer, estimated
16-40% at 10 years and 72% at 40 years [28]. The risk
of metachronous CRC for MMR gene mutation carriers
has been reported to be higher for MLH1 and MSH2
carriers and for subjects aged over 40 years [29].
8. Colonic Localization
The decision regarding which type of procedure to offer
to patients with HNPCC and colon cancer is difficult.
For patients and physicians, the task at hand is to
measure the burden imposed by the larger initial
procedure compared to benefits in the distant future.
Abdominal colectomy with ileorectal anastomosis
(IRA), has been recommended as procedure of choice in
HNPCC patients with newly diagnosed colon cancer, as
opposed to segmental resection. There are no reports of
prospective and/or retrospective studies demonstrating
survival benefit in patients undergoing IRA compared to
those undergoing segmental resection. The disadvantage
of abdominal colectomy with ileorectal anastomosis
compared to segmental resection is mainly in the bowel
frequency. Even though IRA is a more extensive
procedure, it still has low morbidity and mortality [30].
It must be understood that this procedure does not
prevent rectal cancer, which occurs between 3 and 20 %
[31]. Thus, patients with extended resections will need
endoscopic surveillance of the remainder rectum at risk.
The cumulative risk of metachronous CRC was 16% at
10 years, 41% at 20 years, and 62% at 30 years after
segmental colectomy. Patients with HNPCC whose first
colon cancer is treated with more extensive colonic
resection have a lower risk of metachronous CRC than
those receiving less extensive surgery. Other important
issues to consider are the functional results of subtotal
colectomy versus segmental resection (surveys suggest
J Surg Res 2020; 3 (1): 020-030 DOI: 10.26502/jsr.10020051
Journal of Surgery and Research 27
worse functional outcomes, but paradoxically not
increased patient dissatisfaction), age (with not too
much to gain in older patients than in those with many
decades of expected life), and personal preference.
Current recommendations in the USA suggest that
people with HNPCC undergoing surgical resection of
CRC should recieve an extensive resection rather than a
segmental resection, even though this policy has not
previously been proven to be superior to a policy of 1–2
yearly colonoscopic surveillance [32].
In Europe, current guidelines recommend the option of
extensive resection be discussed with patients,
particularly those under the age of 50 years [33].
Therefore in planning the extent of surgical resection for
MMR gene mutation carriers presenting with colon
cancer in the non-emergent setting, surgeons need to
consider patient preference, patient age, bowel and
sphincter function, as well as likely compliance with
surveillance and the quality or otherwise of post-
operative surveillance endoscopy. A heterogeneous
group of 382 carriers of MMR gene mutations (172
MLH1, 167 MSH2, 23 MSH6, and 20 PMS2) with
colorectal cancer who had surgery for their first colon
cancer were analyzed using retrospective cohort
analysis for age-dependent cumulative risks of
metachronous CRC [28]. Detailed information about
interval screening was unavailable, in patients who had
segmental resections, 22% were diagnosed with
metachronous CRC. On the other hand, none of 50
subjects who had extensive colectomy was diagnosed
with metachronous CRC. Furthermore, the risk of
metachronous CRC was reduced by 31% for every 10
cm of bowel removed.
In his study, Maeda [34] evaluated the outcomes in
terms of quality of life achieved by two strategies of
treatment: segmental resection versus total colectomy
with ileo-rectal anastomosis for patients with HNPCC
and CRC. He found that patients younger than 30 years
old appeared to have better outcomes after segmental
resection than IRA. This study differs from a similar
study by Cappel et al [33] that reported only in terms of
absolute survival and found that for young patients (age
27 years) with CRC and a MMR genetic defect, IRA
conferred a survival benefit of 2.3 years relative to
segmental resection. Extended procedure is in general
favoured in the management of the HNPCC patients
with newly diagnosed colorectal cancer. However,
every case is different and treatment needs to be
individualized. We can conclude that in HNPCC,
extended resection are preferable in younger patients,
while segmental resection is a good option in older
individuals [33]. It is necessary to consider not only
survival, but also quality of life when choosing between
segmental resection and IRA. Approximately 25% of
patients after IRA have five or more bowel movements
per day [33]. Day-time and night-time incontinence
occurs in 30% of patients [35].
9. Rectal Localization
In rectal surgery of HNPCC patients different surgical
approaches are possible: local excision, segmental
resection and extended resection. The first alternative is
extremely rarely used and only for selected patients
(important comorbidities and tumour amenable to local
excision). Segmental resection includes anterior
resection with primary anastomosis (LAR), proctectomy
with coloanal anastomosis (CAA) or abdominoperineal
resection (APR), if the sphincters are involved.
Extended resection is represented by restorative
proctocolectomy with ileal pouch anal anastomosis
(RPC), if the sphincter can be saved or proctocolectomy
with ileostomy if the sphincter cannot be saved; the
experience with this type of surgery in HNPCC patients
is still scarce.
J Surg Res 2020; 3 (1): 020-030 DOI: 10.26502/jsr.10020051
Journal of Surgery and Research 28
The limit of segmental resection with primary
anastomosis is the risk of metachronous cancer after
proctectomy, with a median of 88-203 months post
proctectomy [36] and a frequency from 15% to 51%
[31]. In the report by Lee, 3 of 18 patients developed
metachronous colon cancers at a median of 203 months
post proctectomy [36]. RPC, instead, should be
considered as a curative and at the same time
prophylactic procedure, eliminating risk of
metachronous colorectal cancers and in theory should
be the procedure of choice for a patient with HNPCC
and rectal cancer. However, in patients with RPC stool
frequency is increased, with 6-8 daily bowel
movements, at times inability to differentiate stool from
gas and soiling in about 30 % of the cases [37].
Surveillance colonoscopies are mandatory after
segmental rectal resection and pouchoscopies should be
performed after RPC.
A survival advantage was not demonstrated in patients
undergoing extended procedure. Stool frequency was
less in segmental resection patients compared to
extended resections. A study from the Dutch registry
comparing segmental to extended resection in HNPCC
patients, concluded that the functional outcome was
worse after an extended procedure, but that there was no
difference in generic quality of life between the two
procedures [38]. In consideration of RPC as surgical
option, we must explain and discuss approfonditely with
patients about possible postoperative complications,
such as female fecundity reduced by 50%, 1-2% of risk
of erectile or ejaculatory dysfunction and the possibility
of Pouch failure, that can lead to permanent ileostomy
(10%) [39].
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